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1. The futility of long-term predictions in bipolar disorder: mood fluctuations are the result of deterministic chaotic processes

Author

Abigail Ortiz, Kamil Bradler, Maxine Mowete, Stephane MacLean, Julie Garnham, Claire Slaney, Benoit H. Mulsant, and Martin Alda

Subjects
Bipolar disorder, Mood fluctuations, Nonlinear analyses, Episode prediction, Unaffected first-degree relatives, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurophysiology and neuropsychology, QP351-495
Abstract

Abstract Background Understanding the underlying architecture of mood regulation in bipolar disorder (BD) is important, as we are starting to conceptualize BD as a more complex disorder than one of recurring manic or depressive episodes. Nonlinear techniques are employed to understand and model the behavior of complex systems. Our aim was to assess the underlying nonlinear properties that account for mood and energy fluctuations in patients with BD; and to compare whether these processes were different in healthy controls (HC) and unaffected first-degree relatives (FDR). We used three different nonlinear techniques: Lyapunov exponent, detrended fluctuation analysis and fractal dimension to assess the underlying behavior of mood and energy fluctuations in all groups; and subsequently to assess whether these arise from different processes in each of these groups. Results There was a positive, short-term autocorrelation for both mood and energy series in all three groups. In the mood series, the largest Lyapunov exponent was found in HC (1.84), compared to BD (1.63) and FDR (1.71) groups [F (2, 87) = 8.42, p

Published
2021
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2. Internet use by older adults with bipolar disorder: international survey results

Author

Rita Bauer, Tasha Glenn, Sergio Strejilevich, Jörn Conell, Martin Alda, Raffaella Ardau, Bernhard T. Baune, Michael Berk, Yuly Bersudsky, Amy Bilderbeck, Alberto Bocchetta, Angela M. Paredes Castro, Eric Y. W. Cheung, Caterina Chillotti, Sabine Choppin, Alessandro Cuomo, Maria Del Zompo, Rodrigo Dias, Seetal Dodd, Anne Duffy, Bruno Etain, Andrea Fagiolini, Miryam Fernández Hernandez, Julie Garnham, John Geddes, Jonas Gildebro, Michael J. Gitlin, Ana Gonzalez-Pinto, Guy M. Goodwin, Paul Grof, Hirohiko Harima, Stefanie Hassel, Chantal Henry, Diego Hidalgo-Mazzei, Anne Hvenegaard Lund, Vaisnvy Kapur, Girish Kunigiri, Beny Lafer, Erik R. Larsen, Ute Lewitzka, Rasmus W. Licht, Blazej Misiak, Patryk Piotrowski, Ângela Miranda-Scippa, Scott Monteith, Rodrigo Munoz, Takako Nakanotani, René E. Nielsen, Claire O’Donovan, Yasushi Okamura, Yamima Osher, Andreas Reif, Philipp Ritter, Janusz K. Rybakowski, Kemal Sagduyu, Brett Sawchuk, Elon Schwartz, Claire Slaney, Ahmad H. Sulaiman, Kirsi Suominen, Aleksandra Suwalska, Peter Tam, Yoshitaka Tatebayashi, Leonardo Tondo, Julia Veeh, Eduard Vieta, Maj Vinberg, Biju Viswanath, Mark Zetin, Peter C. Whybrow, and Michael Bauer

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurophysiology and neuropsychology, QP351-495
Abstract

Abstract Background The world population is aging and the number of older adults with bipolar disorder is increasing. Digital technologies are viewed as a framework to improve care of older adults with bipolar disorder. This analysis quantifies Internet use by older adults with bipolar disorder as part of a larger survey project about information seeking. Methods A paper-based survey about information seeking by patients with bipolar disorder was developed and translated into 12 languages. The survey was anonymous and completed between March 2014 and January 2016 by 1222 patients in 17 countries. All patients were diagnosed by a psychiatrist. General estimating equations were used to account for correlated data. Results Overall, 47% of older adults (age 60 years or older) used the Internet versus 87% of younger adults (less than 60 years). More education and having symptoms that interfered with regular activities increased the odds of using the Internet, while being age 60 years or older decreased the odds. Data from 187 older adults and 1021 younger adults were included in the analysis excluding missing values. Conclusions Older adults with bipolar disorder use the Internet much less frequently than younger adults. Many older adults do not use the Internet, and technology tools are suitable for some but not all older adults. As more health services are only available online, and more digital tools are developed, there is concern about growing health disparities based on age. Mental health experts should participate in determining the appropriate role for digital tools for older adults with bipolar disorder.

Published
2018
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3. Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes

Author

Ole Kristian Drange, Olav Bjerkehagen Smeland, Alexey A. Shadrin, Per Ivar Finseth, Aree Witoelar, Oleksandr Frei, Psychiatric Genomics Consortium Bipolar Disorder Working Group, Yunpeng Wang, Sahar Hassani, Srdjan Djurovic, Anders M. Dale, Ole A. Andreassen, Eli A Stahl, Gerome Breen, Andreas J Forstner, Andrew McQuillin, Stephan Ripke, Vassily Trubetskoy, Manuel Mattheisen, Jonathan R I Coleman, Heìleìna A Gaspar, Christiaan A de Leeuw, Stacy Steinberg, Jennifer M Whitehead Pavlides, Maciej Trzaskowski, Tune H Pers, Peter A Holmans, Liam Abbott, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D Als, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A Badner, Marie Bækvad-Hansen, Jack D Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Sarah E Bergen, Carsten Bøcker Pedersen, Erlend Bøen, Marco Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, William Byerley, Miquel Casas, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W Craig, Cristiana Cruceanu, David Curtis, Piotr M Czerski, Anders M Dale, Simone de Jong, Franziska Degenhardt, Jurgen Del-Favero, J Raymond DePaulo, Amanda L Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Valentina Escott-Price, Chun Chieh Fan, Sascha B Fischer, Matthew Flickinger, Tatiana M Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B Freimer, Louise Friseìn, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D Gordon, Katherine Gordon-Smith, Elaine K Green, Melissa J Green, Tiffany A Greenwood, Jakob Grove, Weihua Guan, Joseì Guzman Parra, Marian L Hamshere, Martin Hautzinger, Urs Heilbronner, Stefan Herms, Maria Hipolito, Per Hoffmann, Dominic Holland, Laura Huckins, Steìphane Jamain, Jessica S Johnson, Anders Jureìus, Radhika Kandaswamy, Robert Karlsson, James L Kennedy, Sarah Kittel-Schneider, Sarah V Knott, James A Knowles, Manolis Kogevinas, Anna C Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B Lawson, Markus Leber, Phil H Lee, Shawn E Levy, Jun Z Li, Chunyu Liu, Susanne Lucae, Anna Maaser, Donald J MacIntyre, Pamela B Mahon, Wolfgang Maier, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G McInnis, James D McKay, Helena Medeiros, Sarah E Medland, Fan Meng, Lili Milani, Grant W Montgomery, Derek W Morris, Thomas W Mühleisen, Niamh Mullins, Hoang Nguyen, Caroline M Nievergelt, Annelie Nordin Adolfsson, Evaristus A Nwulia, Claire O’Donovan, Loes M Olde Loohuis, Anil P S Ori, Lilijana Oruc, Urban Ösby, Roy H Perlis, Amy Perry, Andrea Pfennig, James B Potash, Shaun M Purcell, Eline J Regeer, Andreas Reif, Ceìline S Reinbold, John P Rice, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M Ruderfer, Euijung Ryu, Cristina Saìnchez-Mora, Alan F Schatzberg, William A Scheftner, Nicholas J Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D Shilling, Engilbert Sigurdsson, Claire Slaney, Olav B Smeland, Janet L Sobell, Christine Søholm Hansen, Anne T Spijker, David St Clair, Michael Steffens, John S Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Robert C Thompson, Thorgeir E Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J Watson, Thomas W Weickert, Stephanie H Witt, Simon Xi, Wei Xu, Allan H Young, Peter Zandi, Peng Zhang, Sebastian Zollner, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lena Backlund, Bernhard T Baune, Frank Bellivier, Wade H Berrettini, Joanna M Biernacka, Douglas H R Blackwood, Michael Boehnke, Anders D Børglum, Aiden Corvin, Nicholas Craddock, Mark J Daly, Udo Dannlowski, ToÞnu Esko, Bruno Etain, Mark Frye, Janice M Fullerton, Elliot S Gershon, Michael Gill, Fernando Goes, Maria Grigoroiu-Serbanescu, Joanna Hauser, David M Hougaard, Christina M Hultman, Ian Jones, Lisa A Jones, Reneì S Kahn, George Kirov, Mikael Landeìn, Marion Leboyer, Cathryn M Lewis, Qingqin S Li, Jolanta Lissowska, Nicholas G Martin, Fermin Mayoral, Susan L McElroy, Andrew M McIntosh, Francis J McMahon, Ingrid Melle, Andres Metspalu, Philip B Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Richard M Myers, Benjamin M Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M Nöthen, Michael C O’Donovan, Ketil J Oedegaard, Michael J Owen, Sara A Paciga, Carlos Pato, Michele T Pato, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Marta Ribaseìs, Marcella Rietschel, Guy A Rouleau, Martin Schalling, Peter R Schofield, Thomas G Schulze, Alessandro Serretti, Jordan W Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Patrick F Sullivan, Gustavo Turecki, Arne E Vaaler, Eduard Vieta, John B Vincent, Thomas Werge, John I Nurnberger, Naomi R Wray, Arianna Di Florio, Howard J Edenberg, Sven Cichon, Roel A Ophoff, Laura J Scott, Ole A Andreassen, John Kelsoe, and Pamela Sklar

Subjects
Alzheimer’s disease, bipolar disorder, GWAS, pleiotropy, cognitive symptoms, affective symptoms, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Background: Alzheimer’s disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits.Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer’s Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework.Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR = 0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR = 0.022, opposite direction of effect).Conclusion: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP.

Published
2019
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4. Erratum to: Online information seeking by patients with bipolar disorder: results from an international multisite survey

Author

Jörn Conell, Rita Bauer, Tasha Glenn, Martin Alda, Raffaella Ardau, Bernhard T. Baune, Michael Berk, Yuly Bersudsky, Amy Bilderbeck, Alberto Bocchetta, Letizia Bossini, Angela Marianne Paredes Castro, Eric Yat Wo Cheung, Caterina Chillotti, Sabine Choppin, Maria Del Zompo, Rodrigo Dias, Seetal Dodd, Anne Duffy, Bruno Etain, Andrea Fagiolini, Julie Garnham, John Geddes, Jonas Gildebro, Ana Gonzalez-Pinto, Guy M. Goodwin, Paul Grof, Hirohiko Harima, Stefanie Hassel, Chantal Henry, Diego Hidalgo-Mazzei, Vaisnvy Kapur, Girish Kunigiri, Beny Lafer, Chun Lam, Erik Roj Larsen, Ute Lewitzka, Rasmus W. Licht, Anne Hvenegaard Lund, Blazej Misiak, Patryk Piotrowski, Scott Monteith, Rodrigo Munoz, Takako Nakanotani, René E. Nielsen, Claire O’Donovan, Yasushi Okamura, Yamima Osher, Andreas Reif, Philipp Ritter, Janusz K. Rybakowski, Kemal Sagduyu, Brett Sawchuk, Elon Schwartz, Ângela Miranda Scippa, Claire Slaney, Ahmad Hatim Sulaiman, Kirsi Suominen, Aleksandra Suwalska, Peter Tam, Yoshitaka Tatebayashi, Leonardo Tondo, Eduard Vieta, Maj Vinberg, Biju Viswanath, Julia Volkert, Mark Zetin, Iñaki Zorrilla, Peter C. Whybrow, and Michael Bauer

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurophysiology and neuropsychology, QP351-495
Published
2017
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5. Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report.

Author

Mirko Manchia, Mazda Adli, Nirmala Akula, Raffaella Ardau, Jean-Michel Aubry, Lena Backlund, Claudio Em Banzato, Bernhard T Baune, Frank Bellivier, Susanne Bengesser, Joanna M Biernacka, Clara Brichant-Petitjean, Elise Bui, Cynthia V Calkin, Andrew Tai Ann Cheng, Caterina Chillotti, Sven Cichon, Scott Clark, Piotr M Czerski, Clarissa Dantas, Maria Del Zompo, J Raymond Depaulo, Sevilla D Detera-Wadleigh, Bruno Etain, Peter Falkai, Louise Frisén, Mark A Frye, Jan Fullerton, Sébastien Gard, Julie Garnham, Fernando S Goes, Paul Grof, Oliver Gruber, Ryota Hashimoto, Joanna Hauser, Urs Heilbronner, Rebecca Hoban, Liping Hou, Stéphane Jamain, Jean-Pierre Kahn, Layla Kassem, Tadafumi Kato, John R Kelsoe, Sarah Kittel-Schneider, Sebastian Kliwicki, Po-Hsiu Kuo, Ichiro Kusumi, Gonzalo Laje, Catharina Lavebratt, Marion Leboyer, Susan G Leckband, Carlos A López Jaramillo, Mario Maj, Alain Malafosse, Lina Martinsson, Takuya Masui, Philip B Mitchell, Frank Mondimore, Palmiero Monteleone, Audrey Nallet, Maria Neuner, Tomás Novák, Claire O'Donovan, Urban Osby, Norio Ozaki, Roy H Perlis, Andrea Pfennig, James B Potash, Daniela Reich-Erkelenz, Andreas Reif, Eva Reininghaus, Sara Richardson, Guy A Rouleau, Janusz K Rybakowski, Martin Schalling, Peter R Schofield, Oliver K Schubert, Barbara Schweizer, Florian Seemüller, Maria Grigoroiu-Serbanescu, Giovanni Severino, Lisa R Seymour, Claire Slaney, Jordan W Smoller, Alessio Squassina, Thomas Stamm, Jo Steele, Pavla Stopkova, Sarah K Tighe, Alfonso Tortorella, Gustavo Turecki, Naomi R Wray, Adam Wright, Peter P Zandi, David Zilles, Michael Bauer, Marcella Rietschel, Francis J McMahon, Thomas G Schulze, and Martin Alda

Subjects
Medicine, Science
Abstract

The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study.Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling.Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders).We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.

Published
2013
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6. Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis

Author

Vipavee Niemsiri, Sara Brin Rosenthal, Caroline M. Nievergelt, Adam X. Maihofer, Maria C. Marchetto, Renata Santos, Tatyana Shekhtman, Ney Alliey-Rodriguez, Amit Anand, Yokesh Balaraman, Wade H. Berrettini, Holli Bertram, Katherine E. Burdick, Joseph R. Calabrese, Cynthia V. Calkin, Carla Conroy, William H. Coryell, Anna DeModena, Lisa T. Eyler, Scott Feeder, Carrie Fisher, Nicole Frazier, Mark A. Frye, Keming Gao, Julie Garnham, Elliot S. Gershon, Fernando S. Goes, Toyomi Goto, Gloria J. Harrington, Petter Jakobsen, Masoud Kamali, Marisa Kelly, Susan G. Leckband, Falk W. Lohoff, Michael J. McCarthy, Melvin G. McInnis, David Craig, Caitlin E. Millett, Francis Mondimore, Gunnar Morken, John I. Nurnberger, Claire O’ Donovan, Ketil J. Øedegaard, Kelly Ryan, Martha Schinagle, Paul D. Shilling, Claire Slaney, Emma K. Stapp, Andrea Stautland, Bruce Tarwater, Peter P. Zandi, Martin Alda, Kathleen M. Fisch, Fred H. Gage, and John R. Kelsoe

Subjects
Psychiatry, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Mental Health, Human Genome, Psychology and Cognitive Sciences, Genetics, Biological Sciences, Serious Mental Illness, Molecular Biology, Medical and Health Sciences, Brain Disorders
Abstract

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E–09 and 4.10E–18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Published
2023

7. The futility of long-term predictions in bipolar disorder: mood fluctuations are the result of deterministic chaotic processes

Author

Claire Slaney, Benoit H. Mulsant, Kamil Bradler, Maxine Mowete, Stephane MacLean, Julie Garnham, Abigail Ortiz, and Martin Alda

Subjects
Neurophysiology and neuropsychology, Episode prediction, Bipolar disorder, Chaotic, Neurosciences. Biological psychiatry. Neuropsychiatry, Lyapunov exponent, symbols.namesake, medicine, Statistical physics, Biological Psychiatry, Mathematics, Mood fluctuations, Research, QP351-495, Autocorrelation, medicine.disease, Psychiatry and Mental health, Nonlinear system, Mood, Unaffected first-degree relatives, Detrended fluctuation analysis, Tukey's range test, symbols, Nonlinear analyses, RC321-571
Abstract

Background Understanding the underlying architecture of mood regulation in bipolar disorder (BD) is important, as we are starting to conceptualize BD as a more complex disorder than one of recurring manic or depressive episodes. Nonlinear techniques are employed to understand and model the behavior of complex systems. Our aim was to assess the underlying nonlinear properties that account for mood and energy fluctuations in patients with BD; and to compare whether these processes were different in healthy controls (HC) and unaffected first-degree relatives (FDR). We used three different nonlinear techniques: Lyapunov exponent, detrended fluctuation analysis and fractal dimension to assess the underlying behavior of mood and energy fluctuations in all groups; and subsequently to assess whether these arise from different processes in each of these groups. Results There was a positive, short-term autocorrelation for both mood and energy series in all three groups. In the mood series, the largest Lyapunov exponent was found in HC (1.84), compared to BD (1.63) and FDR (1.71) groups [F (2, 87) = 8.42, p Conclusions The underlying nature of mood variability is in keeping with that of a chaotic system, which means that fluctuations are generated by deterministic nonlinear process(es) in HC, BD, and FDR. The value of this complex modeling lies in analyzing the nature of the processes involved in mood regulation. It also suggests that the window for episode prediction in BD will be inevitably short.

Published
2021

8. Network-based integrative analysis of lithium response in bipolar disorder using transcriptomic and GWAS data

Author

Vipavee Niemsiri, Sarah Brin Rosenthal, Caroline M. Nievergelt, Adam X. Maihofer, Maria C. Marchetto, Renata Santos, Tatyana Shekhtman, Ney Alliey-Rodriguez, Amit Anand, Yokesh Balaraman, Wade H. Berrettini, Holli Bertram, Katherine E. Burdick, Joseph R. Calabrese, Cynthia V. Calkin, Carla Conroy, William H. Coryell, Anna DeModena, Scott Feeder, Carrie Fisher, Nicole Frazier, Mark A. Frye, Keming Gao, Julie Garnham, Elliot S. Gershon, Fernando Goes, Toyomi Goto, Gloria J. Harrington, Petter Jakobsen, Masoud Kamali, Marisa Kelly, Susan G. Leckband, Falk Lohoff, Michael J. McCarthy, Melvin G. McInnis, David Craig, Caitlin E. Millett, Francis Mondimore, Gunnar Morken, John I. Nurnberger, Claire O’ Donovan, Ketil J. Øedegaard, Kelly Ryan, Martha Schinagle, Paul D. Shilling, Claire Slaney, Emma K. Stapp, Andrea Stautland, Bruce Tarwater, Peter P. Zandi, Martin Alda, Kathleen M. Fisch, Fred H. Gage, and John R. Kelsoe

Abstract

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA- boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric=1.28E- 09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Published
2022

9. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author

Gabriëlla A.M. Blokland, Jakob Grove, Chia-Yen Chen, Chris Cotsapas, Stuart Tobet, Robert Handa, David St Clair, Todd Lencz, Bryan J. Mowry, Sathish Periyasamy, Murray J. Cairns, Paul A. Tooney, Jing Qin Wu, Brian Kelly, George Kirov, Patrick F. Sullivan, Aiden Corvin, Brien P. Riley, Tõnu Esko, Lili Milani, Erik G. Jönsson, Aarno Palotie, Hannelore Ehrenreich, Martin Begemann, Agnes Steixner-Kumar, Pak C. Sham, Nakao Iwata, Daniel R. Weinberger, Pablo V. Gejman, Alan R. Sanders, Joseph D. Buxbaum, Dan Rujescu, Ina Giegling, Bettina Konte, Annette M. Hartmann, Elvira Bramon, Robin M. Murray, Michele T. Pato, Jimmy Lee, Ingrid Melle, Espen Molden, Roel A. Ophoff, Andrew McQuillin, Nicholas J. Bass, Rolf Adolfsson, Anil K. Malhotra, Nicholas G. Martin, Janice M. Fullerton, Philip B. Mitchell, Peter R. Schofield, Andreas J. Forstner, Franziska Degenhardt, Sabrina Schaupp, Ashley L. Comes, Manolis Kogevinas, José Guzman-Parra, Andreas Reif, Fabian Streit, Lea Sirignano, Sven Cichon, Maria Grigoroiu-Serbanescu, Joanna Hauser, Jolanta Lissowska, Fermin Mayoral, Bertram Müller-Myhsok, Beata Świątkowska, Thomas G. Schulze, Markus M. Nöthen, Marcella Rietschel, John Kelsoe, Marion Leboyer, Stéphane Jamain, Bruno Etain, Frank Bellivier, John B. Vincent, Martin Alda, Claire O’Donovan, Pablo Cervantes, Joanna M. Biernacka, Mark Frye, Susan L. McElroy, Laura J. Scott, Eli A. Stahl, Mikael Landén, Marian L. Hamshere, Olav B. Smeland, Srdjan Djurovic, Arne E. Vaaler, Ole A. Andreassen, Bernhard T. Baune, Tracy Air, Martin Preisig, Rudolf Uher, Douglas F. Levinson, Myrna M. Weissman, James B. Potash, Jianxin Shi, James A. Knowles, Roy H. Perlis, Susanne Lucae, Dorret I. Boomsma, Brenda W.J.H. Penninx, Jouke-Jan Hottenga, Eco J.C. de Geus, Gonneke Willemsen, Yuri Milaneschi, Henning Tiemeier, Hans J. Grabe, Alexander Teumer, Sandra Van der Auwera, Uwe Völker, Steven P. Hamilton, Patrik K.E. Magnusson, Alexander Viktorin, Divya Mehta, Niamh Mullins, Mark J. Adams, Gerome Breen, Andrew M. McIntosh, Cathryn M. Lewis, David M. Hougaard, Merete Nordentoft, Ole Mors, Preben B. Mortensen, Thomas Werge, Thomas D. Als, Anders D. Børglum, Tracey L. Petryshen, Jordan W. Smoller, Jill M. Goldstein, Stephan Ripke, Benjamin M. Neale, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee Chee Keong, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Sandra Meier, Carin J. Meijer, Bela Melegh, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Vihra Milanova, Younes Mokrab, Derek W. Morris, Kieran C. Murphy, Inez Myin-Germeys, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Ulrich Schall, Christian R. Schubert, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Hon-Cheong So, Chris C.A. Spencer, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Peter M. Visscher, Douglas H.R. Blackwood, Ariel Darvasi, Enrico Domenici, Michael Gill, Hugh Gurling, Christina M. Hultman, Assen V. Jablensky, Kenneth S. Kendler, Jo Knight, Qingqin S. Li, Jianjun Liu, Steven A. McCarroll, Jennifer L. Moran, Michael J. Owen, Carlos N. Pato, Danielle Posthuma, Pamela Sklar, Jens R. Wendland, Mark J. Daly, Michael C. O’Donovan, Peter Donnelly, Ines Barroso, Jenefer M. Blackwell, Matthew A. Brown, Juan P. Casas, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S. Markus, Christopher G. Mathew, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Stephen J. Sawcer, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Gavin Band, Céline Bellenguez, Colin Freeman, Eleni Giannoulatou, Garrett Hellenthal, Richard Pearson, Matti Pirinen, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Sarah Edkins, Matthew Gillman, Emma Gray, Rhian Gwilliam, Naomi Hammond, Sarah E. Hunt, Alagurevathi Jayakumar, Jennifer Liddle, Owen T. McCann, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Avazeh Tashakkori-Ghanbaria, Matthew Waller, Paul Weston, Pamela Whittaker, Sara Widaa, Mark I. McCarthy, Maria J. Arranz, Steven Bakker, Stephan Bender, Benedicto Crespo-Facorro, Jeremy Hall, Conrad Iyegbe, Stephen Lawrie, Kuang Lin, Don H. Linszen, Ignacio Mata, Muriel Walshe, Matthias Weisbrod, Durk Wiersma, Vassily Trubetskoy, Yunpeng Wang, Jonathan R.I. Coleman, Héléna A. Gaspar, Christiaan A. de Leeuw, Jennifer M. Whitehead Pavlides, Maciej Trzaskowski, Enda M. Byrne, Liam Abbott, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, Miquel Casas, Felecia Cerrato, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W. Craig, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Simone de Jong, Jurgen Del-Favero, J. Raymond DePaulo, Amanda L. Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Chun Chieh Fan, Sascha B. Fischer, Matthew Flickinger, Tatiana M. Foroud, Liz Forty, Christine Fraser, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Weihua Guan, Martin Hautzinger, Urs Heilbronner, Maria Hipolito, Dominic Holland, Laura Huckins, Jessica S. Johnson, Radhika Kandaswamy, Robert Karlsson, Sarah Kittel-Schneider, Anna C. Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Chunyu Liu, Anna Maaser, Donald J. MacIntyre, Pamela B. Mahon, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Fan Meng, Grant W. Montgomery, Thomas W. Mühleisen, Hoang Nguyen, Caroline M. Nievergelt, Annelie Nordin Adolfsson, Evaristus A. Nwulia, Claire O'Donovan, Loes M. Olde Loohuis, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Amy Perry, Andrea Pfennig, Eline J. Regeer, Céline S. Reinbold, John P. Rice, Fabio Rivas, Margarita Rivera, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Nicholas J. Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Christine Søholm Hansen, Anne T. Spijker, Michael Steffens, John S. Strauss, Szabolcs Szelinger, Robert C. Thompson, Thorgeir E. Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J. Watson, Thomas W. Weickert, Simon Xi, Wei Xu, Allan H. Young, Peter Zandi, Peng Zhang, Sebastian Zöllner, Abdel Abdellaoui, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Aartjan T.F. Beekman, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Gregory E. Crawford, Gail Davies, Ian J. Deary, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Fernando S. Goes, Lynsey S. Hall, Thomas F. Hansen, Ian B. Hickie, Georg Homuth, Carsten Horn, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa A. Jones, Eric Jorgenson, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Dean F. MacKinnon, Robert M. Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Christel M. Middeldorp, Evelin Mihailov, Francis M. Mondimore, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O'Reilly, Hogni Oskarsson, Jodie N. Painter, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Jorge A. Quiroz, Per Qvist, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Stanley I. Shyn, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Katherine E. Tansey, Henning Teismann, Wesley Thompson, Pippa A. Thomson, Matthew Traylor, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Shantel Marie Weinsheimer, Jürgen Wellmann, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Klaus Berger, Udo Dannlowski, Katharina Domschke, Caroline Hayward, Andrew C. Heath, Stefan Kloiber, Glyn Lewis, Pamela AF. Madden, Patrik K. Magnusson, Preben Bo Mortensen, Michael C. O'Donovan, Sara A. Paciga, Nancy L. Pedersen, David J. Porteous, Catherine Schaefer, Henry Völzke, Marco Bortolato, Janita Bralten, Cynthia M. Bulik, Christie L. Burton, Caitlin E. Carey, Lea K. Davis, Laramie E. Duncan, Howard J. Edenberg, Lauren Erdman, Stephen V. Faraone, Slavina B. Goleva, Wei Guo, Christopher Hübel, Laura M. Huckins, Ekaterina A. Khramtsova, Joanna Martin, Carol A. Mathews, Elise Robinson, Eli Stahl, Barbara E. Stranger, Michela Traglia, Raymond K. Walters, Lauren A. Weiss, Stacey J. Winham, Yin Yao, Kristjar Skajaa, Markus Nöthen, Michael Owen, Robert H. Yolken, Niels Plath, Jonathan Mill, Daniel Geschwind, Psychiatry 1, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Functional Genomics, Biological Psychology, APH - Mental Health, APH - Methodology, Sociology and Social Gerontology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Blokland, Gabriella AM, Grove, Jakob, Chen, Chia Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, Lee, Sang Hong, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, iPSYCH, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, ANS - Complex Trait Genetics, and ANS - Mood, Anxiety, Psychosis, Stress & Sleep

Subjects
0301 basic medicine, Male, Bipolar Disorder, Schizophrenia/genetics, LD SCORE REGRESSION, Genome-wide association study, 0302 clinical medicine, Receptors, SCHIZOPHRENIA, Psychotic Disorders/genetics, KYNURENINE PATHWAY METABOLISM, Genetics, RISK, Sex Characteristics, Vascular Endothelial Growth Factor, Bipolar Disorder/genetics, Major/genetics, Single Nucleotide, AFFECTIVE STIMULI IMPACT, Schizophrenia, Sulfurtransferases, Major depressive disorder, Female, Depressive Disorder, Major/genetics, Bipolar disorder, Locus (genetics), Genomics, Biology, Polymorphism, Single Nucleotide, Article, DYSPHORIC MOOD, 03 medical and health sciences, Sex differences, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Genotype-by-sex interaction, Biological Psychiatry, Depressive Disorder, Major, Depressive Disorder, GENDER-DIFFERENCES, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], PARAVENTRICULAR NUCLEUS, 3112 Neurosciences, Endothelial Cells, MAJOR DEPRESSION, medicine.disease, Genetic architecture, 030104 developmental biology, Mood, Receptors, Vascular Endothelial Growth Factor, Psychotic Disorders, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

Published
2022

10. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author

Niamh Mullins, JooEun Kang, Adrian I. Campos, Jonathan R.I. Coleman, Alexis C. Edwards, Hanga Galfalvy, Daniel F. Levey, Adriana Lori, Andrey Shabalin, Anna Starnawska, Mei-Hsin Su, Hunna J. Watson, Mark Adams, Swapnil Awasthi, Michael Gandal, Jonathan D. Hafferty, Akitoyo Hishimoto, Minsoo Kim, Satoshi Okazaki, Ikuo Otsuka, Stephan Ripke, Erin B. Ware, Andrew W. Bergen, Wade H. Berrettini, Martin Bohus, Harry Brandt, Xiao Chang, Wei J. Chen, Hsi-Chung Chen, Steven Crawford, Scott Crow, Emily DiBlasi, Philibert Duriez, Fernando Fernández-Aranda, Manfred M. Fichter, Steven Gallinger, Stephen J. Glatt, Philip Gorwood, Yiran Guo, Hakon Hakonarson, Katherine A. Halmi, Hai-Gwo Hwu, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S. Kaplan, Walter H. Kaye, Pamela K. Keel, James L. Kennedy, Kelly L. Klump, Dong Li, Shih-Cheng Liao, Klaus Lieb, Lisa Lilenfeld, Chih-Min Liu, Pierre J. Magistretti, Christian R. Marshall, James E. Mitchell, Eric T. Monson, Richard M. Myers, Dalila Pinto, Abigail Powers, Nicolas Ramoz, Stefan Roepke, Vsevolod Rozanov, Stephen W. Scherer, Christian Schmahl, Marcus Sokolowski, Michael Strober, Laura M. Thornton, Janet Treasure, Ming T. Tsuang, Stephanie H. Witt, D. Blake Woodside, Zeynep Yilmaz, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Tracy M. Air, Martin Alda, Lars Alfredsson, Ole A. Andreassen, Adebayo Anjorin, Vivek Appadurai, María Soler Artigas, Sandra Van der Auwera, M. Helena Azevedo, Nicholas Bass, Claiton H.D. Bau, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Joanna M. Biernacka, Tim B. Bigdeli, Elisabeth B. Binder, Michael Boehnke, Marco P. Boks, Rosa Bosch, David L. Braff, Richard Bryant, Monika Budde, Enda M. Byrne, Wiepke Cahn, Miguel Casas, Enrique Castelao, Jorge A. Cervilla, Boris Chaumette, Sven Cichon, Aiden Corvin, Nicholas Craddock, David Craig, Franziska Degenhardt, Srdjan Djurovic, Howard J. Edenberg, Ayman H. Fanous, Jerome C. Foo, Andreas J. Forstner, Mark Frye, Janice M. Fullerton, Justine M. Gatt, Pablo V. Gejman, Ina Giegling, Hans J. Grabe, Melissa J. Green, Eugenio H. Grevet, Maria Grigoroiu-Serbanescu, Blanca Gutierrez, Jose Guzman-Parra, Steven P. Hamilton, Marian L. Hamshere, Annette Hartmann, Joanna Hauser, Stefanie Heilmann-Heimbach, Per Hoffmann, Marcus Ising, Ian Jones, Lisa A. Jones, Lina Jonsson, René S. Kahn, John R. Kelsoe, Kenneth S. Kendler, Stefan Kloiber, Karestan C. Koenen, Manolis Kogevinas, Bettina Konte, Marie-Odile Krebs, Mikael Landén, Jacob Lawrence, Marion Leboyer, Phil H. Lee, Douglas F. Levinson, Calwing Liao, Jolanta Lissowska, Susanne Lucae, Fermin Mayoral, Susan L. McElroy, Patrick McGrath, Peter McGuffin, Andrew McQuillin, Sarah E. Medland, Divya Mehta, Ingrid Melle, Yuri Milaneschi, Philip B. Mitchell, Esther Molina, Gunnar Morken, Preben Bo Mortensen, Bertram Müller-Myhsok, Caroline Nievergelt, Vishwajit Nimgaonkar, Markus M. Nöthen, Michael C. O’Donovan, Roel A. Ophoff, Michael J. Owen, Carlos Pato, Michele T. Pato, Brenda W.J.H. Penninx, Jonathan Pimm, Giorgio Pistis, James B. Potash, Robert A. Power, Martin Preisig, Digby Quested, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Vanesa Richarte, Marcella Rietschel, Margarita Rivera, Andrea Roberts, Gloria Roberts, Guy A. Rouleau, Diego L. Rovaris, Dan Rujescu, Cristina Sánchez-Mora, Alan R. Sanders, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Alessandro Serretti, Jianxin Shi, Stanley I. Shyn, Lea Sirignano, Pamela Sklar, Olav B. Smeland, Jordan W. Smoller, Edmund J.S. Sonuga-Barke, Gianfranco Spalletta, John S. Strauss, Beata Świątkowska, Maciej Trzaskowski, Gustavo Turecki, Laura Vilar-Ribó, John B. Vincent, Henry Völzke, James T.R. Walters, Cynthia Shannon Weickert, Thomas W. Weickert, Myrna M. Weissman, Leanne M. Williams, Naomi R. Wray, Clement C. Zai, Allison E. Ashley-Koch, Jean C. Beckham, Elizabeth R. Hauser, Michael A. Hauser, Nathan A. Kimbrel, Jennifer H. Lindquist, Benjamin McMahon, David W. Oslin, Xuejun Qin, Esben Agerbo, Anders D. Børglum, Gerome Breen, Annette Erlangsen, Tõnu Esko, Joel Gelernter, David M. Hougaard, Ronald C. Kessler, Henry R. Kranzler, Qingqin S. Li, Nicholas G. Martin, Andrew M. McIntosh, Ole Mors, Merete Nordentoft, Catherine M. Olsen, David Porteous, Robert J. Ursano, Danuta Wasserman, Thomas Werge, David C. Whiteman, Cynthia M. Bulik, Hilary Coon, Ditte Demontis, Anna R. Docherty, Po-Hsiu Kuo, Cathryn M. Lewis, J. John Mann, Miguel E. Rentería, Daniel J. Smith, Eli A. Stahl, Murray B. Stein, Fabian Streit, Virginia Willour, Douglas M. Ruderfer, Manuel Mattheisen, Abdel Abdellaoui, Mark J. Adams, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Jane Hvarregaard Christensen, Toni-Kim Clarke, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. 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Nyholt, Paul F. O’Reilly, Hogni Oskarsson, Caroline Hayward, Andrew C. Heath, Glyn Lewis, Pamela A.F. Madden, Patrik K. Magnusson, Andres Metspalu, Sara A. Paciga, Nancy L. Pedersen, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Danielle Posthuma, Jorge A. Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Engilbert Sigurdsson, Grant C.B. Sinnamon, Johannes H. Smit, Hreinn Stefansson, Stacy Steinberg, Jana Strohmaier, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Alexander Viktorin, Peter M. Visscher, Yunpeng Wang, Bradley T. Webb, Roy H. Perlis, David J. Porteous, Catherine Schaefer, Kari Stefansson, Henning Tiemeier, Rudolf Uher, Patrick F. Sullivan, Kevin S. O’Connell, Brandon Coombes, Zhen Qiao, Thomas D. Als, Sigrid Børte, Alexander W. Charney, Ole Kristian Drange, Michael J. Gandal, Saskia P. Hagenaars, Masashi Ikeda, Nolan Kamitaki, Kristi Krebs, Georgia Panagiotaropoulou, Brian M. Schilder, Laura G. Sloofman, Bendik S. Winsvold, Hong-Hee Won, Liliya Abramova, Kristina Adorjan, Mariam Al Eissa, Diego Albani, Ney Alliey-Rodriguez, Verneri Antilla, Anastasia Antoniou, Ji Hyun Baek, Michael Bauer, Eva C. Beins, Sarah E. Bergen, Armin Birner, Erlend Bøen, Murielle Brum, Ben M. Brumpton, Nathalie Brunkhorst-Kanaan, William Byerley, Murray Cairns, Miquel Casas, Pablo Cervantes, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Julie Cunningham, David Curtis, Piotr M. Czerski, Anders M. Dale, Nina Dalkner, Friederike S. David, Amanda L. Dobbyn, Athanassios Douzenis, Torbjørn Elvsåshagen, I. Nicol Ferrier, Alessia Fiorentino, Tatiana M. Foroud, Liz Forty, Oleksandr Frei, Nelson B. Freimer, Louise Frisén, Katrin Gade, Julie Garnham, Ian R. Gizer, Katherine Gordon-Smith, Tiffany A. Greenwood, José Guzman-Parra, Kyooseob Ha, Magnus Haraldsson, Martin Hautzinger, Urs Heilbronner, Dennis Hellgren, Peter A. Holmans, Laura Huckins, Jessica S. Johnson, Janos L. Kalman, Yoichiro Kamatani, Sarah Kittel-Schneider, Maria Koromina, Thorsten M. Kranz, Michiaki Kubo, Ralph Kupka, Steven A. Kushner, Catharina Lavebratt, Markus Leber, Heon-Jeong Lee, Shawn E. Levy, Catrin Lewis, Martin Lundberg, Sigurdur H. Magnusson, Adam Maihofer, Dolores Malaspina, Eirini Maratou, Lina Martinsson, Nathaniel W. McGregor, James D. McKay, Helena Medeiros, Vincent Millischer, Jennifer L. Moran, Derek W. Morris, Thomas W. Mühleisen, Niamh O’Brien, Claire O’Donovan, Loes M. Olde Loohuis, Lilijana Oruc, Sergi Papiol, Antonio F. Pardiñas, Amy Perry, Andrea Pfennig, Evgenia Porichi, Towfique Raj, Mark H. Rapaport, J. Raymond DePaulo, Eline J. Regeer, Fabio Rivas, Julian Roth, Panos Roussos, Fanny Senner, Sally Sharp, Paul D. Shilling, Claire Slaney, Janet L. 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J., Wasserman, D., Coon, H., Demontis, D., Docherty, A. R., Kuo, P. -H., Mann, J. J., Renteria, M. E., Stein, M. B., Willour, V., Psychiatry, Biological Psychology, APH - Methodology, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, HUS Psychiatry, Department of Public Health, Clinicum, Nuorisopsykiatria, Faculty Common Matters (Faculty of Social Sciences), Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Biostatistics Helsinki, Anna Keski-Rahkonen / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Internal medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Mullins N., Kang J., Campos A.I., Coleman J.R.I., Edwards 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T.F.M., Bacanu S.-A., Baekvad-Hansen M., Beekman A.T.F., Bryois J., Buttenschon H.N., Bybjerg-Grauholm J., Cai N., Christensen J.H., Clarke T.-K., Colodro-Conde L., Couvy-Duchesne B., Crawford G.E., Davies G., Derks E.M., Direk N., Dolan C.V., Dunn E.C., Eley T.C., Escott-Price V., Hassan Kiadeh F.F., Finucane H.K., Frank J., Gaspar H.A., Gill M., Goes F.S., Gordon S.D., Weinsheimer S.M., Wellmann J., Willemsen G., Wu Y., Xi H.S., Yang J., Zhang F., Arolt V., Boomsma D.I., Dannlowski U., de Geus E.J.C., Depaulo J.R., Domenici E., Domschke K., Esko T., Grove J., Hall L.S., Hansen C.S., Hansen T.F., Herms S., Hickie I.B., Homuth G., Horn C., Hottenga J.-J., Hougaard D.M., Howard D.M., Jansen R., Jorgenson E., Knowles J.A., Kohane I.S., Kraft J., Kretzschmar W.W., Kutalik Z., Li Y., Lind P.A., MacIntyre D.J., MacKinnon D.F., Maier R.M., Maier W., Marchini J., Mbarek H., Middeldorp C.M., Mihailov E., Milani L., Mondimore F.M., Montgomery G.W., Mostafavi S., Nauck M., Ng B., Nivard M.G., Nyholt D.R., O'Reilly P.F., Oskarsson H., Hayward C., Heath A.C., Lewis G., Li Q.S., Madden P.A.F., Magnusson P.K., Martin N.G., McIntosh A.M., Metspalu A., Mors O., Nordentoft M., Paciga S.A., Pedersen N.L., Painter J.N., Pedersen C.B., Pedersen M.G., Peterson R.E., Peyrot W.J., Posthuma D., Quiroz J.A., Qvist P., Rice J.P., Riley B.P., Mirza S.S., Schoevers R., Schulte E.C., Shen L., Sigurdsson E., Sinnamon G.C.B., Smit J.H., Smith D.J., Stefansson H., Steinberg S., Streit F., Strohmaier J., Tansey K.E., Teismann H., Teumer A., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Treutlein J., Trubetskoy V., Uitterlinden A.G., Umbricht D., der Auwera S.V., van Hemert A.M., Viktorin A., Visscher P.M., Wang Y., Webb B.T., Perlis R.H., Porteous D.J., Schaefer C., Stefansson K., Tiemeier H., Uher R., Werge T., Lewis C.M., Breen G., Borglum A.D., Sullivan P.F., O'Connell K.S., Coombes B., Qiao Z., Als T.D., Borte S., Charney A.W., Drange O.K., Gandal M.J., Hagenaars S.P., Ikeda M., Kamitaki N., Krebs K., Panagiotaropoulou G., Schilder B.M., Sloofman L.G., Winsvold B.S., Won H.-H., Abramova L., Adorjan K., Al Eissa M., Albani D., Alliey-Rodriguez N., Antilla V., Antoniou A., Baek J.H., Bauer M., Beins E.C., Bergen S.E., Birner A., Boen E., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Byerley W., Cairns M., Cervantes P., Cruceanu C., Cuellar-Barboza A., Cunningham J., Curtis D., Czerski P.M., Dale A.M., Dalkner N., David F.S., Dobbyn A.L., Douzenis A., Elvsashagen T., Ferrier I.N., Fiorentino A., Foroud T.M., Forty L., Frei O., Freimer N.B., Frisen L., Gade K., Garnham J., Gelernter J., Gizer I.R., Gordon-Smith K., Greenwood T.A., Ha K., Haraldsson M., Hautzinger M., Heilbronner U., Hellgren D., Holmans P.A., Huckins L., Johnson J.S., Kalman J.L., Kamatani Y., Kittel-Schneider S., Koromina M., Kranz T.M., Kranzler H.R., Kubo M., Kupka R., Kushner S.A., Lavebratt C., Leber M., Lee H.-J., Levy S.E., Lewis C., Lundberg M., Magnusson S.H., Maihofer A., Malaspina D., Maratou E., Martinsson L., McGregor N.W., McKay J.D., Medeiros H., Millischer V., Moran J.L., Morris D.W., Muhleisen T.W., O'Brien N., O'Donovan C., Olde Loohuis L.M., Oruc L., Papiol S., Pardinas A.F., Perry A., Pfennig A., Porichi E., Raj T., Rapaport M.H., Regeer E.J., Rivas F., Roth J., Roussos P., Ruderfer D.M., Senner F., Sharp S., Shilling P.D., Slaney C., Sobell J.L., Artigas M.S., Spijker A.T., Stein D.J., Terao C., Toma C., Tooney P., Tsermpini E.-E., Vawter M.P., Vedder H., Xi S., Xu W., Kay Yang J.M., Young A.H., Young H., Zandi P.P., Zhou H., HUNT All-In Psychiatry, Babadjanova G., Backlund L., Bengesser S., Blackwood D.H.R., Carr V.J., Catts S., Dikeos D., Etain B., Ferentinos P., Gawlik M., Gershon E.S., Henskens F., Hillert J., Hong K.S., Hultman C.M., Hveem K., Iwata N., Jablensky A.V., Kirov G., Lochner C., Loughland C., Mathews C.A., McMahon F.J., Michie P., Mowry B., Neale B.M., Nievergelt C.M., Oedegaard K.J., Olsson T., Pantelis C., Patrinos G.P., Reininghaus E.Z., Saito T., Schall U., Schalling M., Scott R.J., Weickert C.S., Stordal E., Vaaler A.E., Vieta E., Waldman I.D., Zwart J.-A., Nurnberger J.I., Stahl E.A., Di Florio A., Adan R.A.H., Ando T., Aschauer H., Baker J.H., Bencko V., Birgegard A., Boden J.M., Boehm I., Boni C., Perica V.B., Buehren K., Bulik C.M., Burghardt R., Carlberg L., Cassina M., Clementi M., Cone R.D., Courtet P., Crowley J.J., Danner U.N., Davis O.S.P., de Zwaan M., Dedoussis G., Degortes D., DeSocio J.E., Dick D.M., Dina C., Dmitrzak-Weglarz M., Martinez E.D., Duncan L.E., Egberts K., Mattingsdal M., McDevitt S., Meulenbelt I., Micali N., Mitchell J., Mitchell K., Monteleone P., Monteleone A.M., Munn-Chernoff M.A., Nacmias B., Navratilova M., Ntalla I., Olsen C.M., O'Toole J.K., Padyukov L., Palotie A., Pantel J., Papezova H., Parker R., Pearson J.F., Ehrlich S., Escaramis G., Espeseth T., Estivill X., Farmer A., Favaro A., Fischer K., Floyd J.A.B., Focker M., Foretova L., Forzan M., Franklin C.S., Gambaro G., Giuranna J., Giusti-Rodriquez P., Gonidakis F., Gordon S., Mayora M.G., Guillaume S., Hanscombe K.B., Hatzikotoulas K., Hebebrand J., Helder S.G., Henders A.K., Herpertz-Dahlmann B., Herzog W., Hinney A., Horwood L.J., Hubel C., Petersen L.V., Purves K.L., Raevuori A., Reichborn-Kjennerud T., Ricca V., Ripatti S., Ritschel F., Roberts M., Rybakowski F., Santonastaso P., Scherag A., Schmidt U., Schork N.J., Schosser A., Seitz J., Slachtova L., Slagboom P.E., Slof-Op 't Landt M.C.T., Slopien A., Soranzo N., Sorbi S., Southam L., Steen V.W., Huckins L.M., Hudson J.I., Imgart H., Inoko H., Janout V., Jordan J., Julia A., Kalsi G., Kaminska D., Kaprio J., Karhunen L., Karwautz A., Kas M.J.H., Kennedy M.A., Keski-Rahkonen A., Kiezebrink K., Kim Y.-R., Kirk K.M., Klareskog L., Knudsen G.P.S., Larsen J.T., Le Hellard S., Leppa V.M., Lichtenstein P., Lin B.D., Lundervold A., Luykx J., Maj M., Mannik K., Marsal S., Stuber G.D., Szatkiewicz J.P., Tachmazidou I., Tenconi E., Tortorella A., Tozzi F., Tsitsika A., Tyszkiewicz-Nwafor M., Tziouvas K., van Elburg A.A., van Furth E.F., Wade T.D., Wagner G., Walton E., Whiteman D.C., Wichmann H.E., Widen E., Yao S., Zeggini E., Zerwas S., Zipfel S., Jungkunz M., Dietl L., Schwarze C.E., Dahmen N., Schott B.H., Mobascher A., Crivelli S., Dennis M.F., Harvey P.D., Carter B.W., Huffman J.E., Jacobson D., Madduri R., Olsen M.K., Pestian J., Gaziano J.M., Muralidhar S., Ramoni R., Beckham J., Chang K.-M., O'Donnell C.J., Tsao P.S., Breeling J., Huang G., Romero J.P.C., Moser J., Whitbourne S.B., Brewer J.V., Aslan M., Connor T., Argyres D.P., Stephens B., Brophy M.T., Humphries D.E., Selva L.E., Do N., Shayan S., Cho K., Pyarajan S., Hauser E., Sun Y., Zhao H., Wilson P., McArdle R., Dellitalia L., Mattocks K., Harley J., Zablocki C.J., Whittle J., Jacono F., Gutierrez S., Gibson G., Hammer K., Kaminsky L., Villareal G., Kinlay S., Xu J., Hamner M., Mathew R., Bhushan S., Iruvanti P., Godschalk M., Ballas Z., Ivins D., Mastorides S., Moorman J., Gappy S., Klein J., Ratcliffe N., Florez H., Okusaga O., Murdoch M., Sriram P., Yeh S.S., Tandon N., Jhala D., Aguayo S., Cohen D., Sharma S., Liangpunsakul S., Oursler K.A., Whooley M., Ahuja S., Constans J., Meyer P., Greco J., Rauchman M., Servatius R., Gaddy M., Wallbom A., Morgan T., Stapley T., Sherman S., Ross G., Tsao P., Strollo P., Boyko E., Meyer L., Gupta S., Huq M., Fayad J., Hung A., Lichy J., Hurley R., Robey B., Striker R., Erlangsen A., Kessler R.C., Porteous D., Ursano R.J., Wasserman D., Coon H., Demontis D., Docherty A.R., Kuo P.-H., Mann J.J., Renteria M.E., Stein M.B., and Willour V.

Subjects
LD SCORE REGRESSION, Genome-wide association study, Suicide, Attempted, 3124 Neurology and psychiatry, 0302 clinical medicine, Risk Factors, Insomnia, Suicide attempt, GWAS, Suïcidi, Depression (differential diagnoses), Cause of death, Psychiatry, 0303 health sciences, Factors de risc en les malalties, Mental Disorders, Genetic Correlation, Genome-wide Association Study, Pleiotropy, Polygenicity, Suicide, Suicide Attempt, DEPRESSION, 3. Good health, Genetic correlation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Depressive Disorder, Major, Mental illness, Cohort, SEX, medicine.symptom, Human, medicine.medical_specialty, Risk factors in diseases, BF, Locus (genetics), BEHAVIORS, Psykiatri, EVENTS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, ddc:610, GENOME-WIDE ASSOCIATION, IDEATION, Socioeconomic status, METAANALYSIS, Biological Psychiatry, 030304 developmental biology, business.industry, Risk Factor, Genetic architecture, THOUGHTS, RC0321, business, Malalties mentals, 030217 neurology & neurosurgery
Abstract

Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu), which is supported by the Office of Research Infrastructure of the National Institutes of Health (Grant Nos. S10OD018522 and S10OD026880). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. This work was funded by the National Institutes of Health (Grant Nos. R01MH116269 and R01MH121455 [to DMR]), NIGMS of the National Institutes of Health (Grant No. T32GM007347 [to JK]), and the Brain & Behavior Research Foundation (NARSAD Young Investigator Award No. 29551 [to NM])., BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., Office of Research Infrastructure of the National Institutes of Health S10OD018522 S10OD026880, United States Department of Health & Human Services, National Institutes of Health (NIH) - USA R01MH116269 R01MH121455, NIH National Institute of General Medical Sciences (NIGMS) T32GM007347 NARSAD 29551

Published
2022

11. Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients

Author

Michael McCarthy, Claire O'Donovan, Urs Heilbronner, Ichiro Kusumi, Eduard Vieta, Liping Hou, Hsi-Chung Chen, Claire Slaney, Maria Grigoroiu-Serbanescu, Kazufumi Akiyama, Michael Bauer, Janusz K. Rybakowski, Frank Bellivier, Marion Leboyer, Katzutaka Shimoda, Palmiero Monteleone, Cristiana Cruceanu, Alessio Squassina, Stephanie H. Witt, Tadafumi Kato, Giovanni Severino, Alfonso Tortorella, J. Raymond DePaulo, Martin Alda, Louise Frisén, Mazda Adl, Martin Schalling, Per Hoffmann, Susan G. Leckband, Jean-Pierre Kahn, Jean-Michel Aubry, Francis J. McMahon, Sven Cichon, Alexandre Dayer, Tatyana Shekhtman, Franziska Degenhardt, James B. Potash, Bruno Etain, Joseph Frank, Antonio Benabarre, Bernhard T. Baune, Gloria Roberts, Ryota Hashimoto, Tomas Novak, Paul D. Shilling, Julia Veeh, Joanna M. Biernacka, Barbara König, Peter Falkai, Philip B. Mitchell, Urban Ösby, Esther Jiménez, Sébastien Gard, Mark A. Frye, Sarah Kittel-Schneider, Layla Kassem, Fasil Tekola-Ayele, Armin Birner, Cynthia Marie-Claire, Raffaella Ardau, Abesh Kumar Bhattacharjee, Stéphane Jamain, Julie Garnham, Guy A. Rouleau, Caterina Chillotti, Piotr M. Czerski, Thomas G. Schulze, Gustavo Turecki, Anbupalam Thalamuthu, Claudia Pisanu, Azmeraw T. Amare, Marina Mitjans, Sergi Papiol, Mario Maj, Bárbara Arias, Janice M. Fullerton, Nina Dalkner, Peter R. Schofield, Susanne Bengesser, Stefan Herms, Klaus Oliver Schubert, Francis M. Mondimore, Eva Z. Reininghaus, Fernando S. Goes, Lena Backlund, Francesc Colom, Catharina Lavebratt, Christian Simhandl, Marcella Rietschel, Micah Cearns, Mikael Landén, Norio Ozaki, Gonzalo Laje, Barbara W. Schweizer, Nirmala Akula, Andrea Pfennig, Yi-Hsiang Hsu, John R. Kelsoe, Lina Martinsson, Markus M. Nöthen, Caroline M. Nievergelt, Pavla Stopkova, Mirko Manchia, Susan L. McElroy, Peter P. Zandi, Scott R. Clark, Joanna Hauser, Andreas J. Forstner, Po-Hsiu Kuo, Andreas Reif, Maria Del Zompo, Paul Grof, Fabian Streit, Ewa Ferensztajn-Rochowiak, Pablo Cervantes, Thomas Stamm, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, APH - Digital Health, Schubert, K. O., Thalamuthu, A., Amare, A. T., Frank, J., Streit, F., Adl, M., Akula, N., Akiyama, K., Ardau, R., Arias, B., Aubry, J. -M., Backlund, L., Bhattacharjee, A. K., Bellivier, F., Benabarre, A., Bengesser, S., Biernacka, J. M., Birner, A., Marie-Claire, C., Cearns, M., Cervantes, P., Chen, H. -C., Chillotti, C., Cichon, S., Clark, S. R., Cruceanu, C., Czerski, P. M., Dalkner, N., Dayer, A., Degenhardt, F., Del Zompo, M., Depaulo, J. R., Etain, B., Falkai, P., Forstner, A. J., Frisen, L., Frye, M. A., Fullerton, J. M., Gard, S., Garnham, J. S., Goes, F. S., Grigoroiu-Serbanescu, M., Grof, P., Hashimoto, R., Hauser, J., Heilbronner, U., Herms, S., Hoffmann, P., Hou, L., Hsu, Y. -H., Jamain, S., Jimenez, E., Kahn, J. -P., Kassem, L., Kuo, P. -H., Kato, T., Kelsoe, J., Kittel-Schneider, S., Ferensztajn-Rochowiak, E., Konig, B., Kusumi, I., Laje, G., Landen, M., Lavebratt, C., Leboyer, M., Leckband, S. G., Maj, M., Manchia, M., Martinsson, L., Mccarthy, M. J., Mcelroy, S., Colom, F., Mitjans, M., Mondimore, F. M., Monteleone, P., Nievergelt, C. M., Nothen, M. M., Novak, T., O'Donovan, C., Ozaki, N., Osby, U., Papiol, S., Pfennig, A., Pisanu, C., Potash, J. B., Reif, A., Reininghaus, E., Rouleau, G. A., Rybakowski, J. K., Schalling, M., Schofield, P. R., Schweizer, B. W., Severino, G., Shekhtman, T., Shilling, P. D., Shimoda, K., Simhandl, C., Slaney, C. M., Squassina, A., Stamm, T., Stopkova, P., Tekola-Ayele, F., Tortorella, A., Turecki, G., Veeh, J., Vieta, E., Witt, S. H., Roberts, G., Zandi, P. P., Alda, M., Bauer, M., Mcmahon, F. J., Mitchell, P. B., Schulze, T. G., Rietschel, M., and Baune, B. T.

Subjects
Oncology, Multifactorial Inheritance, Treatment response, medicine.medical_specialty, Lithium (medication), Bipolar disorder, Poor responder, Neurosciences. Biological psychiatry. Neuropsychiatry, Lithium, DISEASE, Article, Cellular and Molecular Neuroscience, Risk Factors, Internal medicine, medicine, Humans, Manic-depressive illness, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Depressió psíquica, METAANALYSIS, Biological Psychiatry, Depression (differential diagnoses), MANIA, Depressive Disorder, Depressive Disorder, Major, Trastorn bipolar, Depression, business.industry, Major, medicine.disease, Pathway analysis, Liti, COMPARATIVE EFFICACY, Psychiatry and Mental health, Mental depression, Schizophrenia, Polygenic risk score, Esquizofrènia, Pharmacogenomics, business, RC321-571, medicine.drug
Abstract

Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium’s therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.

Published
2021

12. Prediction of lithium response using clinical data

Author

Janusz K. Rybakowski, Paul Grof, Giovanni Severino, Alberto Bocchetta, Alexandra Suwalska, Claire O'Donovan, Claudia Pisanu, Caterina Chillotti, Thomas Trappenberg, Anne Berghöfer, Tomas Hajek, Marco Pinna, P. Zvolsky, Martin Alda, Leonardo Tondo, Abraham Nunes, E. Grof, Raffaella Ardau, Julie Garnham, Bruno Müller-Oerlinghausen, Pablo Cervantes, Claire Slaney, Valeria Deiana, M. Del Zompo, and Mirko Manchia

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Bipolar Disorder, Sample (statistics), Machine Learning, 03 medical and health sciences, 0302 clinical medicine, Cohen's kappa, Maintenance therapy, Antimanic Agents, Risk Factors, Clinical Decision Rules, Sleep Initiation and Maintenance Disorders, Internal medicine, medicine, Humans, Bipolar disorder, Age of Onset, Receiver operating characteristic, business.industry, Clinical course, Middle Aged, medicine.disease, 030227 psychiatry, 3. Good health, Random forest, Psychiatry and Mental health, Treatment Outcome, ROC Curve, Feature (computer vision), Area Under Curve, Disease Progression, Lithium Compounds, Female, business, 030217 neurology & neurosurgery
Abstract

Objective Promptly establishing maintenance therapy could reduce morbidity and mortality in patients with bipolar disorder. Using a machine learning approach, we sought to evaluate whether lithium responsiveness (LR) is predictable using clinical markers. Method Our data are the largest existing sample of direct interview-based clinical data from lithium-treated patients (n = 1266, 34.7% responders), collected across seven sites, internationally. We trained a random forest model to classify LR-as defined by the previously validated Alda scale-against 180 clinical predictors. Results Under appropriate cross-validation procedures, LR was predictable in the pooled sample with an area under the receiver operating characteristic curve of 0.80 (95% CI 0.78-0.82) and a Cohen kappa of 0.46 (0.4-0.51). The model demonstrated a particularly low false-positive rate (specificity 0.91 [0.88-0.92]). Features related to clinical course and the absence of rapid cycling appeared consistently informative. Conclusion Clinical data can inform out-of-sample LR prediction to a potentially clinically relevant degree. Despite the relevance of clinical course and the absence of rapid cycling, there was substantial between-site heterogeneity with respect to feature importance. Future work must focus on improving classification of true positives, better characterizing between- and within-site heterogeneity, and further testing such models on new external datasets.

Published
2019

13. Brain age in bipolar disorders: Effects of lithium treatment

Author

Holly Van Gestel, Rudolf Uher, Claire Slaney, Martin Alda, Joanne Petite, Kyle Johnson, Katja Franke, Carl A. Helmick, Tomas Hajek, and Julie Garnham

Subjects
Adult, Male, Oncology, Treatment response, medicine.medical_specialty, Bipolar Disorder, Lithium (medication), Machine Learning, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Humans, Medicine, Dementia, business.industry, Age Factors, Brain, General Medicine, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Accelerated aging, 030227 psychiatry, 3. Good health, Psychiatry and Mental health, Neuroprotective Agents, Multivariate Analysis, Lithium Compounds, Female, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Objective:Bipolar disorders increase the risk of dementia and show biological and brain alterations, which resemble accelerated aging. Lithium may counter some of these processes and lower the risk of dementia. However, until now no study has specifically investigated the effects of Li on brain age.Methods:We acquired structural magnetic resonance imaging scans from 84 participants with bipolar disorders (41 with and 43 without Li treatment) and 45 controls. We used a machine learning model trained on an independent sample of 504 controls to estimate the individual brain ages of study participants, and calculated BrainAGE by subtracting chronological from the estimated brain age.Results:BrainAGE was significantly greater in non-Li relative to Li or control participants, F(2, 125) = 10.22, p Conclusions:Bipolar disorders were associated with greater, whereas Li treatment with lower discrepancy between brain and chronological age. These findings support the neuroprotective effects of Li, which were sufficiently pronounced to affect a complex, multivariate measure of brain structure. The association between Li treatment and BrainAGE was independent of long-term thymoprophylactic response and thus may generalize beyond bipolar disorders, to neurodegenerative disorders.

Published
2019

14. The Humoral Response to the BNT162b2 Vaccine in Hemodialysis Patients

Author

Shelly Bolotin, Julie Garnham-Takaoka, Anne-Claude Gingras, Kevin Yau, Alyson Takaoka, Michelle A. Hladunewich, Jerome A. Leis, Kento T. Abe, David Naimark, Matthew J. Oliver, Vanessa Tran, Sarah I. Mullin, Keelia Quinn De Launay, Karen Colwill, Ellen Shadowitz, Allison McGeer, Jeffrey Perl, Sharon E. Straus, and Christopher T. Chan

Subjects
medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, medicine.medical_treatment, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Confidence interval, Vaccination, Rate difference, Internal medicine, Cohort, medicine, Hemodialysis, business, Dialysis
Abstract

ImportanceHemodialysis patients have an exceptionally high mortality from COVID-19 and this patient population often has a poor response to vaccinations. Randomized controlled trials for COVID-19 vaccines included few patients with kidney disease, therefore vaccine immunogenicity is uncertain in this population.ObjectiveEvaluate the SARS-CoV-2 antibody response in chronic hemodialysis patients following one versus two doses of BNT162b2 COVID-19 vaccination compared to health care worker controls and convalescent serum.DesignProspective observational cohort study.SettingSingle centre study in Toronto, Ontario, Canada.Participants142 in-centre hemodialysis patients and 35 health care worker controls.ExposureBNT162b2 (Pfizer-BioNTech) COVID-19 vaccine.Main Outcomes and MeasuresSARS-CoV-2 IgG antibodies to the spike protein (anti-spike), receptor binding domain (anti-RBD), and nucleocapsid protein (anti-NP) were measured in 66 hemodialysis patients receiving one vaccine dose following a public health policy change, 76 patients receiving two vaccine doses, and 35 health care workers receiving two vaccine doses.ResultsDetectable anti-NP suggestive of natural SARS-CoV-2 infection was detected in 15/142 (11%) of patients at baseline while only three patients had prior RT-PCR confirmed COVID-19. Two additional patients contracted COVID-19 after receiving two doses of vaccine. In patients receiving a single BNT162b2 dose, seroconversion occurred in 53/66 (80%) for anti-spike and 35/66 (55%) for anti-RBD by 28 days post dose, but only 15/66 (23%) and 4/66 (6%), respectively attained a robust response as defined by reaching the median level of anti-spike and anti-RBD in convalescent serum from COVID-19 survivors. In patients receiving two doses of BNT162b2 vaccine, seroconversion occurred in 69/72 (96%) for anti-spike and 63/72 (88%) for anti-RBD by 2 weeks following the second dose while 52/72 (72%) and 43/76 (41%) reached the median convalescent serum level of anti-spike and anti-RBD, respectively. In contrast, 35/35 (100%) of health care workers exceeded the median level of anti-spike and anti-RBD found in convalescent serum 2-4 weeks after the second dose.Conclusions and RelevanceThis study confirms poor immunogenicity 28 days following a single dose of BNT162b2 vaccine in the hemodialysis population, supporting adherence to recommended vaccination schedules, and avoiding delay of the second dose in these at-risk individuals.Key PointsQuestionWhat is the serologic response to the BNT162b2 COVID-19 vaccine in hemodialysis patients?FindingsIn this prospective observational study, humoral response was compared in 66 hemodialysis patients sampled 28 days after receipt of one dose of vaccine to 76 patients who received two doses of vaccine sampled 14 days after the second dose. Among those receiving one dose, 6% had anti-RBD response above the median level of convalescent serum versus 41% who received two doses.MeaningGiven that hemodialysis patients exhibit a poor humoral response to a single dose of BNT162b2 vaccine, the second dose should not be delayed.

Published
2021

15. Characterization of Age and Polarity at Onset in Bipolar Disorder

Author

Aiden Corvin, Maria Grigoroiu-Serbanescu, Mark Hyman Rapaport, Frederike T. Fellendorf, Urs Heilbronner, Mariam M. Al Eissa, John J Nurnberger, Claire O'Donovan, Claire Slaney, Mark A. Frye, Niamh L. O'Brien, Roland Hasler, Michael John Owen, Michael Conlon O'Donovan, Farah Klöhn-Saghatolislam, Markus M. Nöthen, Scott R. Clark, Mikael Landén, Lina Jonsson, Peter Falkai, Qingqin S. Li, Alessio Squassina, Simon Schmitt, Gustavo Turecki, Heike Anderson-Schmidt, Jonathan Repple, Sofie R. Aminoff, Eduard Vieta, Katherine Gordon-Smith, Stéphane Jamain, William Byerley, Hélène Richard-Lepouriel, Fermín Mayoral, Francis J. McMahon, Marin Veldic, Ingrid Melle, Andrew McQuillin, Nicholas Bass, Gloria Roberts, Douglas M. Ruderfer, John B. Vincent, Nelson B. Freimer, Kirov George, Wei Xu, Susan L. McElroy, Ceylan Balaban, Marco P. Boks, Franziska Degenhardt, Paul E. Croarkin, Wade H. Berrettini, Piotr M. Czerski, Fernando S. Goes, Peter P. Zandi, Sabrina K. Schaupp, Barbara W. Schweizer, Andrew M. McIntosh, Marcella Rietschel, Helena Pelin, Evelyn J. Bromet, Marion Leboyer, Ole A. Andreassen, Georgia Panagiotaropoulou, Alessia Fiorentino, Sally I. Sharp, Torbjørn Elvsåshagen, Kristina Adorjan, Monika Budde, Lisa Jones, Thomas G. Schulze, Vihra Milanova, Janos Kalman, Tim B. Bigdeli, Esther Jiménez, Abigail Ortiz, Dolores Malaspina, Kevin S. O’Connell, Sergi Papiol, Mario Maj, Tim Hahn, Frederike Stein, Jordan W. Smoller, Tomas Novak, Katrin Gade, J. Raymond DePaulo, Sarah Kittel-Schneider, Julia-Katharina Pfarr, Martin Alda, James A. Knowles, Sven Cichon, David Craig, Eli A. Stahl, William A. Scheftner, Bruno Etain, Annabel Vreeker, Guy A. Rouleau, Stephan Ripke, Clement C. Zai, Frank Bellivier, Giovanni Severino, Palmiero Monteleone, Ian Jones, Bertram Müller-Myhsok, Mark Adams, John Strauss, Philip B. Mitchell, Andreas Reif, Fabian Streit, Roel A. Ophoff, James L. Kennedy, Nils Opel, Raffaella Ardau, Paul Grof, Peter R. Schofield, Susanne Bengesser, Maria Hake, Loes M. Olde Loohuis, Joanna Pawlak, Daniela Reich-Erkelenz, Ingrid Agartz, Maria Del Zompo, Antonio Benabarre, Bernhard T. Baune, Arianna Di Florio, Ashley L. Comes, Michael Gill, Cristiana Cruceanu, Susanne Meinert, William Coryell, Alessio Maria Monteleone, Fanny Senner, Trine Vik Lagerberg, Jose Guzman-Parra, Erik Pålsson, Elliot S. Gershon, Melvin G. McInnis, Pavla Stopkova, Nikolaos Koutsouleris, René S. Kahn, Janice M. Fullerton, Howard J. Edenberg, Tilo Kircher, Nina Dalkner, Udo Dannlowski, Rolf Adolfsson, Alfonso Tortorella, Jean-Michel Aubry, James B. Potash, Catina Chillotti, Eva Z. Reininghaus, Janet L. Sobell, Thorsten M. Kranz, Tina Meller, Ayman H. Fanous, Kai Ringwald, K Oliver Schubert, Andreas J. Forstner, Till F. M. Andlauer, Helena Medeiros, Mirko Manchia, Joanna M. Biernacka, Katharina Brosch, Julie Garnham, Olav B. Smeland, Eva C. Schulte, Carlos N. Pato, Nicholas John Craddock, Srdjan Djurovic, Pablo Cervantes, Michele T. Pato, John R. Kelsoe, Claudia Pisanu, Joanna Twarowska-Hauser, and William Lawson

Subjects
0303 health sciences, medicine.medical_specialty, business.industry, Genome-wide association study, Disease, Heritability, medicine.disease, Genetic architecture, 03 medical and health sciences, 0302 clinical medicine, Autism spectrum disorder, Schizophrenia, Internal medicine, medicine, Bipolar disorder, business, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

BackgroundStudying the phenotypic and genetic characteristics of age and polarity at onset (AAO, PAO) in bipolar disorder (BD) can provide new insights into disease pathology and facilitate the development of screening tools.AimsTo examine the genetic architecture of AAO and PAO and their association with BD disease characteristics.MethodsGenome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (N=12977) and PAO (N=6773) were conducted in BD patients of 34 cohorts and a replication sample (N=2237). The association of onset with disease characteristics was investigated in two of these cohorts.ResultsEarlier AAO was associated with an increased risk of psychotic symptoms, suicidality, and fewer episodes. A depressive onset correlated with lifetime suicidality and a manic onset with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in SNV-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased polygenic scores for autism spectrum disorder (β=-0.34 years, SE=0.08), major depression (β=-0.34 years, SE=0.08), schizophrenia (β=-0.39 years, SE=0.08), and educational attainment (β=-0.31 years, SE=0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.ConclusionsAAO and PAO are associated with indicators of BD severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents, and phenotype definitions introduce significant heterogeneity, affecting analyses.RELEVANCE STATEMENTIn the largest study to systematically characterize age at onset (N=12977) and polarity at onset (N=6773) in bipolar disorder, we describe an association between illness onset characteristics and indicators of severity, confirming their clinical relevance. Our study shows that that early illness onset is associated with genetic liability for a broad range of psychiatric disorders. However, we also highlight systematic differences in age at onset across cohorts, continents, and phenotype definitions. This heterogeneity results in reduced heritability and affects genetic analyses, underscoring the need for the development of standardized phenotype definitions.

Published
2021

16. Clinical predictors of non-response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study

Author

Paul D. Shilling, John I. Nurnberger, Michael McCarthy, Martin Alda, Megan Ritchey, Wade H. Berrettini, Vigdis Elin Giever Syrstad, Cynthia V. Calkin, Peter P. Zandi, Gloria Harrington, Fernando S. Goes, William Coryell, Elliot S. Gershon, Yokesh Balaraman, Toyomi Goto, Elizabeth Karberg, Abesh Kumar Bhattacharjee, Joseph R. Calabrese, Bruce Tarwater, Caroline M. Nievergelt, Helle K. Schoeyen, Kelly A. Ryan, John R. Kelsoe, Joanna M. Biernacka, Julie Garnham, Masoud Kamali, Kara Glazer, Falk W. Lohoff, Francis M. Mondimore, Gunnar Morken, Yian Lin, Ney Alliey-Rodriguez, Mark A. Frye, Nicole Frazier, Petter Jakobsen, Marth Shaw, Ole A. Andreassen, Melvin G. McInnis, Adam X. Maihofer, Martha Schinagle, Emma K. Stapp, Susan G. Leckband, Keming Gao, Amit Anand, Carrie Fisher, Marisa Kelly, Claire Slaney, Andrea Stautland, Carla Conroy, Ketil J. Oedegaard, Anna DeModena, Nicole D'Arcangelo, and Holli Bertram

Subjects
medicine.medical_specialty, Bipolar Disorder, Lithium (medication), business.industry, Lithium, medicine.disease, Treatment failure, First line treatment, Psychiatry and Mental health, Pharmacotherapy, Treatment Outcome, Prospective trial, Pharmacogenetics, Internal medicine, Partial response, Pharmacogenomics, medicine, Lithium Compounds, Humans, Bipolar disorder, Prospective Studies, business, Biological Psychiatry, medicine.drug
Abstract

Background Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. Methods The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. Results A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. Conclusions In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy. publishedVersion

Published
2021

17. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author

James McKay, Frank Bellivier, Mark A. Frye, Bertram Müller-Myhsok, Fermín Mayoral, I. Nicol Ferrier, Marion Leboyer, Fabian Streit, Dan J. Stein, James L. Kennedy, Christine Søholm Hansen, Scott D. Gordon, Beata Świątkowska, Valentina Escott-Price, Michael Bauer, Lina Martinsson, Donald J. MacIntyre, Oleksandr Frei, Daniel J. Smith, Sara A. Paciga, Takeo Saito, Jennifer L. Moran, Verneri Antilla, C Pantelis, Tomas Olsson, Swapnil Awasthi, Lena Backlund, Eirini Maratou, Martin Schalling, John B. Vincent, Niamh Mullins, Sarah E. Bergen, Niamh L. O'Brien, Marco P. Boks, Carsten Bøcker Pedersen, Mikael Landén, Franziska Degenhardt, Hang Zhou, Margarita Rivera, Andrew M. McIntosh, Manuel Mattheisen, Shawn Levy, Roy H. Perlis, John P. Rice, Sigurdur H. Magnusson, Amanda Dobbyn, Michael Conlon O'Donovan, Julien Bryois, Wolfgang Maier, John-Anker Zwart, J. Raymond DePaulo, Martin Alda, Laura G. Sloofman, Friederike Sophie David, James A. Knowles, Aiden Corvin, Thomas G. Schulze, Markus M. Nöthen, Nolan Kamitaki, Nina Dalkner, Brandon J. Coombes, Gustavo Turecki, Allan H. Young, Caroline M. Nievergelt, Patricia T. Michie, Ingrid Agartz, Towfique Raj, Diego Albani, Maria Grigoroiu-Serbanescu, Bernhard T. Baune, Kyooseob Ha, Vincent Millischer, Engilbert Sigurdsson, Eva C. Beins, Nicholas G. Martin, Gulja Babadjanova, Josef Frank, Eva Z. Reininghaus, Patrick F. Sullivan, Ian R. Gizer, Guy A. Rouleau, Carmel M. Loughland, Christine Lochner, Thorsten M. Kranz, Amy Perry, Arne E. Vaaler, Mariam M. Al Eissa, Simon Xi, Claire O'Donovan, Josep Antoni Ramos-Quiroga, Ketil J. Oedegaard, Helmut Vedder, Carol A. Mathews, Panagiotis Ferentinos, Tim B. Bigdeli, Derek W. Morris, Per Hoffmann, Mark Hyman Rapaport, Peter P. Zandi, Michael John Owen, Douglas M. Ruderfer, Anders D. Børglum, Catharina Lavebratt, Thorgeir E. Thorgeirsson, Paul A. Tooney, Michiaki Kubo, Steven A. Kushner, Jan Hillert, Loes M. Olde Loohuis, Anastasia Antoniou, Murielle Brum, Chikashi Terao, Nathaniel W. McGregor, Fabio Rivas, James B. Potash, Kevin S. O’Connell, Susanne Lucae, Brian M. Schilder, Katrin Gade, Stephan Ripke, Kristina Adorjan, Kari Stefansson, Tiffany A. Greenwood, Panos Roussos, Sarah Kittel-Schneider, Steven A. McCarroll, Sergi Papiol, Heon Jeong Lee, Assen Jablensky, Liliya Abramova, Dennis Hellgren, Jonas Bybjerg-Grauholm, Martin Lundberg, Hong-Hee Won, William Byerley, Lars Alfredsson, Joel Gelernter, Andrew McQuillin, Claire Slaney, Marta Ribasés, Stephanie H. Witt, Yoichiro Kamatani, Kyung Sue Hong, Marie Bækvad-Hansen, María Soler Artigas, Julie M. Cunningham, Fanny Senner, Stacy Steinberg, Paul D. Shilling, Nakao Iwata, Eystein Stordal, Armin Birner, Sarah E. Medland, Miquel Casas, Ben Michael Brumpton, Erlend Bøen, Bryan J. Mowry, Jolanta Lissowska, Francis J. McMahon, Howard J. Edenberg, Grant W. Montgomery, John I. Nurnberger, Stéphane Jamain, Claudio Toma, Ney Alliey-Rodriguez, Ole Mors, Micha Gawlik, David Curtis, Catrin Lewis, Evangelia-Eirini Tsermpini, Georgia Panagiotaropoulou, Marcella Rietschel, Jessica Yang, Ian Jones, Eduard Vieta, Ole A. Andreassen, Richard M. Myers, Dimitris Dikeos, Melissa J. Green, Janet L. Sobell, Maria Koromina, Piotr M. Czerski, Lilijana Oruc, Sven Cichon, Udo Dannlowski, Bruno Etain, Monika Budde, Alessia Fiorentino, Naomi R. Wray, Qingqin S. Li, Murray J. Cairns, Jonathan R. I. Coleman, Jose Guzman-Parra, Andreas J. Forstner, Hannah Young, Alfredo B. Cuellar-Barboza, Julian Roth, Torbjørn Elvsåshagen, Zhen Qiao, Thomas Werge, Athanassios Douzenis, Cristiana Cruceanu, Rolf Adolfsson, Peter Holmans, Vaughan J. Carr, Thomas W. Weickert, Masashi Ikeda, Joanna M. Biernacka, Lea Sirignano, Adam X. Maihofer, Ralph W. Kupka, John Strauss, Anders M. Dale, Elliot S. Gershon, Jakob Grove, Arianna Di Florio, Helena Medeiros, Ingrid Melle, Preben Bo Mortensen, Kristi Krebs, Saskia P. Hagenaars, Liz Forty, Stanley V. Catts, David M. Hougaard, Marianne Giørtz Pedersen, Andreas Reif, Toni-Kim Clarke, Anne T. Spijker, Danielle Posthuma, Manolis Kogevinas, Michael Boehnke, Rosa Bosch, Gerome Breen, Benjamin M. Neale, Jessica S. Johnson, Katherine Gordon-Smith, Cristina Sánchez-Mora, Alexander W. Charney, Henry R. Kranzler, Digby Quested, René S. Kahn, Lili Milani, Merete Nordentoft, Nathalie Brunkhorst-Kanaan, Laura M. Huckins, James T.R. Walters, Sigrid Børte, Antonio F. Pardiñas, Kristian Hveem, Julie Garnham, Jacob Lawrence, Vassily Trubetskoy, Rodney J. Scott, Nicholas Bass, Carlos N. Pato, Andrea Pfennig, Wei Xu, Calwing Liao, Nicholas John Craddock, Thomas Damm Als, Christina M. Hultman, Fernando S. Goes, Adebayo Anjorin, Evgenia Porichi, Frans Henskens, Nelson B. Freimer, Janice M. Fullerton, Cathryn M. Lewis, Srdjan Djurovic, Roel A. Ophoff, Phil Lee, Peter McGuffin, Gunnar Morken, George P. Patrinos, Alessandro Serretti, Cynthia Shannon Weickert, Pablo Cervantes, Bendik S. Winsvold, Tatiana Foroud, Tõnu Esko, Ulrich Schall, Michele T. Pato, Ji Hyun Baek, John R. Kelsoe, Olav B. Smeland, Janos Kalman, Eva C. Schulte, Joanna Hauser, Urs Heilbronner, Magnús Haraldsson, Martin Hautzinger, Lea Zillich, Eline J. Regeer, Douglas Blackwood, Laura J. Scott, Jordan W. Smoller, Michael J. Gandal, Marquis P. Vawter, Philip B. Mitchell, Ole Kristian Drange, Peter R. Schofield, Susanne Bengesser, Stefan Herms, George Kirov, Markus Leber, Louise Frisén, Thomas W. Mühleisen, Susan L. McElroy, Irwin D. Waldman, Wade H. Berrettini, Sally I. Sharp, Minsoo Kim, Lisa Jones, Eli A. Stahl, Hreinn Stefansson, Esben Agerbo, Dolores Malaspina, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), APH - Digital Health, Mullins N., Forstner A.J., O'Connell K.S., Coombes B., Coleman J.R.I., Qiao Z., Als T.D., Bigdeli T.B., Borte S., Bryois J., Charney A.W., Drange O.K., Gandal M.J., Hagenaars S.P., Ikeda M., Kamitaki N., Kim M., Krebs K., Panagiotaropoulou G., Schilder B.M., Sloofman L.G., Steinberg S., Trubetskoy V., Winsvold B.S., Won H.-H., Abramova L., Adorjan K., Agerbo E., Al Eissa M., Albani D., Alliey-Rodriguez N., Anjorin A., Antilla V., Antoniou A., Awasthi S., Baek J.H., Baekvad-Hansen M., Bass N., Bauer M., Beins E.C., Bergen S.E., Birner A., Bocker Pedersen C., Boen E., Boks M.P., Bosch R., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Budde M., Bybjerg-Grauholm J., Byerley W., Cairns M., Casas M., Cervantes P., Clarke T.-K., Cruceanu C., Cuellar-Barboza A., Cunningham J., Curtis D., Czerski P.M., Dale A.M., Dalkner N., David F.S., Degenhardt F., Djurovic S., Dobbyn A.L., Douzenis A., Elvsashagen T., Escott-Price V., Ferrier I.N., Fiorentino A., Foroud T.M., Forty L., Frank J., Frei O., Freimer N.B., Frisen L., Gade K., Garnham J., Gelernter J., Giortz Pedersen M., Gizer I.R., Gordon S.D., Gordon-Smith K., Greenwood T.A., Grove J., Guzman-Parra J., Ha K., Haraldsson M., Hautzinger M., Heilbronner U., Hellgren D., Herms S., Hoffmann P., Holmans P.A., Huckins L., Jamain S., Johnson J.S., Kalman J.L., Kamatani Y., Kennedy J.L., Kittel-Schneider S., Knowles J.A., Kogevinas M., Koromina M., Kranz T.M., Kranzler H.R., Kubo M., Kupka R., Kushner S.A., Lavebratt C., Lawrence J., Leber M., Lee H.-J., Lee P.H., Levy S.E., Lewis C., Liao C., Lucae S., Lundberg M., MacIntyre D.J., Magnusson S.H., Maier W., Maihofer A., Malaspina D., Maratou E., Martinsson L., Mattheisen M., McCarroll S.A., McGregor N.W., McGuffin P., McKay J.D., Medeiros H., Medland S.E., Millischer V., Montgomery G.W., Moran J.L., Morris D.W., Muhleisen T.W., O'Brien N., O'Donovan C., Olde Loohuis L.M., Oruc L., Papiol S., Pardinas A.F., Perry A., Pfennig A., Porichi E., Potash J.B., Quested D., Raj T., Rapaport M.H., DePaulo J.R., Regeer E.J., Rice J.P., Rivas F., Rivera M., Roth J., Roussos P., Ruderfer D.M., Sanchez-Mora C., Schulte E.C., Senner F., Sharp S., Shilling P.D., Sigurdsson E., Sirignano L., Slaney C., Smeland O.B., Smith D.J., Sobell J.L., Soholm Hansen C., Soler Artigas M., Spijker A.T., Stein D.J., Strauss J.S., Swiatkowska B., Terao C., Thorgeirsson T.E., Toma C., Tooney P., Tsermpini E.-E., Vawter M.P., Vedder H., Walters J.T.R., Witt S.H., Xi S., Xu W., Yang J.M.K., Young A.H., Young H., Zandi P.P., Zhou H., Zillich L., Adolfsson R., Agartz I., Alda M., Alfredsson L., Babadjanova G., Backlund L., Baune B.T., Bellivier F., Bengesser S., Berrettini W.H., Blackwood D.H.R., Boehnke M., Borglum A.D., Breen G., Carr V.J., Catts S., Corvin A., Craddock N., Dannlowski U., Dikeos D., Esko T., Etain B., Ferentinos P., Frye M., Fullerton J.M., Gawlik M., Gershon E.S., Goes F.S., Green M.J., Grigoroiu-Serbanescu M., Hauser J., Henskens F., Hillert J., Hong K.S., Hougaard D.M., Hultman C.M., Hveem K., Iwata N., Jablensky A.V., Jones I., Jones L.A., Kahn R.S., Kelsoe J.R., Kirov G., Landen M., Leboyer M., Lewis C.M., Li Q.S., Lissowska J., Lochner C., Loughland C., Martin N.G., Mathews C.A., Mayoral F., McElroy S.L., McIntosh A.M., McMahon F.J., Melle I., Michie P., Milani L., Mitchell P.B., Morken G., Mors O., Mortensen P.B., Mowry B., Muller-Myhsok B., Myers R.M., Neale B.M., Nievergelt C.M., Nordentoft M., Nothen M.M., O'Donovan M.C., Oedegaard K.J., Olsson T., Owen M.J., Paciga S.A., Pantelis C., Pato C., Pato M.T., Patrinos G.P., Perlis R.H., Posthuma D., Ramos-Quiroga J.A., Reif A., Reininghaus E.Z., Ribases M., Rietschel M., Ripke S., Rouleau G.A., Saito T., Schall U., Schalling M., Schofield P.R., Schulze T.G., Scott L.J., Scott R.J., Serretti A., Shannon Weickert C., Smoller J.W., Stefansson H., Stefansson K., Stordal E., Streit F., Sullivan P.F., Turecki G., Vaaler A.E., Vieta E., Vincent J.B., Waldman I.D., Weickert T.W., Werge T., Wray N.R., Zwart J.-A., Biernacka J.M., Nurnberger J.I., Cichon S., Edenberg H.J., Stahl E.A., McQuillin A., Di Florio A., Ophoff R.A., Andreassen O.A., IMRB - 'Neuropsychiatrie translationnelle' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Etain, Bruno

Subjects
Multifactorial Inheritance, Bipolar Disorder, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Medizin, Genome-wide association study, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, MESH: Bipolar Disorder, Chromosomes, Human, Spectrum disorder, Genetics, 0303 health sciences, Bipolar Disorder/genetics, MESH: Genetic Predisposition to Disease, MESH: Case-Control Studies, Phenotype, Schizophrenia, Synaptic signaling, Case-Control Studie, Human, Quantitative Trait Loci, Biology, MESH: Phenotype, MESH: Chromosomes, Human, Article, 03 medical and health sciences, MESH: Major Histocompatibility Complex, SDG 3 - Good Health and Well-being, ddc:570, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, Multifactorial Inheritance/genetics, MESH: Genome, Human, 030304 developmental biology, MESH: Humans, Genome, Human, Risk Factor, Chromosomes, Human/genetics, Mental illness, medicine.disease, MESH: Quantitative Trait Loci, Human genetics, Psychologie, Case-Control Studies, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, MESH: Genome-Wide Association Study, Expression quantitative trait loci, MESH: Multifactorial Inheritance, Quantitative Trait Loci/genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

International audience; Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Published
2021

18. Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study

Author

Eduard Vieta, Liping Hou, Markus M. Nöthen, Martin Schalling, Thomas Stamm, Thomas G. Schulze, Norio Ozaki, Claire O'Donovan, Azmeraw T. Amare, Alessio Squassina, Alfonso Tortorella, Kazufumi Akiyama, Urs Heilbronner, Caroline M. Nievergelt, Frank Bellivier, Palmiero Monteleone, Mirko Manchia, Tadafumi Kato, Per Hoffmann, Jean-Michel Aubry, Claudia Pisanu, Pavla Stopkova, Lena Backlund, Anthony Batzler, James B. Potash, Susan L. McElroy, Jean-Pierre Kahn, Guy A. Rouleau, Bernhard T. Baune, Francis M. Mondimore, Beth Larrabee, Peter P. Zandi, Christian Simhandl, Susan G. Leckband, Andrea Pfennig, Maria Del Zompo, Francis J. McMahon, Tatyana Shekhtman, Giovanni Severino, Tomas Novak, Andreas J. Forstner, Marcella Rietschel, Paul Grof, Maria Grigoroiu-Serbanescu, Ryota Hashimoto, Nirmala Akula, Sarah Kittel-Schneider, John R. Kelsoe, Andreas Reif, Joanna M. Biernacka, Barbara W. Schweizer, Janice M. Fullerton, Sébastien Gard, Julie Garnham, Barbara König, Mark A. Frye, Michael Bauer, Po-Hsiu Kuo, Janusz K. Rybakowski, Joanna Hauser, Pablo Cervantes, Gonzalo Laje, Urban Ösby, Nina Dalkner, Ewa Ferensztajn-Rochowiak, Mikael Landén, Hsi-Chung Chen, Claire Slaney, Eva Z. Reininghaus, Katzutaka Shimoda, Esther Jiménez, Cristiana Cruceanu, Francesc Colom, Catharina Lavebratt, Abesh Kumar Bhattacharjee, Marina Mitjans, Sergi Papiol, Stephanie H. Witt, Sven Cichon, Bruno Etain, Layla Kassem, Caterina Chillotti, Fernando S. Goes, Franziska Degenhardt, J. Raymond DePaulo, Martin Alda, Ichiro Kusumi, Peter Falkai, Antoni Benabarre, Stéphane Jamain, Philip B. Mitchell, Raffaella Ardau, Peter R. Schofield, Susanne Bengesser, Stefan Herms, Klaus Oliver Schubert, Mario Maj, Paul D. Shilling, Mazda Adli, Louise Frisén, Brandon J. Coombes, Gustavo Turecki, Scott R. Clark, Bárbara Arias, Vincent Millischer, Michael McCarthy, Marion Leboyer, Lina Martinsson, Piotr M. Czerski, Coombes, Brandon J, Millischer, Vincent, Batzler, Anthony, Larrabee, Beth, Hou, Liping, Papiol, Sergi, Heilbronner, Ur, Adli, Mazda, Akiyama, Kazufumi, Akula, Nirmala, Amare, Azmeraw T, Ardau, Raffaella, Arias, Barbara, Aubry, Jean-Michel, Backlund, Lena, Bauer, Michael, Baune, Bernhard T, Bellivier, Frank, Benabarre, Antoni, Bengesser, Susanne, Bhattacharjee, Abesh Kumar, Cervantes, Pablo, Chen, Hsi-Chung, Chillotti, Caterina, Cichon, Sven, Clark, Scott R, Colom, Francesc, Cruceanu, Cristiana, Czerski, Piotr M, Dalkner, Nina, Degenhardt, Franziska, Del Zompo, Maria, Depaulo, J Raymond, Étain, Bruno, Falkai, Peter, Ferensztajn-Rochowiak, Ewa, Forstner, Andreas J, Frisen, Louise, Gard, Sébastien, Garnham, Julie S, Goes, Fernando S, Grigoroiu-Serbanescu, Maria, Grof, Paul, Hashimoto, Ryota, Hauser, Joanna, Herms, Stefan, Hoffmann, Per, Jamain, Stephane, Jiménez, Esther, Kahn, Jean-Pierre, Kassem, Layla, Kato, Tadafumi, Kelsoe, John R, Kittel-Schneider, Sarah, König, Barbara, Kuo, Po-Hsiu, Kusumi, Ichiro, Laje, Gonzalo, Landén, Mikael, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G, Maj, Mario, Manchia, Mirko, Martinsson, Lina, Mccarthy, Michael J, Mcelroy, Susan L, Mitchell, Philip B, Mitjans, Marina, Mondimore, Francis M, Monteleone, Palmiero, Nievergelt, Caroline M, Nöthen, Markus M, Novák, Toma, O'Donovan, Claire, Osby, Urban, Ozaki, Norio, Pfennig, Andrea, Pisanu, Claudia, Potash, James B, Reif, Andrea, Reininghaus, Eva, Rietschel, Marcella, Rouleau, Guy A, Rybakowski, Janusz K, Schalling, Martin, Schofield, Peter R, Schubert, Klaus Oliver, Schweizer, Barbara W, Severino, Giovanni, Shekhtman, Tatyana, Shilling, Paul D, Shimoda, Katzutaka, Simhandl, Christian, Slaney, Claire M, Squassina, Alessio, Stamm, Thoma, Stopkova, Pavla, Tortorella, Alfonso, Turecki, Gustavo, Vieta, Eduard, Witt, Stephanie H, Zandi, Peter P, Fullerton, Janice M, Alda, Martin, Frye, Mark A, Schulze, Thomas G, Mcmahon, Francis J, and Biernacka, Joanna M

Subjects
medicine.medical_specialty, Lithium (medication), business.industry, Bipolar disorder, General Medicine, medicine.disease, Polygenic risk scores, Attention-deficit/hyperactivity disorder, Lithium response, Adherence, medicine, Attention deficit hyperactivity disorder, Association (psychology), Psychiatry, business, Depression (differential diagnoses), 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit, Research Article, medicine.drug
Abstract

Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = −0.14; 95% confidence interval [CI]: −0.24 to −0.03; p value = 0.010) and MDD (β = −0.16; 95% CI: −0.27 to −0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34–1.93; p value = 2e−7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.

Published
2021

19. Genome-wide association study of over 40,000 bipolar disorder cases provides new insights into the underlying biology

Author

Niamh Mullins, Andreas J. Forstner, Kevin S. O’Connell, Brandon Coombes, Jonathan R. I. Coleman, Zhen Qiao, Thomas D. Als, Tim B. Bigdeli, Sigrid Børte, Julien Bryois, Alexander W. Charney, Ole Kristian Drange, Michael J. Gandal, Saskia P. Hagenaars, Masashi Ikeda, Nolan Kamitaki, Minsoo Kim, Kristi Krebs, Georgia Panagiotaropoulou, Brian M. Schilder, Laura G. Sloofman, Stacy Steinberg, Vassily Trubetskoy, Bendik S. Winsvold, Hong-Hee Won, Liliya Abramova, Kristina Adorjan, Esben Agerbo, Mariam Al Eissa, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Anastasia Antoniou, Swapnil Awasthi, Ji Hyun Baek, Marie Bækvad-Hansen, Nicholas Bass, Michael Bauer, Eva C. Beins, Sarah E. Bergen, Armin Birner, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, Rosa Bosch, Murielle Brum, Ben M. Brumpton, Nathalie Brunkhorst-Kanaan, Monika Budde, Jonas Bybjerg-Grauholm, William Byerley, Murray Cairns, Miquel Casas, Pablo Cervantes, Toni-Kim Clarke, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Julie Cunningham, David Curtis, Piotr M. Czerski, Anders M. Dale, Nina Dalkner, Friederike S. David, Franziska Degenhardt, Srdjan Djurovic, Amanda L. Dobbyn, Athanassios Douzenis, Torbjørn Elvsåshagen, Valentina Escott-Price, I. Nicol Ferrier, Alessia Fiorentino, Tatiana M. Foroud, Liz Forty, Josef Frank, Oleksandr Frei, Nelson B. Freimer, Louise Frisén, Katrin Gade, Julie Garnham, Joel Gelernter, Marianne Giørtz Pedersen, Ian R. Gizer, Scott D. Gordon, Katherine Gordon-Smith, Tiffany A. Greenwood, Jakob Grove, José Guzman-Parra, Kyooseob Ha, Magnus Haraldsson, Martin Hautzinger, Urs Heilbronner, Dennis Hellgren, Stefan Herms, Per Hoffmann, Peter A. Holmans, Laura Huckins, Stéphane Jamain, Jessica S. Johnson, Janos L. Kalman, Yoichiro Kamatani, James L. Kennedy, Sarah Kittel-Schneider, James A. Knowles, Manolis Kogevinas, Maria Koromina, Thorsten M. Kranz, Henry R. Kranzler, Michiaki Kubo, Ralph Kupka, Steven A. Kushner, Catharina Lavebratt, Jacob Lawrence, Markus Leber, Heon-Jeong Lee, Phil H. Lee, Shawn E. Levy, Catrin Lewis, Calwing Liao, Susanne Lucae, Martin Lundberg, Donald J. MacIntyre, Sigurdur H. Magnusson, Wolfgang Maier, Adam Maihofer, Dolores Malaspina, Eirini Maratou, Lina Martinsson, Manuel Mattheisen, Steven A. McCarroll, Nathaniel W. McGregor, Peter McGuffin, James D. McKay, Helena Medeiros, Sarah E. Medland, Vincent Millischer, Grant W. Montgomery, Jennifer L. Moran, Derek W. Morris, Thomas W. Mühleisen, Niamh O’Brien, Claire O’Donovan, Loes M. Olde Loohuis, Lilijana Oruc, Sergi Papiol, Antonio F. Pardiñas, Amy Perry, Andrea Pfennig, Evgenia Porichi, James B. Potash, Digby Quested, Towfique Raj, Mark H. Rapaport, J. Raymond DePaulo, Eline J. Regeer, John P. Rice, Fabio Rivas, Margarita Rivera, Julian Roth, Panos Roussos, Douglas M. Ruderfer, Cristina Sánchez-Mora, Eva C. Schulte, Fanny Senner, Sally Sharp, Paul D. Shilling, Engilbert Sigurdsson, Lea Sirignano, Claire Slaney, Olav B. Smeland, Daniel J. Smith, Janet L. Sobell, Christine Søholm Hansen, Maria Soler Artigas, Anne T. Spijker, Dan J. Stein, John S. Strauss, Beata Świątkowska, Chikashi Terao, Thorgeir E. Thorgeirsson, Claudio Toma, Paul Tooney, Evangelia-Eirini Tsermpini, Marquis P. Vawter, Helmut Vedder, James T. R. Walters, Stephanie H. Witt, Simon Xi, Wei Xu, Jessica Mei Kay Yang, Allan H. Young, Hannah Young, Peter P. Zandi, Hang Zhou, Lea Zillich, HUNT All-In Psychiatry, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lars Alfredsson, Gulja Babadjanova, Lena Backlund, Bernhard T. Baune, Frank Bellivier, Susanne Bengesser, Wade H. Berrettini, Douglas H. R. Blackwood, Michael Boehnke, Anders D. Børglum, Gerome Breen, Vaughan J. Carr, Stanley Catts, Aiden Corvin, Nicholas Craddock, Udo Dannlowski, Dimitris Dikeos, Tõnu Esko, Bruno Etain, Panagiotis Ferentinos, Mark Frye, Janice M. Fullerton, Micha Gawlik, Elliot S. Gershon, Fernando S. Goes, Melissa J. Green, Maria Grigoroiu-Serbanescu, Joanna Hauser, Frans Henskens, Jan Hillert, Kyung Sue Hong, David M. Hougaard, Christina M. Hultman, Kristian Hveem, Nakao Iwata, Assen V. Jablensky, Ian Jones, Lisa A. Jones, René S. Kahn, John R. Kelsoe, George Kirov, Mikael Landén, Marion Leboyer, Cathryn M. Lewis, Qingqin S. Li, Jolanta Lissowska, Christine Lochner, Carmel Loughland, Nicholas G. Martin, Carol A. Mathews, Fermin Mayoral, Susan L. McElroy, Andrew M. McIntosh, Francis J. McMahon, Ingrid Melle, Patricia Michie, Lili Milani, Philip B. Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bryan Mowry, Bertram Müller-Myhsok, Richard M. Myers, Benjamin M. Neale, Caroline M. Nievergelt, Merete Nordentoft, Markus M. Nöthen, Michael C. O’Donovan, Ketil J. Oedegaard, Tomas Olsson, Michael J. Owen, Sara A. Paciga, Chris Pantelis, Carlos Pato, Michele T. Pato, George P. Patrinos, Roy H. Perlis, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Andreas Reif, Eva Z. Reininghaus, Marta Ribasés, Marcella Rietschel, Stephan Ripke, Guy A. Rouleau, Takeo Saito, Ulrich Schall, Martin Schalling, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Rodney J. Scott, Alessandro Serretti, Cynthia Shannon Weickert, Jordan W. Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Fabian Streit, Patrick F. Sullivan, Gustavo Turecki, Arne E. Vaaler, Eduard Vieta, John B. Vincent, Irwin D. Waldman, Thomas W. Weickert, Thomas Werge, Naomi R. Wray, John-Anker Zwart, Joanna M. Biernacka, John I. Nurnberger, Sven Cichon, Howard J. Edenberg, Eli A. Stahl, Andrew McQuillin, Arianna Di Florio, Roel A. Ophoff, and Ole A. Andreassen

Subjects
Genetics, 0303 health sciences, Druggability, Genome-wide association study, Biology, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Expression quantitative trait loci, medicine, Bipolar disorder, Synaptic signaling, Prefrontal cortex, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. BD risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating eQTL data implicated 15 genes robustly linked to BD via gene expression, including druggable genes such as HTR6, MCHR1, DCLK3 and FURIN. This GWAS provides the best-powered BD polygenic scores to date, when applied in both European and diverse ancestry samples. Analyses of BD subtypes indicated high but imperfect genetic correlation between BD type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Published
2020

20. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author

Niamh, Mullins, Andreas J, Forstner, Kevin S, O'Connell, Brandon, Coombes, Jonathan R I, Coleman, Zhen, Qiao, Thomas D, Als, Tim B, Bigdeli, Sigrid, Børte, Julien, Bryois, Alexander W, Charney, Ole Kristian, Drange, Michael J, Gandal, Saskia P, Hagenaars, Masashi, Ikeda, Nolan, Kamitaki, Minsoo, Kim, Kristi, Krebs, Georgia, Panagiotaropoulou, Brian M, Schilder, Laura G, Sloofman, Stacy, Steinberg, Vassily, Trubetskoy, Bendik S, Winsvold, Hong-Hee, Won, Liliya, Abramova, Kristina, Adorjan, Esben, Agerbo, Mariam, Al Eissa, Diego, Albani, Ney, Alliey-Rodriguez, Adebayo, Anjorin, Verneri, Antilla, Anastasia, Antoniou, Swapnil, Awasthi, Ji Hyun, Baek, Marie, Bækvad-Hansen, Nicholas, Bass, Michael, Bauer, Eva C, Beins, Sarah E, Bergen, Armin, Birner, Carsten, Bøcker Pedersen, Erlend, Bøen, Marco P, Boks, Rosa, Bosch, Murielle, Brum, Ben M, Brumpton, Nathalie, Brunkhorst-Kanaan, Monika, Budde, Jonas, Bybjerg-Grauholm, William, Byerley, Murray, Cairns, Miquel, Casas, Pablo, Cervantes, Toni-Kim, Clarke, Cristiana, Cruceanu, Alfredo, Cuellar-Barboza, Julie, Cunningham, David, Curtis, Piotr M, Czerski, Anders M, Dale, Nina, Dalkner, Friederike S, David, Franziska, Degenhardt, Srdjan, Djurovic, Amanda L, Dobbyn, Athanassios, Douzenis, Torbjørn, Elvsåshagen, Valentina, Escott-Price, I Nicol, Ferrier, Alessia, Fiorentino, Tatiana M, Foroud, Liz, Forty, Josef, Frank, Oleksandr, Frei, Nelson B, Freimer, Louise, Frisén, Katrin, Gade, Julie, Garnham, Joel, Gelernter, Marianne, Giørtz Pedersen, Ian R, Gizer, Scott D, Gordon, Katherine, Gordon-Smith, Tiffany A, Greenwood, Jakob, Grove, José, Guzman-Parra, Kyooseob, Ha, Magnus, Haraldsson, Martin, Hautzinger, Urs, Heilbronner, Dennis, Hellgren, Stefan, Herms, Per, Hoffmann, Peter A, Holmans, Laura, Huckins, Stéphane, Jamain, Jessica S, Johnson, Janos L, Kalman, Yoichiro, Kamatani, James L, Kennedy, Sarah, Kittel-Schneider, James A, Knowles, Manolis, Kogevinas, Maria, Koromina, Thorsten M, Kranz, Henry R, Kranzler, Michiaki, Kubo, Ralph, Kupka, Steven A, Kushner, Catharina, Lavebratt, Jacob, Lawrence, Markus, Leber, Heon-Jeong, Lee, Phil H, Lee, Shawn E, Levy, Catrin, Lewis, Calwing, Liao, Susanne, Lucae, Martin, Lundberg, Donald J, MacIntyre, Sigurdur H, Magnusson, Wolfgang, Maier, Adam, Maihofer, Dolores, Malaspina, Eirini, Maratou, Lina, Martinsson, Manuel, Mattheisen, Steven A, McCarroll, Nathaniel W, McGregor, Peter, McGuffin, James D, McKay, Helena, Medeiros, Sarah E, Medland, Vincent, Millischer, Grant W, Montgomery, Jennifer L, Moran, Derek W, Morris, Thomas W, Mühleisen, Niamh, O'Brien, Claire, O'Donovan, Loes M, Olde Loohuis, Lilijana, Oruc, Sergi, Papiol, Antonio F, Pardiñas, Amy, Perry, Andrea, Pfennig, Evgenia, Porichi, James B, Potash, Digby, Quested, Towfique, Raj, Mark H, Rapaport, J Raymond, DePaulo, Eline J, Regeer, John P, Rice, Fabio, Rivas, Margarita, Rivera, Julian, Roth, Panos, Roussos, Douglas M, Ruderfer, Cristina, Sánchez-Mora, Eva C, Schulte, Fanny, Senner, Sally, Sharp, Paul D, Shilling, Engilbert, Sigurdsson, Lea, Sirignano, Claire, Slaney, Olav B, Smeland, Daniel J, Smith, Janet L, Sobell, Christine, Søholm Hansen, Maria, Soler Artigas, Anne T, Spijker, Dan J, Stein, John S, Strauss, Beata, Świątkowska, Chikashi, Terao, Thorgeir E, Thorgeirsson, Claudio, Toma, Paul, Tooney, Evangelia-Eirini, Tsermpini, Marquis P, Vawter, Helmut, Vedder, James T R, Walters, Stephanie H, Witt, Simon, Xi, Wei, Xu, Jessica Mei Kay, Yang, Allan H, Young, Hannah, Young, Peter P, Zandi, Hang, Zhou, Lea, Zillich, Rolf, Adolfsson, Ingrid, Agartz, Martin, Alda, Lars, Alfredsson, Gulja, Babadjanova, Lena, Backlund, Bernhard T, Baune, Frank, Bellivier, Susanne, Bengesser, Wade H, Berrettini, Douglas H R, Blackwood, Michael, Boehnke, Anders D, Børglum, Gerome, Breen, Vaughan J, Carr, Stanley, Catts, Aiden, Corvin, Nicholas, Craddock, Udo, Dannlowski, Dimitris, Dikeos, Tõnu, Esko, Bruno, Etain, Panagiotis, Ferentinos, Mark, Frye, Janice M, Fullerton, Micha, Gawlik, Elliot S, Gershon, Fernando S, Goes, Melissa J, Green, Maria, Grigoroiu-Serbanescu, Joanna, Hauser, Frans, Henskens, Jan, Hillert, Kyung Sue, Hong, David M, Hougaard, Christina M, Hultman, Kristian, Hveem, Nakao, Iwata, Assen V, Jablensky, Ian, Jones, Lisa A, Jones, René S, Kahn, John R, Kelsoe, George, Kirov, Mikael, Landén, Marion, Leboyer, Cathryn M, Lewis, Qingqin S, Li, Jolanta, Lissowska, Christine, Lochner, Carmel, Loughland, Nicholas G, Martin, Carol A, Mathews, Fermin, Mayoral, Susan L, McElroy, Andrew M, McIntosh, Francis J, McMahon, Ingrid, Melle, Patricia, Michie, Lili, Milani, Philip B, Mitchell, Gunnar, Morken, Ole, Mors, Preben Bo, Mortensen, Bryan, Mowry, Bertram, Müller-Myhsok, Richard M, Myers, Benjamin M, Neale, Caroline M, Nievergelt, Merete, Nordentoft, Markus M, Nöthen, Michael C, O'Donovan, Ketil J, Oedegaard, Tomas, Olsson, Michael J, Owen, Sara A, Paciga, Chris, Pantelis, Carlos, Pato, Michele T, Pato, George P, Patrinos, Roy H, Perlis, Danielle, Posthuma, Josep Antoni, Ramos-Quiroga, Andreas, Reif, Eva Z, Reininghaus, Marta, Ribasés, Marcella, Rietschel, Stephan, Ripke, Guy A, Rouleau, Takeo, Saito, Ulrich, Schall, Martin, Schalling, Peter R, Schofield, Thomas G, Schulze, Laura J, Scott, Rodney J, Scott, Alessandro, Serretti, Cynthia, Shannon Weickert, Jordan W, Smoller, Hreinn, Stefansson, Kari, Stefansson, Eystein, Stordal, Fabian, Streit, Patrick F, Sullivan, Gustavo, Turecki, Arne E, Vaaler, Eduard, Vieta, John B, Vincent, Irwin D, Waldman, Thomas W, Weickert, Thomas, Werge, Naomi R, Wray, John-Anker, Zwart, Joanna M, Biernacka, John I, Nurnberger, Sven, Cichon, Howard J, Edenberg, Eli A, Stahl, Andrew, McQuillin, Arianna, Di Florio, Roel A, Ophoff, and Ole A, Andreassen

Subjects
Major Histocompatibility Complex, Multifactorial Inheritance, Bipolar Disorder, Phenotype, Genome, Human, Risk Factors, Case-Control Studies, Quantitative Trait Loci, Chromosomes, Human, Humans, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Published
2020

21. The Genetics of the Mood Disorder Spectrum: Genome-wide Association Analyses of More Than 185,000 Cases and 439,000 Controls

Author

Jonathan R.I. Coleman, Héléna A. Gaspar, Julien Bryois, Gerome Breen, Enda M. Byrne, Andreas J. Forstner, Peter A. Holmans, Christiaan A. de Leeuw, Manuel Mattheisen, Andrew McQuillin, Jennifer M. Whitehead Pavlides, Tune H. Pers, Stephan Ripke, Eli A. Stahl, Stacy Steinberg, Vassily Trubetskoy, Maciej Trzaskowski, Yunpeng Wang, Liam Abbott, Abdel Abdellaoui, Mark J. Adams, Annelie Nordin Adolfsson, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D. Als, Till F.M. Andlauer, Adebayo Anjorin, Verneri Antilla, Sandra Van der Auwera, Swapnil Awasthi, Silviu-Alin Bacanu, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Aartjan T.F. Beekman, Richard Belliveau, Sarah E. Bergen, Tim B. Bigdeli, Elisabeth B. Binder, Erlend Bøen, Marco Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, William Byerley, Na Cai, Miquel Casas, Enrique Castelao, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Jane Hvarregaard Christensen, Claire Churchhouse, David St Clair, Toni-Kim Clarke, Lucía Colodro-Conde, William Coryell, Baptiste Couvy-Duchesne, David W. Craig, Gregory E. Crawford, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Gail Davies, Ian J. Deary, Franziska Degenhardt, Jurgen Del-Favero, J Raymond DePaulo, Eske M. Derks, Nese Direk, Srdjan Djurovic, Amanda L. Dobbyn, Conor V. Dolan, Ashley Dumont, Erin C. Dunn, Thalia C. Eley, Torbjørn Elvsåshagen, Valentina Escott-Price, Chun Chieh Fan, Hilary K. Finucane, Sascha B. Fischer, Matthew Flickinger, Jerome C. Foo, Tatiana M. Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B. Freimer, Louise Frisén, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Fernando S. Goes, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Jakob Grove, Weihua Guan, Lynsey S. Hall, Marian L. Hamshere, Christine Søholm Hansen, Thomas F. Hansen, Martin Hautzinger, Urs Heilbronner, Albert M. van Hemert, Stefan Herms, Ian B. Hickie, Maria Hipolito, Per Hoffmann, Dominic Holland, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, Laura Huckins, Marcus Ising, Stéphane Jamain, Rick Jansen, Jessica S. Johnson, Simone de Jong, Eric Jorgenson, Anders Juréus, Radhika Kandaswamy, Robert Karlsson, James L. Kennedy, Farnush Farhadi Hassan Kiadeh, Sarah Kittel-Schneider, James A. Knowles, Manolis Kogevinas, Isaac S. Kohane, Anna C. Koller, Julia Kraft, Warren W. Kretzschmar, Jesper Krogh, Ralph Kupka, Zoltán Kutalik, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Yihan Li, Penelope A. Lind, Chunyu Liu, Loes M. Olde Loohuis, Anna Maaser, Donald J. MacIntyre, Dean F. MacKinnon, Pamela B. Mahon, Wolfgang Maier, Robert M. Maier, Jonathan Marchini, Lina Martinsson, Hamdi Mbarek, Steve McCarroll, Patrick McGrath, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Divya Mehta, Fan Meng, Christel M. Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Saira Saeed Mirza, Francis M. Mondimore, Grant W. Montgomery, Derek W. Morris, Sara Mostafavi, Thomas W. Mühleisen, Niamh Mullins, Matthias Nauck, Bernard Ng, Hoang Nguyen, Caroline M. Nievergelt, Michel G. Nivard, Evaristus A. Nwulia, Dale R. Nyholt, Claire O'Donovan, Paul F. O'Reilly, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Hogni Oskarsson, Jodie N. Painter, José Guzman Parra, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Amy Perry, Roseann E. Peterson, Erik Pettersson, Wouter J. Peyrot, Andrea Pfennig, Giorgio Pistis, Shaun M. Purcell, Jorge A. Quiroz, Per Qvist, Eline J. Regeer, Andreas Reif, Céline S. Reinbold, John P. Rice, Brien P. Riley, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M. Ruderfer, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Robert Schoevers, Nicholas J. Schork, Eva C. Schulte, Tatyana Shehktman, Ling Shen, Jianxin Shi, Paul D. Shilling, Stanley I. Shyn, Engilbert Sigurdsson, Claire Slaney, Olav B. Smeland, Johannes H. Smit, Daniel J. Smith, Janet L. Sobell, Anne T. Spijker, Michael Steffens, John S. Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Robert C. Thompson, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, André G. Uitterlinden, Daniel Umbricht, Helmut Vedder, Alexander Viktorin, Peter M. Visscher, Weiqing Wang, Stanley J. Watson, Bradley T. Webb, Cynthia Shannon Weickert, Thomas W. Weickert, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Stephanie H. Witt, Yang Wu, Hualin S. Xi, Wei Xu, Jian Yang, Allan H. Young, Peter Zandi, Peng Zhang, Futao Zhang, Sebastian Zollner, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Volker Arolt, Lena Backlund, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Wade H. Berrettini, Joanna M. Biernacka, Douglas H.R. Blackwood, Michael Boehnke, Dorret I. Boomsma, Aiden Corvin, Nicholas Craddock, Mark J. Daly, Udo Dannlowski, Enrico Domenici, Katharina Domschke, Tõnu Esko, Bruno Etain, Mark Frye, Janice M. Fullerton, Elliot S. Gershon, E.J.C. de Geus, Michael Gill, Fernando Goes, Hans J. Grabe, Maria Grigoroiu-Serbanescu, Steven P. Hamilton, Joanna Hauser, Caroline Hayward, Andrew C. Heath, David M. Hougaard, Christina M. Hultman, Ian Jones, Lisa A. Jones, René S. Kahn, Kenneth S. Kendler, George Kirov, Stefan Kloiber, Mikael Landén, Marion Leboyer, Glyn Lewis, Qingqin S. Li, Jolanta Lissowska, Susanne Lucae, Pamela A.F. Madden, Patrik K. Magnusson, Nicholas G. Martin, Fermin Mayoral, Susan L. McElroy, Andrew M. McIntosh, Francis J. McMahon, Ingrid Melle, Andres Metspalu, Philip B. Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Richard M. Myers, Benjamin M. Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M. Nöthen, Michael C. O'Donovan, Ketil J. Oedegaard, Michael J. Owen, Sara A. Paciga, Carlos Pato, Michele T. Pato, Nancy L. Pedersen, Brenda W.J. H. Penninx, Roy H. Perlis, David J. Porteous, Danielle Posthuma, James B. Potash, Martin Preisig, Josep Antoni Ramos-Quiroga, Marta Ribasés, Marcella Rietschel, Guy A. Rouleau, Catherine Schaefer, Martin Schalling, Peter R. Schofield, Thomas G. Schulze, Alessandro Serretti, Jordan W. Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Henning Tiemeier, Gustavo Turecki, Rudolf Uher, Arne E. Vaaler, Eduard Vieta, John B. Vincent, Henry Völzke, Myrna M. Weissman, Thomas Werge, Ole A. Andreassen, Anders D. Børglum, Sven Cichon, Howard J. Edenberg, Arianna Di Florio, John Kelsoe, Douglas F. Levinson, Cathryn M. Lewis, John I. Nurnberger, Roel A. Ophoff, Laura J. Scott, Pamela Sklar, Patrick F. Sullivan, Naomi R. Wray, APH - Methodology, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Epidemiology, Erasmus MC other, Urology, Psychiatry, Internal Medicine, Medical Informatics, Immunology, Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, Coleman J.R.I., Gaspar H.A., Bryois J., Byrne E.M., Forstner A.J., Holmans P.A., de Leeuw C.A., Mattheisen M., McQuillin A., Whitehead Pavlides J.M., Pers T.H., Ripke S., Stahl E.A., Steinberg S., Trubetskoy V., Trzaskowski M., Wang Y., Abbott L., Abdellaoui A., Adams M.J., Adolfsson A.N., Agerbo E., Akil H., Albani D., Alliey-Rodriguez N., Als T.D., Andlauer T.F.M., Anjorin A., Antilla V., Van der Auwera S., Awasthi S., Bacanu S.-A., Badner J.A., Baekvad-Hansen M., Barchas J.D., Bass N., Bauer M., Beekman A.T.F., Belliveau R., Bergen S.E., Bigdeli T.B., Binder E.B., Boen E., Boks M., Boocock J., Budde M., Bunney W., Burmeister M., Buttenschon H.N., Bybjerg-Grauholm J., Byerley W., Cai N., Casas M., Castelao E., Cerrato F., Cervantes P., Chambert K., Charney A.W., Chen D., Christensen J.H., Churchhouse C., St Clair D., Clarke T.-K., Colodro-Conde L., Coryell W., Couvy-Duchesne B., Craig D.W., Crawford G.E., Cruceanu C., Czerski P.M., Dale A.M., Davies G., Deary I.J., Degenhardt F., Del-Favero J., DePaulo J.R., Derks E.M., Direk N., Djurovic S., Dobbyn A.L., Dolan C.V., Dumont A., Dunn E.C., Eley T.C., Elvsashagen T., Escott-Price V., Fan C.C., Finucane H.K., Fischer S.B., Flickinger M., Foo J.C., Foroud T.M., Forty L., Frank J., Fraser C., Freimer N.B., Frisen L., Gade K., Gage D., Garnham J., Giambartolomei C., Goes F.S., Goldstein J., Gordon S.D., Gordon-Smith K., Green E.K., Green M.J., Greenwood T.A., Grove J., Guan W., Hall L.S., Hamshere M.L., Hansen C.S., Hansen T.F., Hautzinger M., Heilbronner U., van Hemert A.M., Herms S., Hickie I.B., Hipolito M., Hoffmann P., Holland D., Homuth G., Horn C., Hottenga J.-J., Huckins L., Ising M., Jamain S., Jansen R., Johnson J.S., de Jong S., Jorgenson E., Jureus A., Kandaswamy R., Karlsson R., Kennedy J.L., Hassan Kiadeh F.F., Kittel-Schneider S., Knowles J.A., Kogevinas M., Kohane I.S., Koller A.C., Kraft J., Kretzschmar W.W., Krogh J., Kupka R., Kutalik Z., Lavebratt C., Lawrence J., Lawson W.B., Leber M., Lee P.H., Levy S.E., Li J.Z., Li Y., Lind P.A., Liu C., Olde Loohuis L.M., Maaser A., MacIntyre D.J., MacKinnon D.F., Mahon P.B., Maier W., Maier R.M., Marchini J., Martinsson L., Mbarek H., McCarroll S., McGrath P., McGuffin P., McInnis M.G., McKay J.D., Medeiros H., Medland S.E., Mehta D., Meng F., Middeldorp C.M., Mihailov E., Milaneschi Y., Milani L., Mirza S.S., Mondimore F.M., Montgomery G.W., Morris D.W., Mostafavi S., Muhleisen T.W., Mullins N., Nauck M., Ng B., Nguyen H., Nievergelt C.M., Nivard M.G., Nwulia E.A., Nyholt D.R., O'Donovan C., O'Reilly P.F., Ori A.P.S., Oruc L., Osby U., Oskarsson H., Painter J.N., Parra J.G., Pedersen C.B., Pedersen M.G., Perry A., Peterson R.E., Pettersson E., Peyrot W.J., Pfennig A., Pistis G., Purcell S.M., Quiroz J.A., Qvist P., Regeer E.J., Reif A., Reinbold C.S., Rice J.P., Riley B.P., Rivas F., Rivera M., Roussos P., Ruderfer D.M., Ryu E., Sanchez-Mora C., Schatzberg A.F., Scheftner W.A., Schoevers R., Schork N.J., Schulte E.C., Shehktman T., Shen L., Shi J., Shilling P.D., Shyn S.I., Sigurdsson E., Slaney C., Smeland O.B., Smit J.H., Smith D.J., Sobell J.L., Spijker A.T., Steffens M., Strauss J.S., Streit F., Strohmaier J., Szelinger S., Tansey K.E., Teismann H., Teumer A., Thompson R.C., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Treutlein J., Uitterlinden A.G., Umbricht D., Vedder H., Viktorin A., Visscher P.M., Wang W., Watson S.J., Webb B.T., Weickert C.S., Weickert T.W., Weinsheimer S.M., Wellmann J., Willemsen G., Witt S.H., Wu Y., Xi H.S., Xu W., Yang J., Young A.H., Zandi P., Zhang P., Zhang F., Zollner S., Adolfsson R., Agartz I., Alda M., Arolt V., Backlund L., Baune B.T., Bellivier F., Berger K., Berrettini W.H., Biernacka J.M., Blackwood D.H.R., Boehnke M., Boomsma D.I., Corvin A., Craddock N., Daly M.J., Dannlowski U., Domenici E., Domschke K., Esko T., Etain B., Frye M., Fullerton J.M., Gershon E.S., de Geus E.J.C., Gill M., Goes F., Grabe H.J., Grigoroiu-Serbanescu M., Hamilton S.P., Hauser J., Hayward C., Heath A.C., Hougaard D.M., Hultman C.M., Jones I., Jones L.A., Kahn R.S., Kendler K.S., Kirov G., Kloiber S., Landen M., Leboyer M., Lewis G., Li Q.S., Lissowska J., Lucae S., Madden P.A.F., Magnusson P.K., Martin N.G., Mayoral F., McElroy S.L., McIntosh A.M., McMahon F.J., Melle I., Metspalu A., Mitchell P.B., Morken G., Mors O., Mortensen P.B., Muller-Myhsok B., Myers R.M., Neale B.M., Nimgaonkar V., Nordentoft M., Nothen M.M., O'Donovan M.C., Oedegaard K.J., Owen M.J., Paciga S.A., Pato C., Pato M.T., Pedersen N.L., Penninx B.W.J.H., Perlis R.H., Porteous D.J., Posthuma D., Potash J.B., Preisig M., Ramos-Quiroga J.A., Ribases M., Rietschel M., Rouleau G.A., Schaefer C., Schalling M., Schofield P.R., Schulze T.G., Serretti A., Smoller J.W., Stefansson H., Stefansson K., Stordal E., Tiemeier H., Turecki G., Uher R., Vaaler A.E., Vieta E., Vincent J.B., Volzke H., Weissman M.M., Werge T., Andreassen O.A., Borglum A.D., Cichon S., Edenberg H.J., Di Florio A., Kelsoe J., Levinson D.F., Lewis C.M., Nurnberger J.I., Ophoff R.A., Scott L.J., Sklar P., Sullivan P.F., Wray N.R., and Breen G.

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Genetic correlation, Genome-wide association study, Mood Disorder, Bipolar disorder, Population, BF, Genomics, Major depressive disorder, Affective disorder, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, mental disorders, medicine, Animals, ddc:610, education, Depression (differential diagnoses), Biological Psychiatry, 030304 developmental biology, Genetic association, Genetics, Depressive Disorder, Major, 0303 health sciences, education.field_of_study, Animal, business.industry, Risk Factor, medicine.disease, 3. Good health, Affective disorders, 030104 developmental biology, Mood, Mood disorders, RC0321, Biological psychiatry, business, 030217 neurology & neurosurgery, Clinical psychology
Abstract

BackgroundMood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders.MethodsTo clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424).ResultsSeventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder.ConclusionsThe mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum.

Published
2020

22. Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder

Author

Marco Pinna, Claire O'Donovan, Pablo Cervantes, Leonardo Tondo, Maria Del Zompo, Tomas Hajek, Paul Grof, Bruno Müller-Oerlinghausen, Alessio Squassina, Andreas J. Forstner, Julie Garnham, Giovanni Severino, Alberto Bocchetta, Mirko Manchia, Marcella Rietschel, Caterina Chillotti, Guy A. Rouleau, Francis J. McMahon, Martin Alda, Markus M. Nöthen, Anne Berghöfer, P. Zvolsky, Thomas G. Schulze, Will Stone, Manuel Mattheisen, Raffaella Ardau, Eva Grof, Rudolf Uher, Claudia Pisanu, Franziska Degenhardt, Valeria Deiana, Thomas Trappenberg, Claire Slaney, Aleksandra Suwalska, Janusz K. Rybakowski, Abraham Nunes, and Gustavo Turecki

Subjects
Oncology, Psychosis, medicine.medical_specialty, Bipolar Disorder, Lithium (medication), education, Lithium, Predictive markers, Article, lcsh:RC321-571, Cellular and Molecular Neuroscience, Text mining, Antimanic Agents, Internal medicine, medicine, Humans, Bipolar disorder, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Receiver operating characteristic, Genetic heterogeneity, business.industry, medicine.disease, Phenotype, Personalized medicine, Psychiatry and Mental health, Mood, Lithium Compounds, business, medicine.drug
Abstract

Predicting lithium response (LiR) in bipolar disorder (BD) may inform treatment planning, but phenotypic heterogeneity complicates discovery of genomic markers. We hypothesized that patients with “exemplary phenotypes”—those whose clinical features are reliably associated with LiR and non-response (LiNR)—are more genetically separable than those with less exemplary phenotypes. Using clinical data collected from people with BD (n = 1266 across 7 centers; 34.7% responders), we computed a “clinical exemplar score,” which measures the degree to which a subject’s clinical phenotype is reliably predictive of LiR/LiNR. For patients whose genotypes were available (n = 321), we evaluated whether a subgroup of responders/non-responders with the top 25% of clinical exemplar scores (the “best clinical exemplars”) were more accurately classified based on genetic data, compared to a subgroup with the lowest 25% of clinical exemplar scores (the “poor clinical exemplars”). On average, the best clinical exemplars of LiR had a later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best clinical exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR [0.83, 0.98]), compared to 0.66 [0.61, 0.80] (p = 0.0032) among poor clinical exemplars. Variants in the Alzheimer’s amyloid–secretase pathway, along with G-protein-coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were informative predictors. This study must be replicated on larger samples and extended to predict response to other mood stabilizers.

Published
2020

23. The association between lithium use and neurocognitive performance in patients with bipolar disorder

Author

Toyomi Goto, Caitlin E. Millett, Nicole Frazier, Ney Alliey-Rodriguez, Else-Marie Løberg, Kara Glazer, John R. Kelsoe, Martha Shaw, Julie Garnham, Carrie Fisher, Falk W. Lohoff, Candice L. Schwebel, Anna DeModena, Petter Jakobsen, Mark A. Frye, Michael McCarthy, Melvin G. McInnis, Paul D. Shilling, Ketil J. Oedegaard, Katherine E. Burdick, Yokesh Balaraman, Scott E. Feeder, Cynthia V. Calkin, Amit Anand, Gloria Harrington, Manuela Russo, Emma K. Stapp, Martha Schinagle, Wade H. Berrettini, Peter P. Zandi, Marisa Kelly, Claire Slaney, Carla Conroy, Joseph R. Calabrese, Bruce Tarwater, Susan G. Leckband, Fernando S. Goes, Kelly A. Ryan, Abigail Ortiz, John I. Nurnberger, Megan Ritchey, Gunnar Morken, Caroline M. Nievergelt, Martin Alda, Holli Bertram, Elliot S. Gershon, William Coryell, Keming Gao, Adam X. Maihofer, and Masoud Kamali

Subjects
medicine.medical_specialty, Bipolar Disorder, Lithium (medication), Clinical Trials and Supportive Activities, Lithium, Neuropsychological Tests, Medical and Health Sciences, Article, Treatment of bipolar disorder, 03 medical and health sciences, 0302 clinical medicine, Cognition, Clinical Research, Internal medicine, Behavioral and Social Science, medicine, Humans, Bipolar disorder, Pharmacology, Psychiatry, California Verbal Learning Test, business.industry, Psychology and Cognitive Sciences, Wechsler Adult Intelligence Scale, medicine.disease, Serious Mental Illness, 030227 psychiatry, Brain Disorders, Psychiatry and Mental health, Mood, Mental Health, Cross-Sectional Studies, business, Neurocognitive, 030217 neurology & neurosurgery, medicine.drug
Abstract

Lithium remains the gold standard for the treatment of bipolar disorder (BD); however, its use has declined over the years mainly due to the side effects and the subjective experience of cognitive numbness reported by patients. In the present study, we aim to methodically test the effects of lithium on neurocognitive functioning in the largest single cohort (n = 262) of BD patients reported to date by harnessing the power of a multi-site, ongoing clinical trial of lithium monotherapy. At the cross-sectional level, multivariate analysis of covariance (MANCOVA) was conducted to examine potential group differences across neurocognitive tests [California Verbal Learning Test (CVLT trials 1–5,CVLT delayed recall), Wechsler Digit Symbol, Trail-making Test parts A and B (TMT-A; TMT-B), and a global cognition index]. At the longitudinal level, on a subset of patients (n = 88) who achieved mood stabilization with lithium monotherapy, we explored the effect of lithium treatment across time on neurocognitive functioning. There were no differences at baseline between BD patients that were taking lithium compared with those that were not. At follow-up a significant neurocognitive improvement in the global cognitive index score [F = 31.69; p

Published
2020

24. Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study

Author

Francis M. Mondimore, Farah Klohn-Sagatholislam, Jana Strohmaier, Jens Wiltfang, Jay Raymond DePaulo, Udo Dannlowski, Markus Jäger, Moritz E. Wigand, Ion Anghelescu, Michael Bauer, Louise Frisén, Ashley L. Comes, Carsten Spitzer, Claire Slaney, Janice M. Fullerton, Giovanni Severino, Janusz K. Rybakowski, Andreas J. Fallgatter, Maria Hake, Martin Alda, Peter R. Schofield, Susanne Bengesser, Nirmala Akula, Stefan Herms, Paul D. Shilling, Franziska Degenhardt, Mazda Adli, Armin Birner, Alexandre Dayer, Cristiana Cruceanu, Fanny Senner, Peter Falkai, Maria Del Zompo, Mark A. Frye, Christian Simhandl, Stéphane Jamain, Andrea Pfennig, Layla Kassem, Sébastien Gard, Heike Anderson-Schmidt, Marion Leboyer, Peter P. Zandi, Susan L. McElroy, Martin Schalling, Sebastian Stierl, Detlef E. Dietrich, Frank Bellivier, Palmiero Monteleone, Sybille Schulz, Caterina Chillotti, Volker Arolt, Michael McCarthy, Alfonso Tortorella, Andreas Thiel, Marcella Rietschel, Kristina Adorjan, Tatyana Shekhtman, Maria Grigoroiu-Serbanescu, Jean-Michel Aubry, Daniela Reich-Erkelenz, Laura Flatau, Markus Reitt, Harald Scherk, Here Folkerts, Julia Veeh, Joanna Hauser, Fernando S. Goes, Philip B. Mitchell, Gustavo Turecki, John R. Kelsoe, Thomas Stamm, Sophia Stegmaier, Georg Juckel, Markus M. Nöthen, Lina Martinsson, Bárbara Arias, Vanessa Nieratschker, Clara Brichant-Petitjean, Antonio Benabarre, Bernhard T. Baune, James B. Potash, Urs Heilbronner, Caroline M. Nievergelt, Raffaella Ardau, Mikael Landén, Pablo Cervantes, Pavla Stopkova, Adam Wright, Tomas Novak, Scott R. Clark, Manfred Koller, Gonzalo Laje, Katrin Gade, Andreas J. Forstner, Sarah Kittel-Schneider, Susan G. Leckband, Sebastian Kliwicki, Guy A. Rouleau, Kim Bartholdi, Martin von Hagen, Per Hoffmann, Eva C. Schulte, Alessio Squassina, Monika Budde, Thomas G. Schulze, Eduard Vieta, Liping Hou, Jörg Zimmermann, Barbara König, Stephan Ripke, Sarah K. Tighe, Jean-Pierre Kahn, Julie Garnham, Piotr M. Czerski, Janos Kalman, Anna Gryaznova, Francis J. McMahon, Mario Maj, Thomas Becker, Thomas Ethofer, Andreas Reif, Carsten Konrad, Mirko Manchia, Lena Backlund, Jens Reimer, Urban Ösby, Esther Jiménez, Abesh Kumar Bhattacharjee, Marina Mitjans, Sergi Papiol, Stephanie H. Witt, Sven Cichon, Bruno Etain, Till F. M. Andlauer, Joanna M. Biernacka, Max Schmauß, Christian Figge, Fabian U. Lang, N. Lackner, Eva Z. Reininghaus, Francesc Colom, Catharina Lavebratt, K Oliver Schubert, Kalman, Janos L, Papiol, Sergi, Forstner, Andreas J, Heilbronner, Ur, Degenhardt, Franziska, Strohmaier, Jana, Adli, Mazda, Adorjan, Kristina, Akula, Nirmala, Alda, Martin, Anderson-Schmidt, Heike, Andlauer, Till Fm, Anghelescu, Ion-George, Ardau, Raffaella, Arias, Bárbara, Arolt, Volker, Aubry, Jean-Michel, Backlund, Lena, Bartholdi, Kim, Bauer, Michael, Baune, Bernhard T, Becker, Thoma, Bellivier, Frank, Benabarre, Antonio, Bengesser, Susanne, Bhattacharjee, Abesh Kumar, Biernacka, Joanna M, Birner, Armin, Brichant-Petitjean, Clara, Budde, Monika, Cervantes, Pablo, Chillotti, Caterina, Cichon, Sven, Clark, Scott R, Colom, Francesc, Comes, Ashley L, Cruceanu, Cristiana, Czerski, Piotr M, Dannlowski, Udo, Dayer, Alexandre, Del Zompo, Maria, Depaulo, Jay Raymond, Dietrich, Detlef E, Étain, Bruno, Ethofer, Thoma, Falkai, Peter, Fallgatter, Andrea, Figge, Christian, Flatau, Laura, Folkerts, Here, Frisen, Louise, Frye, Mark A, Fullerton, Janice M, Gade, Katrin, Gard, Sébastien, Garnham, Julie S, Goes, Fernando S, Grigoroiu-Serbanescu, Maria, Gryaznova, Anna, Hake, Maria, Hauser, Joanna, Herms, Stefan, Hoffmann, Per, Hou, Liping, Jäger, Marku, Jamain, Stephane, Jiménez, Esther, Juckel, Georg, Kahn, Jean-Pierre, Kassem, Layla, Kelsoe, John, Kittel-Schneider, Sarah, Kliwicki, Sebastian, Klohn-Sagatholislam, Farah, Koller, Manfred, König, Barbara, Konrad, Carsten, Lackner, Nina, Laje, Gonzalo, Landén, Mikael, Lang, Fabian U, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G, Maj, Mario, Manchia, Mirko, Martinsson, Lina, Mccarthy, Michael J, Mcelroy, Susan L, Mcmahon, Francis J, Mitchell, Philip B, Mitjans, Marina, Mondimore, Francis M, Monteleone, Palmiero, Nieratschker, Vanessa, Nievergelt, Caroline M, Novák, Toma, Ösby, Urban, Pfennig, Andrea, Potash, James B, Reich-Erkelenz, Daniela, Reif, Andrea, Reimer, Jen, Reininghaus, Eva, Reitt, Marku, Ripke, Stephan, Rouleau, Guy A, Rybakowski, Janusz K, Schalling, Martin, Scherk, Harald, Schmauß, Max, Schofield, Peter R, Schubert, K Oliver, Schulte, Eva C, Schulz, Sybille, Senner, Fanny, Severino, Giovanni, Shekhtman, Tatyana, Shilling, Paul D, Simhandl, Christian, Slaney, Claire M, Spitzer, Carsten, Squassina, Alessio, Stamm, Thoma, Stegmaier, Sophia, Stierl, Sebastian, Stopkova, Pavla, Thiel, Andrea, Tighe, Sarah K, Tortorella, Alfonso, Turecki, Gustavo, Vieta, Eduard, Veeh, Julia, von Hagen, Martin, Wigand, Moritz E, Wiltfang, Jen, Witt, Stephanie, Wright, Adam, Zandi, Peter P, Zimmermann, Jörg, Nöthen, Marku, Rietschel, Marcella, and Schulze, Thomas G

Subjects
Adult, Male, Oncology, Multifactorial Inheritance, medicine.medical_specialty, Schizophrenia/genetics, Disease onset, Adolescent, early onset, Late onset, ddc:616.89, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Bipolar disorder, Child, Research Articles, Biological Psychiatry, bipolar disorder, Trastorn bipolar, business.industry, Bipolar Disorder/genetics, age at onset, polygenic risk score, schizophrenia, Age Factors, Bipolar Disorder, Female, Middle Aged, Phenotype, Schizophrenia, Original Articles, medicine.disease, Genetic architecture, 030227 psychiatry, Psychiatry and Mental health, Institutional repository, Clinical research, Esquizofrènia, Original Article, business, 030217 neurology & neurosurgery
Abstract

OBJECTIVES: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients. METHODS: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models. RESULTS: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. CONCLUSIONS: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype. peerReviewed

Published
2018

25. Evaluation of the SARS-CoV-2 Antibody Response to the BNT162b2 Vaccine in Patients Undergoing Hemodialysis

Author

Alyson Takaoka, Anne-Claude Gingras, Jerome A. Leis, Michelle A. Hladunewich, Tatjana Sukovic, Kento T. Abe, Sarah I. Mullin, Allison McGeer, Vanessa Tran, Christopher T. Chan, Kevin Yau, Julie Garnham-Takaoka, Ellen Shadowitz, Anny Gonzalez, David Naimark, Sharon E. Straus, Shelly Bolotin, Jeffrey Perl, Keelia Quinn De Launay, Karen Colwill, and Matthew J. Oliver

Subjects
Male, medicine.medical_specialty, COVID-19 Vaccines, medicine.medical_treatment, Population, Dose-Response Relationship, Immunologic, Renal Dialysis, Interquartile range, Internal medicine, medicine, Humans, Prospective Studies, Seroconversion, Prospective cohort study, education, Pandemics, BNT162 Vaccine, Original Investigation, Aged, Aged, 80 and over, education.field_of_study, SARS-CoV-2, business.industry, Research, Mortality rate, COVID-19, General Medicine, medicine.disease, Vaccination, Online Only, Nephrology, Case-Control Studies, Immunoglobulin G, Spike Glycoprotein, Coronavirus, Female, Hemodialysis, business, Kidney disease
Abstract

Key Points Question What is the serologic response to the BNT162b2 COVID-19 vaccine in patients undergoing hemodialysis? Findings In this cohort study of 142 patients receiving hemodialysis, humoral response was compared in 66 patients sampled 28 days after receipt of 1 dose of vaccine with 76 patients who received 2 doses of vaccine sampled 14 days after the second dose. Among those receiving 1 dose, 6% had antireceptor binding domain response above the median level of convalescent serum vs 41% of those who received 2 doses at 1 week, increasing to 60% by 2 weeks. Meaning The findings of this study suggest that, given that patients receiving hemodialysis appeared to exhibit a poor humoral response to a single dose of BNT162b2 vaccine, the second dose should not be delayed., Importance Patients undergoing hemodialysis have a high mortality rate associated with COVID-19, and this patient population often has a poor response to vaccinations. Randomized clinical trials for COVID-19 vaccines included few patients with kidney disease; therefore, vaccine immunogenicity is uncertain in this population. Objective To evaluate the SARS-CoV-2 antibody response in patients undergoing chronic hemodialysis following 1 vs 2 doses of BNT162b2 COVID-19 vaccination compared with health care workers serving as controls and convalescent serum. Design, Setting, and Participants A prospective, single-center cohort study was conducted between February 2 and April 17, 2021, in Toronto, Ontario, Canada. Participants included 142 patients receiving in-center hemodialysis and 35 health care worker controls. Exposures BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine. Main Outcomes and Measures SARS-CoV-2 IgG antibodies to the spike protein (anti-spike), receptor binding domain (anti-RBD), and nucleocapsid protein (anti-NP). Results Among the 142 participants undergoing maintenance hemodialysis, 94 (66%) were men; median age was 72 (interquartile range, 62-79) years. SARS-CoV-2 IgG antibodies were measured in 66 patients receiving 1 vaccine dose following a public health policy change, 76 patients receiving 2 vaccine doses, and 35 health care workers receiving 2 vaccine doses. Detectable anti-NP suggestive of natural SARS-CoV-2 infection was detected in 15 of 142 (11%) patients at baseline, and only 3 patients had prior COVID-19 confirmed by reverse transcriptase polymerase chain reaction testing. Two additional patients contracted COVID-19 after receiving 2 doses of vaccine. In 66 patients receiving a single BNT162b2 dose, seroconversion occurred in 53 (80%) for anti-spike and 36 (55%) for anti-RBD by 28 days postdose, but a robust response, defined by reaching the median levels of antibodies in convalescent serum from COVID-19 survivors, was noted in only 15 patients (23%) for anti-spike and 4 (6%) for anti-RBD in convalescent serum from COVID-19 survivors. In patients receiving 2 doses of BNT162b2 vaccine, seroconversion occurred in 69 of 72 (96%) for anti-spike and 63 of 72 (88%) for anti-RBD by 2 weeks following the second dose and median convalescent serum levels were reached in 52 of 72 patients (72%) for anti-spike and 43 of 72 (60%) for anti-RBD. In contrast, all 35 health care workers exceeded the median level of anti-spike and anti-RBD found in convalescent serum 2 to 4 weeks after the second dose. Conclusions and Relevance This study suggests poor immunogenicity 28 days following a single dose of BNT162b2 vaccine in the hemodialysis population, supporting adherence to recommended vaccination schedules and avoiding delay of the second dose in these at-risk individuals., This cohort study examines the immune response of patients receiving maintenance hemodialysis to vaccination with 1 vs 2 doses of the BNT162b2 vaccine.

Published
2021

27. Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder

Author

Yokesh Balaraman, Gloria Harrington, Julie Garnham, Petter Jakobsen, David K. Welsh, Szabolcs Szelinger, Martin Alda, Ney Alliey-Rodriguez, Susan G. Leckband, Ole A. Andreasson, Nicole Frazier, Abigail Ortiz, Clara Conroy, Holli Bertram, Marisa Kelly, Sarah Obral, Joseph R. Calabrese, Bruce Tarwater, Claire Slaney, Andrea Stautland, Paul D. Shilling, David Craig, Candice L. Schwebel, Cynthia V. Calkin, Scott E. Feeder, Toyomi Goto, Emma K. Stapp, Heather Wei, Elizabeth Karberg, Caroline M. Nievergelt, Melvin G. McInnis, Anna DeModena, Nicole D'Arcangelo, Kelly A. Ryan, Wade H. Berrettini, Peter P. Zandi, Keming Gao, Martha Schinagle, Michael McCarthy, Ana M. Claasen, Ketil J. Oedegaard, John I. Nurnberger, Megan Ritchey, Kristen J. Brennand, Carrie Fisher, Mark A. Frye, Fred H. Gage, John R. Kelsoe, Gunnar Morken, Fernando S. Goes, Masoud Kamali, Francis M. Mondimore, Adam X. Maihofer, Amit Anand, Tatyana Shekhtman, William Coryell, Kara Glazer, Martha Shaw, Elliot S. Gershon, Falk W. Lohoff, Srdjan Djurovic, and Helle K. Schoeyen

Subjects
Bipolar Disorder, Lithium (medication), Genotyping Techniques, Medical and Health Sciences, Mice, 0302 clinical medicine, Antimanic Agents, Inositol 1,4,5-Trisphosphate Receptors, Prospective Studies, Cells, Cultured, 5-Trisphosphate Receptors, Psychiatry, Cultured, Depression, Mood stabilizer, Single Nucleotide, Period Circadian Proteins, Serious Mental Illness, Circadian Rhythm, Psychiatry and Mental health, Mental Health, Lithium Compounds, medicine.symptom, Sleep Research, Mania, medicine.drug, Adult, medicine.medical_specialty, medicine.drug_class, Period (gene), Cells, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Clinical Research, Internal medicine, medicine, Animals, Humans, Circadian rhythm, Bipolar disorder, Polymorphism, Pharmacology, business.industry, Psychology and Cognitive Sciences, Chronotype, Fibroblasts, medicine.disease, Inositol 1, 030227 psychiatry, Brain Disorders, Endocrinology, Luminescent Measurements, NIH 3T3 Cells, business, 030217 neurology & neurosurgery
Abstract

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patients, we measured circadian rhythms in fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-R patients were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD. © 2018. This is the authors’ accepted and refereed manuscript to the article. Locked until 16.5.2019 due to copyright restrictions.

Published
2019

28. Polygenic scores for major depressive disorder and depressive symptoms predict response to lithium in patients with bipolar disorder

Author

Michael McCarthy, Alfonso Tortorella, Jean-Michel Aubry, James B. Potash, Hsi-Chung Chen, Eduard Vieta, Claire Slaney, Frank Bellivier, Claire O'Donovan, Palmiero Monteleone, Alexandre Dayer, Lena Backlund, Michael Bauer, Nina Dalkner, Christian Simhandl, Liping Hou, Katzutaka Shimoda, Cristiana Cruceanu, Janusz K. Rybakowski, Lina Martinsson, Gonzalo Laje, Susan G. Leckband, Andrea Hofmann, Micah Cearns, Eva Z. Reininghaus, Barbara W. Schweizer, Pablo Cervantes, Marcella Rietschel, Ryota Hashimoto, Paul Grof, Tomas Novak, Yi-Hsiang Hsu, Stephanie H. Witt, John R. Kelsoe, Julia Veeh, Thomas Stamm, Francesc Colom, Catharina Lavebratt, Adam Wright, Maria Grigoroiu-Serbanescu, Philip B. Mitchell, Ichiro Kusumi, Sarah Kittel-Schneider, Urs Heilbronner, Julie Garnham, Sven Cichon, Layla Kassem, Norio Ozaki, Piotr M. Czerski, Markus M. Nöthen, Peter Falkai, Bruno Etain, Mirko Manchia, Joanna Hauser, Urban Ösby, Caroline M. Nievergelt, Fasil Tekola-Ayele, Stéphane Jamain, Thomas G. Schulze, Clara Brichant-Petitjean, Antonio Benabarre, Bernhard T. Baune, Esther Jiménez, Joanna M. Biernacka, Paul D. Shilling, Caterina Chillotti, Barbara König, Abesh Kumar Bhattacharjee, Scott R. Clark, Andrea Pfennig, Mazda Adli, Raffaella Ardau, Marina Mitjans, Armin Birner, Andreas Reif, Sergi Papiol, Mario Maj, Giovanni Severino, Martin Schalling, Fernando S. Goes, Susan L. McElroy, Franziska Degenhardt, Louise Frisén, Pavla Stopkova, Peter P. Zandi, J. Raymond DePaulo, Martin Alda, Peter R. Schofield, Per Hoffmann, Susanne Bengesser, Stefan Herms, Klaus Oliver Schubert, Sebastian Kliwicki, Guy A. Rouleau, Andreas J. Forstner, Gustavo Turecki, Bárbara Arias, Azmeraw T. Amare, Marion Leboyer, Maria Del Zompo, Po-Hsiu Kuo, Nirmala Akula, Francis M. Mondimore, Sébastien Gard, Mark A. Frye, Mikael Landén, Alessio Squassina, Jean-Pierre Kahn, Francis J. McMahon, Kazufumi Akiyama, Tadafumi Kato, Tatyana Shekhtman, and Janice M. Fullerton

Subjects
Oncology, medicine.medical_specialty, Lithium (medication), business.industry, Genome-wide association study, Logistic regression, medicine.disease, 030227 psychiatry, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Quartile, Internal medicine, Medicine, Major depressive disorder, Bipolar disorder, business, 030217 neurology & neurosurgery, Depression (differential diagnoses), medicine.drug, Genetic association
Abstract

BackgroundLithium is a first-line medication for bipolar disorder (BD), but only ~30% of patients respond optimally to the drug. Since genetic factors are known to mediate lithium treatment response, we hypothesized whether polygenic susceptibility to the spectrum of depression traits is associated with treatment outcomes in patients with BD. In addition, we explored the potential molecular underpinnings of this relationship.MethodsWeighted polygenic scores (PGSs) were computed for major depressive disorder (MDD) and depressive symptoms (DS) in BD patients from the Consortium on Lithium Genetics (ConLi+Gen; n=2,586) who received lithium treatment. Lithium treatment outcome was assessed using the ALDA scale. Summary statistics from genome-wide association studies (GWAS) in MDD (130,664 cases and 330,470 controls) and DS (n=161,460) were used for PGS weighting. Associations between PGSs of depression traits and lithium treatment response were assessed by binary logistic regression. We also performed a cross-trait meta-GWAS, followed by Ingenuity® Pathway Analysis.OutcomesBD patients with a low polygenic load for depressive traits were more likely to respond well to lithium, compared to patients with high polygenic load (MDD: OR =1.64 [95%CI: 1.26-2.15], lowest vs highest PGS quartiles; DS: OR=1.53 [95%CI: 1.18-2.00]). Associations were significant for type 1, but not type 2 BD. Cross-trait GWAS and functional characterization implicated voltage-gated potassium channels, insulin-related pathways, mitogen-activated protein-kinase (MAPK) signaling, and miRNA expression.InterpretationGenetic loading to depression traits in BD patients lower their odds of responding optimally to lithium. Our findings support the emerging concept of a lithium-responsive biotype in BD.FundingSee attached details

Published
2018
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29. Nonlinear dynamics of mood regulation in unaffected first-degree relatives of bipolar disorder patients

Author

Martin Alda, Julie Garnham, Claire Slaney, Kamil Bradler, McLean S, and Abigail Ortiz

Subjects
Adult, Male, medicine.medical_specialty, Bipolar Disorder, Visual Analog Scale, Visual analogue scale, Audiology, Anxiety, Self-Control, 03 medical and health sciences, 0302 clinical medicine, Healthy control, Or education, medicine, Humans, Bipolar disorder, First-degree relatives, business.industry, Low resolution, Middle Aged, medicine.disease, Cyclothymic Disorder, 030227 psychiatry, Psychiatry and Mental health, Clinical Psychology, Affect, Mood, Nonlinear Dynamics, Case-Control Studies, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Mood regulation is a complex and poorly understood process. In this study, we aimed to analyze the underlying dynamics of mood regulation in unaffected first degree relatives of patients diagnosed with bipolar disorder using time-series analysis.We recruited 30 unaffected first-degree relatives of bipolar disorder patients. Participants rated their mood, anxiety and energy levels using a paper-based visual analog scale; they recorded their sleep and life events as well. Participants provided information on these variables over a three month period, twice per day. We compared their data using Box-Jenkins time series analysis with data from 30 healthy controls (HC) and 30 euthymic bipolar patients (BD) to obtain information on the autocorrelation and cross-correlation of the series, and calculated entropy for mood, anxiety and energy series.We analyzed 14,980 data points: 5200 in the healthy control group; 4970 in the bipolar group and 4810 in the unaffected relatives group. There were no significant differences between groups in terms of age, sex or education levels. Using Kolmogorov-Smirnov test, we found that individual measures were normally distributed in the whole sample (D = 0.23, p 0.1). Autocorrelation functions for mood in all groups are governed by the ARIMA (1,1,0) model, which means that current values in the series are related to one previous point only. In terms of entropy for the mood series, unaffected relatives and bipolar patients showed lower values [mean (SD) : 1.028 ± 0.679; 1.042 ± 0.680], respectively, compared to healthy controls [(1.476 ± 0.33); F (2,74) = 4.39, p 0.01]. The same case was seen in the energy series, with lower values in the unaffected relatives and bipolar patient groups [mean (SD) : 1.644 ± 0.566; 1.511 ± 0.879], respectively, compared to healthy controls [2.230 ± 0.531; F(2, 75) = 7.89, p 0.001].Low resolution for the visual analog scale.Using nonlinear analyses, we found that the underlying structure of mood regulation in unaffected relatives is undistinguishable from the one found in bipolar patients. Compared to healthy controls, both bipolar patients and their unaffected relatives showed lower entropy levels, which is in keeping with a more rigid system, not as flexible to cope with the demands of a changing environment.

Published
2018

30. Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder: A genome-wide association study

Author

Claire O'Donovan, Gustavo Turecki, Frank Bellivier, Palmiero Monteleone, Tatyana Shekhtman, Bárbara Arias, Paul Grof, Sébastien Gard, Tomas Novak, Maria Del Zompo, Martin Schalling, Sarah Kittel-Schneider, Hsi-Chung Chen, Eduard Vieta, Claire Slaney, Katzutaka Shimoda, J. Raymond DePaulo, Martin Alda, Liping Hou, Kazufumi Akiyama, Louise Frisén, Gonzalo Laje, Maria Grigoroiu-Serbanescu, Mikael Landén, Nirmala Akula, Cristiana Cruceanu, Tadafumi Kato, Marion Leboyer, Lina Martinsson, Alessio Squassina, Andrea Hofmann, James B. Potash, Barbara König, Markus M. Nöthen, Giovanni Severino, Michael McCarthy, Philip B. Mitchell, Mario Maj, Ichiro Kusumi, Caroline M. Nievergelt, Jean-Pierre Kahn, Ryota Hashimoto, Joanna M. Biernacka, Sebastian Kliwicki, Francis J. McMahon, Guy A. Rouleau, Thomas Stamm, Pablo Cervantes, Alexandre Dayer, Julia Volkert, Po-Hsiu Kuo, Urs Heilbronner, Per Hoffmann, Janice M. Fullerton, Raffaella Ardau, Julie Garnham, Scott R. Clark, Layla Kassem, Fasil Tekola-Ayele, Peter R. Schofield, Nina Dalkner, Caterina Chillotti, Susanne Bengesser, Stefan Herms, Klaus Oliver Schubert, Francis M. Mondimore, Alfonso Tortorella, Adam Wright, Joanna Hauser, Peter P. Zandi, Piotr M. Czerski, Eva Z. Reininghaus, Fernando S. Goes, Jean-Michel Aubry, Antonio Benabarre, Bernhard T. Baune, Thomas G. Schulze, Francesc Colom, Marcella Rietschel, Andrea Pfennig, Catharina Lavebratt, Andreas J. Forstner, Paul D. Shilling, Mazda Adli, Armin Birner, Andreas Reif, Mirko Manchia, Susan G. Leckband, Azmeraw T. Amare, Susan L. McElroy, Michael Bauer, Norio Ozaki, Urban Ösby, Janusz K. Rybakowski, Pavla Stopkova, Esther Jiménez, Christian Simhandl, Abesh Kumar Bhattacharjee, Yi-Hsiang Hsu, John R. Kelsoe, Marina Mitjans, Sergi Papiol, Clara Brichant-Petitjean, Mark A. Frye, Stephanie H. Witt, Franziska Degenhardt, Sven Cichon, Bruno Etain, Lena Backlund, Peter Falkai, Barbara W. Schweizer, Stéphane Jamain, Amare, Azmeraw T., Schubert, Klaus Oliver, Hou, Liping, Clark, Scott R., Papiol, Sergi, Heilbronner, Ur, Degenhardt, Franziska, Tekola-Ayele, Fasil, Hsu, Yi-Hsiang, Shekhtman, Tatyana, Adli, Mazda, Akula, Nirmala, Akiyama, Kazufumi, Ardau, Raffaella, Arias, Bã¡rbara, Aubry, Jean-Michel, Backlund, Lena, Bhattacharjee, Abesh Kumar, Bellivier, Frank, Benabarre, Antonio, Bengesser, Susanne, Biernacka, Joanna M., Birner, Armin, Brichant-Petitjean, Clara, Cervantes, Pablo, Chen, Hsi-Chung, Chillotti, Caterina, Cichon, Sven, Cruceanu, Cristiana, Czerski, Piotr M., Dalkner, Nina, Dayer, Alexandre, Del Zompo, Maria, Depaulo, J. Raymond, à tain, Bruno, Falkai, Peter, Forstner, Andreas J., Frisen, Louise, Frye, Mark A., Fullerton, Janice M., Gard, Sã©bastien, Garnham, Julie S., Goes, Fernando S., Grigoroiu-Serbanescu, Maria, Grof, Paul, Hashimoto, Ryota, Hauser, Joanna, Herms, Stefan, Hoffmann, Per, Hofmann, Andrea, Jamain, Stephane, Jimã©nez, Esther, Kahn, Jean-Pierre, Kassem, Layla, Kuo, Po-Hsiu, Kato, Tadafumi, Kelsoe, John, Kittel-Schneider, Sarah, Kliwicki, Sebastian, Kã¶nig, Barbara, Kusumi, Ichiro, Laje, Gonzalo, Landã©n, Mikael, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G., Tortorella, Alfonso, Manchia, Mirko, Martinsson, Lina, Mccarthy, Michael J., Mcelroy, Susan, Colom, Francesc, Mitjans, Marina, Mondimore, Francis M., Monteleone, Palmiero, Nievergelt, Caroline M., Nã¶then, Markus M., Novã¡k, Toma, O'Donovan, Claire, Ozaki, Norio, à sby, Urban, Pfennig, Andrea, Potash, James B., Reif, Andrea, Reininghaus, Eva, Rouleau, Guy A., Rybakowski, Janusz K., Schalling, Martin, Schofield, Peter R., Schweizer, Barbara W., Severino, Giovanni, Shilling, Paul D., Shimoda, Katzutaka, Simhandl, Christian, Slaney, Claire M., Squassina, Alessio, Stamm, Thoma, Stopkova, Pavla, Maj, Mario, Turecki, Gustavo, Vieta, Eduard, Volkert, Julia, Witt, Stephanie, Wright, Adam, Zandi, Peter P., Mitchell, Philip B., Bauer, Michael, Alda, Martin, Rietschel, Marcella, Mcmahon, Francis J., Schulze, Thomas G., and Baune, Bernhard T.

Subjects
Male, Oncology, Multifactorial Inheritance, Bipolar Disorder, Lithium (medication), Genome-wide association study, THERAPY, chemistry.chemical_compound, ddc:616.89, 0302 clinical medicine, HLA Antigens, Spectrum disorder, Original Investigation, RISK, Mood stabilizer, Middle Aged, GLYCOGEN-SYNTHASE KINASE-3, 3. Good health, PREVALENCE, Treatment Outcome, Schizophrenia, Psychiatry and Mental Health, Female, Schizophrenic Psychology, Genetic Load, GLYCOGEN-SYNTHASE KINASE-3, CYTOKINE PRODUCTION, PROPHYLACTIC LITHIUM, SPECTRUM DISORDER, RISK, PREVALENCE, METAANALYSIS, GENETICS, THERAPY, PROFILE, medicine.drug, Adult, medicine.medical_specialty, Genotype, GENETICS, medicine.drug_class, PROFILE, PROPHYLACTIC LITHIUM, 03 medical and health sciences, Lithium Carbonate, Internal medicine, mental disorders, medicine, Humans, Bipolar disorder, Psychiatry, METAANALYSIS, SPECTRUM DISORDER, Inflammation, business.industry, Lithium carbonate, Odds ratio, CYTOKINE PRODUCTION, medicine.disease, 030227 psychiatry, chemistry, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

IMPORTANCE Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ). OBJECTIVES To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association. DESIGN, SETTING, AND PARTICIPANTS A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013.Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017. MAIN OUTCOMES AND MEASURES Treatment response to lithiumwas defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained. RESULTS Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 ? 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95%CI, 1.42-8.41) at the first decile to 2.03 (95%CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines. CONCLUSIONS AND RELEVANCE This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.

Published
2018

31. Early-onset and very-early-onset bipolar disorder: distinct or similar clinical conditions?

Author

Claire Slaney, Claire O'Donovan, Cynthia V. Calkin, Tomas Hajek, Abigail Ortiz, Martin Alda, Julie Garnham, Lukas Propper, and Martina Ruzickova

Subjects
Adult, Male, Canada, medicine.medical_specialty, Bipolar Disorder, Bipolar I disorder, Adolescent, Global Assessment of Functioning, Comorbidity, Logistic regression, 03 medical and health sciences, Bipolar II disorder, 0302 clinical medicine, Internal medicine, medicine, Humans, Family, Bipolar disorder, Age of Onset, Biological Psychiatry, Reference group, Depression (differential diagnoses), Psychiatric Status Rating Scales, Depressive Disorder, Major, Psychopathology, Mood Disorders, Middle Aged, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Mood, Attention Deficit Disorder with Hyperactivity, Female, Psychology, 030217 neurology & neurosurgery, Clinical psychology
Abstract

Objective This study aimed to examine differences in the clinical presentation of very-early-onset (VEO) and early-onset (EO) bipolar disorder (BD) not fully explored previously. Methods We selected two groups of subjects with BD from the Maritime Bipolar Registry based on age at onset of first major mood episode (VEO with onset prior to age 15 years; EO ranging from 15 to 18 years) and compared them with a reference group (onset after 18 years of age). There were 363 subjects (240 with bipolar I disorder and 123 with bipolar II disorder; mean age 44.2 ± 12.8 (SD) years), with 41 subjects in the VEO and 95 in the EO groups. Results In comparison with the EO and reference groups, more subjects in the VEO group developed major depression as an index episode (88% for the VEO group versus 61% for the EO group and 54% for the reference group), and had an unremitting clinical course (65% versus 42% and 42%, respectively), rapid cycling (54% versus 34% and 28%, respectively), and comorbid attention-deficit hyperactivity disorder (17% versus 1% and 3%, respectively); a higher proportion of the VEO group had first-degree relatives with affective disorders compared with the EO and reference groups (0.41 versus 0.32 and 0.29, respectively), and they had lower scores on the Global Assessment of Functioning scale (mean scores of 64 versus 70 and 70). Overall, the EO group was similar to the reference group on most measures, except for increased suicidal behavior VEO 53%, EO 44% and reference group 25%). The results of polychotomous logistic regression also support the view that VEO BD represents a rather specific subtype of BD. Conclusions Our results suggest the recognized correlates of early-onset BD may be driven by subjects at the lowest end of the age at onset spectrum.

Published
2015

32. Insulin resistance and outcome in bipolar disorder

Author

Claire Slaney, Martin Alda, Julie Garnham, Tomas Hajek, Cynthia V. Calkin, M. Claire O’Donovan, Martina Ruzickova, and Rudolf Uher

Subjects
Adult, Blood Glucose, Male, medicine.medical_specialty, Bipolar Disorder, Adolescent, Lithium (medication), medicine.medical_treatment, Type 2 diabetes, Lithium, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Antimanic Agents, Internal medicine, medicine, Humans, Insulin, Bipolar disorder, Antipsychotic, Aged, Aged, 80 and over, Odds ratio, Middle Aged, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Cross-Sectional Studies, Treatment Outcome, Endocrinology, Diabetes Mellitus, Type 2, Case-Control Studies, Disease Progression, Female, Insulin Resistance, Psychology, Body mass index, 030217 neurology & neurosurgery, medicine.drug
Abstract

BackgroundLittle is known about the impact of insulin resistance on bipolar disorder.AimsTo examine the relationships between insulin resistance, type 2 diabetes and clinical course and treatment outcomes in bipolar disorder.MethodWe measured fasting glucose and insulin in 121 adults with bipolar disorder. We diagnosed type 2 diabetes and determined insulin resistance. The National Institute of Mental Health Life Chart was used to record the course of bipolar disorder and the Alda scale to establish response to prophylactic lithium treatment.ResultsPatients with bipolar disorder and type 2 diabetes or insulin resistance had three times higher odds of a chronic course of bipolar disorder compared with euglycaemic patients (50% and 48.7% respectively v. 27.3%, odds ratio (OR) = 3.07, P = 0.007), three times higher odds of rapid cycling (38.5% and 39.5% respectively v. 18.2%, OR = 3.13, P = 0.012) and were more likely to be refractory to lithium treatment (36.8% and 36.7% respectively v. 3.2%, OR = 8.40, PConclusionsComorbid insulin resistance may be an important factor in resistance to treatment in bipolar disorder.

Published
2015

33. Transcriptomic Imputation of Bipolar Disorder and Bipolar subtypes reveals 29 novel associated genes

Author

Thomas G. Schulze, Eduard Vieta, Melissa J. Green, Jakob Grove, Ingrid Melle, Preben Bo Mortensen, Nicholas J. Schork, Thorgeir E. Thorgeirsson, Jonas Bybjerg-Grauholm, Margit Burmeister, Peter R. Schofield, Szabolcs Szelinger, Fermín Mayoral, Katherine Gordon-Smith, Qingqin S. Li, Claire O'Donovan, Josep Antoni Ramos-Quiroga, Derek W. Morris, Douglas M. Ruderfer, Stefan Herms, Huckins Lm, Martin Hautzinger, Eline J. Regeer, Sebastian Zöllner, Gustavo Turecki, Christine Søholm Hansen, Helena Medeiros, Laura J. Scott, Annelie Nordin Adolfsson, Helmut Vedder, Thomas W. Weickert, Nelson B. Freimer, Céline S. Reinbold, James McKay, Cathryn M. Lewis, Eric R. Gamazon, Frank Bellivier, Marie B¾kvad-Hansen, Srdjan Djurovic, Chun Chieh Fan, Ole A. Andreassen, Solveig K. Sieberts, Jack D. Barchas, David Curtis, Elaine K. Green, Tatiana Foroud, Shaun Purcell, Mette A. Peters, Joanna M. Biernacka, Fabian Streit, Alan F. Schatzberg, James L. Kennedy, Tiffany A. Greenwood, Bertram Müller-Myhsok, Robin Kramer, Swapnil Awasthi, Jordan W. Smoller, Cristina Sánchez-Mora, George Kirov, Ulrik Fredrik Malt, Gabriel E. Hoffman, Liz Forty, Pablo Cervantes, Jose Guzman Parra, Nicholas G. Martin, William Byerley, J. Raymond DePaulo, Martin Alda, Anil P.S. Ori, Menachem Fromer, William E. Bunney, Valentina Escott-Price, Judith A. Badner, Danielle Posthuma, Judith Allardyce, M. Ribasés, Manolis Kogevinas, Stephanie H. Witt, Anne T. Spijker, James A. Knowles, Simon Xi, Jun Li, Francis J. McMahon, Nancy J. Cox, Marcella Rietschel, Markus Leber, Laura M. Huckins, John I. Nurnberger, M. Casas, Marco P. Boks, Maria Hipolito, Evaristus A. Nwulia, Gerome Breen, Franziska Degenhardt, Janice M. Fullerton, Carlos N. Pato, Urs Heilbronner, Piotr M. Czerski, Michael Steffens, Monika Budde, Nicholas John Craddock, Katrin Gade, Bernie Devlin, Sarah Kittel-Schneider, Enrico Domenci, Weihua Guan, Sarah E. Bergen, Fan Meng, Eystein Stordal, Janet L. Sobell, Naomi R. Wray, Engilbert Sigurdsson, Marion Leboyer, Sven Cichon, Pamela Sklar, Bruno Etain, Richard M. Myers, Melvin G. McInnis, Steve McCarroll, Nicholas Bass, Christine Fraser, Thomas W. Mühleisen, Anna Maaser, Patrick F. Sullivan, Mark A. Frye, Amanda Dobbyn, John P. Rice, Amy Perry, Wei Xu, Thomas Damm Als, Anders D. Børglum, Anna C. Koller, Michael Conlon O'Donovan, Pamela B. Mahon, Sara A. Paciga, Douglas Blackwood, Michael Bauer, Fernando S. Goes, Susanne Lucae, Markus M. Nöthen, Josef Frank, Grant W. Montgomery, Scott D. Gordon, Philip B. Mitchell, Hoang T. Nguyen, Huda Akil, Chunyu Liu, Stanley J. Watson, Allan H. Young, Roel A. Ophoff, Caroline M. Nievergelt, John B. Vincent, Robert Karlsson, Kari Stefansson, Thomas Werge, Niamh Mullins, William A. Scheftner, Elliot S. Gershon, Peter McGuffin, Ralph Kupka, Mikael Landén, Matthew Flickinger, Claudia Giambartolomei, Carsten Bøcker Pedersen, Michael John Owen, Diego Albani, Hae Kyung Im, Andres Metspalu, Gunnar Morken, Panos Roussos, Tõnu Esko, Andrew M. McIntosh, Vishwajit L. Nimgaonkar, Per Hoffmann, Olav B. Smeland, Stéphane Jamain, Ole Mors, Vahram Haroutunian, Anders Juréus, Shawn Levy, Roy H. Perlis, Whitney McFadden, James Boocock, Ney Alliey-Rodriguez, Stacy Steinberg, Paul D. Shilling, Arne E. Vaaler, David Craig, Sarah E. Medland, Donald J. MacIntyre, William Coryell, Jens Treutlein, Joanna Hauser, Cynthia Shannon Weickert, Jana Strohmaier, Guy A. Rouleau, Michele T. Pato, John R. Kelsoe, Arianna Di Florio, Radhika Kandaswamy, David M. Hougaard, Toni-Kim Clarke, Susan L. McElroy, Ian Jones, Sarah Knott, Tatyana Shehktman, Wade H. Berrettini, John Strauss, Anders M. Dale, Peter P. Zandi, Andreas Reif, Claire Slaney, Julie Garnham, Margarita Rivera, Michael Gill, Lisa Jones, Cristiana Cruceanu, Sascha B. Fischer, Marian L. Hamshere, Lilijana Oruc, Weiqing Wang, Eli A. Stahl, Wolfgang Maier, Peng Zhang, Hreinn Stefansson, Ingrid Agartz, Bernhard T. Baune, Esben Agerbo, Alessandro Serretti, Robert C. Thompson, Ketil J. Oedegaard, William Lawson, Merete Nordentoft, Jacob Lawrence, Fabio Rivas, James B. Potash, Aiden Corvin, Christina M. Hultman, Maria Grigoroiu-Serbanescu, Marianne Giørtz Pedersen, Michael Boehnke, René S. Kahn, Lili Milani, Jurgen Del-Favero, Veera M. Rajagopal, Jolanta Lissowska, Howard J. Edenberg, Udo Dannlowski, Rolf Adolfsson, Andrea Pfennig, Adebayo Anjorin, and Torbjørn Elvsåshagen

Subjects
Genotype, Expression quantitative trait loci, medicine, Genome-wide association study, Locus (genetics), Bipolar disorder, Computational biology, Biology, medicine.disease, Phenotype, Genetic architecture, Imputation (genetics)
Abstract

Bipolar disorder is a complex neuropsychiatric disorder presenting with episodic mood disturbances. In this study we use a transcriptomic imputation approach to identify novel genes and pathways associated with bipolar disorder, as well as three diagnostically and genetically distinct subtypes. Transcriptomic imputation approaches leverage well-curated and publicly available eQTL reference panels to create gene-expression prediction models, which may then be applied to “impute” genetically regulated gene expression (GREX) in large GWAS datasets. By testing for association between phenotype and GREX, rather than genotype, we hope to identify more biologically interpretable associations, and thus elucidate more of the genetic architecture of bipolar disorder.We applied GREX prediction models for 13 brain regions (derived from CommonMind Consortium and GTEx eQTL reference panels) to 21,488 bipolar cases and 54,303 matched controls, constituting the largest transcriptomic imputation study of bipolar disorder (BPD) to date. Additionally, we analyzed three specific BPD subtypes, including 14,938 individuals with subtype 1 (BD-I), 3,543 individuals with subtype 2 (BD-II), and 1,500 individuals with schizoaffective subtype (SAB).We identified 125 gene-tissue associations with BPD, of which 53 represent independent associations after FINEMAP analysis. 29/53 associations were novel; i.e., did not lie within 1Mb of a locus identified in the recent PGC-BD GWAS. We identified 37 independent BD-I gene-tissue associations (10 novel), 2 BD-II associations, and 2 SAB associations. Our BPD, BD-I and BD-II associations were significantly more likely to be differentially expressed in post-mortem brain tissue of BPD, BD-I and BD-II cases than we might expect by chance. Together with our pathway analysis, our results support long-standing hypotheses about bipolar disorder risk, including a role for oxidative stress and mitochondrial dysfunction, the post-synaptic density, and an enrichment of circadian rhythm and clock genes within our results.

Published
2017

34. High genetic loading of schizophrenia predicts poor response to lithium in patients with bipolar disorder: A polygenic score and cross-trait genetic analysis

Author

Peter R. Schofield, Susanne Bengesser, Stefan Herms, Klaus Oliver Schubert, Susan G. Leckband, Maria Grigoroiu-Serbanescu, Scott R. Clark, Michael McCarthy, Thomas Stamm, Michael Bauer, Marion Leboyer, Layla Kassem, Fasil Tekola-Ayele, Caterina Chillotti, Andrea Hofmann, Fernando S. Goes, Urs Heilbronner, Tomas Novak, Francesc Colom, Philip B. Mitchell, Janusz K. Rybakowski, Alexandre Dayer, Piotr M. Czerski, Kazufumi Akiyama, Antonio Benabarre, Bernhard T. Baune, Sarah Kittel-Schneider, Nina Dalkner, Gustavo Turecki, Raffaella Ardau, Sébastien Gard, Gonzalo Laje, Mark A. Frye, Tadafumi Kato, Bárbara Arias, Norio Ozaki, Francis M. Mondimore, Per Hoffmann, Hsi-Chung Chen, Claire Slaney, Eva Z. Reininghaus, Andrea Pfennig, Susan L. McElroy, Katzutaka Shimoda, Louise Frisén, Peter P. Zandi, Maria Del Zompo, Nirmala Akula, Ryota Hashimoto, Catharina Lavebratt, Cristiana Cruceanu, Pavla Stopkova, Ichiro Kusumi, Paul Grof, Andreas J. Forstner, Janice M. Fullerton, Julie Garnham, Mikael Landén, Giovanni Severino, Paul D. Shilling, Mazda Adli, Armin Birner, Alessio Squassina, Frank Bellivier, Alfonso Tortorella, Lina Martinsson, Palmiero Monteleone, Jean-Michel Aubry, James B. Potash, Pablo Cervantes, Jean-Pierre Kahn, Francis J. McMahon, Po-Hsiu Kuo, Tatyana Shekhtman, Mirko Manchia, Joanna M. Biernacka, Barbara König, J. Raymond DePaulo, Martin Alda, Joanna Hauser, Christian Simhandl, Yi-Hsiang Hsu, John R. Kelsoe, Clara Brichant-Petitjean, Azmeraw T. Amare, Peter Falkai, Stéphane Jamain, Franziska Degenhardt, Marcella Rietschel, Stephanie H. Witt, Markus M. Nöthen, Caroline M. Nievergelt, Eduard Vieta, Liping Hou, Sven Cichon, Julia Volkert, Bruno Etain, Lena Backlund, Barbara W. Schweizer, Urban Ösby, Esther Jiménez, Abesh Kumar Bhattacharjee, Marina Mitjans, Sergi Papiol, Mario Maj, Adam Wright, Thomas G. Schulze, Martin Schalling, Sebastian Kliwicki, Guy A. Rouleau, Andreas Reif, and Claire O'Donovan

Subjects
Oncology, medicine.medical_specialty, Lithium (medication), business.industry, medicine.drug_class, Genome-wide association study, Mood stabilizer, Odds ratio, medicine.disease, 3. Good health, 030227 psychiatry, Treatment of bipolar disorder, 03 medical and health sciences, 0302 clinical medicine, Schizophrenia, Internal medicine, Pharmacogenomics, mental disorders, medicine, Bipolar disorder, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

ImportanceLithium is a first-line mood stabilizer for the maintenance treatment of Bipolar Disorder (BPD). However, the efficacy of lithium varies widely, with a non-response rate of up to 30%. Biological response markers and predictors are lacking.ObjectiveGenetic factors are thought to mediate lithium treatment response, and the previously reported genetic overlap between BPD and schizophrenia (SCZ) led us to test whether a polygenic score (PGS) for SCZ could predict lithium treatment response in BPD. Further, we explored the potential molecular underpinnings of this association.DesignWeighted SCZ PGSs were computed at ten p-value thresholds (PT) using summary statistics from a genome-wide association study (GWAS) of 36,989 SCZ cases, and genotype data for BPD patients from the Consortium on Lithium Genetics (ConLi+Gen). For functional exploration, we performed a cross-trait meta-GWAS and pathway analysis, combining GWAS summary statistics on SCZ and lithium treatment response.SettingInternational multicenter GWAS.ParticipantsPatients with BPD who had undergone lithium treatment were genotyped and retrospectively assessed for long-term treatment response (n=2,586).Main outcome measuresClinical treatment response to lithium was defined on both the categorical and continuous scales using the ALDA score. The effect measures include odds ratios (ORs) and the proportion of variance explained (R2), and a significant association was determined at pResultsThe PGS for SCZ was inversely associated with lithium treatment response in the categorical outcome (p=8×10−5), at PT−2. Patients with BPD who had low polygenic load for SCZ responded better to lithium, with ORs for lithium response ranging from 3.46 [95%CI: 1.42-8.41 at 1stdecile] to 2.03 [95%CI: 0.86-4.81 at the 9th decile], compared to the patients in the 10thdecile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA complex and inflammatory cytokines (TNFα, IL-4, IFNγ) as molecular contributors to lithium treatment response in BPD.Conclusions and RelevanceThe study provides, for the first-time, evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.Key PointsQuestionDoes a polygenic score for Schizophrenia (SCZ) predict response to lithium in patients with Bipolar Disorder (BPD)? What are the molecular drivers of the association between SCZ and lithium treatment response?FindingsWe found an inverse association between genetic loading for SCZ risk variants and response to lithium in patients with BPD. Genetic variants in the HLA region on chromosome 6, the antigen presentation pathway and markers of inflammation (TNFα, IL-4, IFNγ) point to molecular underpinnings of lithium treatment response in BPD.MeaningIn patients with BPD, an assessment of a polygenic load for SCZ risk variants may assist in conjunction with clinical data to predict whether they would respond to lithium treatment.

Published
2017

35. Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

Author

Eli A Stahl, Gerome Breen, Andreas J Forstner, Andrew McQuillin, Stephan Ripke, Vassily Trubetskoy, Manuel Mattheisen, Yunpeng Wang, Jonathan R I Coleman, Héléna A Gaspar, Christiaan A de Leeuw, Stacy Steinberg, Jennifer M Whitehead Pavlides, Maciej Trzaskowski, Tune H Pers, Peter A Holmans, Liam Abbott, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D Als, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A Badner, Marie Bækvad-Hansen, Jack D Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Sarah E Bergen, Carsten Bøcker Pedersen, Erlend Bøen, Marco Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, William Byerley, Miquel Casas, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W Craig, Cristiana Cruceanu, David Curtis, Piotr M Czerski, Anders M Dale, Simone de Jong, Franziska Degenhardt, Jurgen Del-Favero, J Raymond DePaulo, Srdjan Djurovic, Amanda L Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Valentina Escott-Price, Chun Chieh Fan, Sascha B Fischer, Matthew Flickinger, Tatiana M Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B Freimer, Louise Frisén, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D Gordon, Katherine Gordon-Smith, Elaine K Green, Melissa J Green, Tiffany A Greenwood, Jakob Grove, Weihua Guan, JoséGuzman Parra, Marian L Hamshere, Martin Hautzinger, Urs Heilbronner, Stefan Herms, Maria Hipolito, Per Hoffmann, Dominic Holland, Laura Huckins, Stéphane Jamain, Jessica S Johnson, Anders Juréus, Radhika Kandaswamy, Robert Karlsson, James L Kennedy, Sarah Kittel-Schneider, Sarah V Knott, James A Knowles, Manolis Kogevinas, Anna C Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B Lawson, Markus Leber, Phil H Lee, Shawn E Levy, Jun Z Li, Chunyu Liu, Susanne Lucae, Anna Maaser, Donald J MacIntyre, Pamela B Mahon, Wolfgang Maier, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G McInnis, James D McKay, Helena Medeiros, Sarah E Medland, Fan Meng, Lili Milani, Grant W Montgomery, Derek W Morris, Thomas W Mühleisen, Niamh Mullins, Hoang Nguyen, Caroline M Nievergelt, Annelie Nordin Adolfsson, Evaristus A Nwulia, Claire O’Donovan, Loes M Olde Loohuis, Anil P S Ori, Lilijana Oruc, Urban Ösby, Roy H Perlis, Amy Perry, Andrea Pfennig, James B Potash, Shaun M Purcell, Eline J Regeer, Andreas Reif, Céline S Reinbold, John P Rice, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M Ruderfer, Euijung Ryu, Cristina Sánchez-Mora, Alan F Schatzberg, William A Scheftner, Nicholas J Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D Shilling, Engilbert Sigurdsson, Claire Slaney, Olav B Smeland, Janet L Sobell, Christine Søholm Hansen, Anne T Spijker, David St Clair, Michael Steffens, John S Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Robert C Thompson, Thorgeir E Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J Watson, Thomas W Weickert, Stephanie H Witt, Simon Xi, Wei Xu, Allan H Young, Peter Zandi, Peng Zhang, Sebastian Zollner, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lena Backlund, Bernhard T Baune, Frank Bellivier, Wade H Berrettini, Joanna M Biernacka, Douglas H R Blackwood, Michael Boehnke, Anders D Børglum, Aiden Corvin, Nicholas Craddock, Mark J Daly, Udo Dannlowski, Tõnu Esko, Bruno Etain, Mark Frye, Janice M Fullerton, Elliot S Gershon, Michael Gill, Fernando Goes, Maria Grigoroiu-Serbanescu, Joanna Hauser, David M Hougaard, Christina M Hultman, Ian Jones, Lisa A Jones, RenéS Kahn, George Kirov, Mikael Landén, Marion Leboyer, Cathryn M Lewis, Qingqin S Li, Jolanta Lissowska, Nicholas G Martin, Fermin Mayoral, Susan L McElroy, Andrew M McIntosh, Francis J McMahon, Ingrid Melle, Andres Metspalu, Philip B Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Richard M Myers, Benjamin M Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M Nöthen, Michael C O’Donovan, Ketil J Oedegaard, Michael J Owen, Sara A Paciga, Carlos Pato, Michele T Pato, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Marta Ribasés, Marcella Rietschel, Guy A Rouleau, Martin Schalling, Peter R Schofield, Thomas G Schulze, Alessandro Serretti, Jordan W Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Patrick F Sullivan, Gustavo Turecki, Arne E Vaaler, Eduard Vieta, John B Vincent, Thomas Werge, John I Nurnberger, Naomi R Wray, Arianna Di Florio, Howard J Edenberg, Sven Cichon, Roel A Ophoff, Laura J Scott, Ole A Andreassen, John Kelsoe, and Pamela Sklar

Subjects
0303 health sciences, medicine.medical_specialty, business.industry, medicine.disease, European descent, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Genomewide association, medicine, Bipolar disorder, medicine.symptom, Psychiatry, business, Mania, 030217 neurology & neurosurgery, Depression (differential diagnoses), 030304 developmental biology
Abstract

Bipolar disorder is a highly heritable psychiatric disorder that features episodes of mania and depression. We performed the largest genome-wide association study to date, including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 sentinel variants at loci with P-4 in an independent sample of 9,412 cases and 137,760 controls. In the combined analysis, 30 loci reached genome-wide significant evidence for association, of which 20 were novel. These significant loci contain genes encoding ion channels and neurotransmitter transporters (CACNA1C, GRIN2A, SCN2A, SLC4A1), synaptic components (RIMS1, ANK3), immune and energy metabolism components. Bipolar disorder type I (depressive and manic episodes; ~73% of our cases) is strongly genetically correlated with schizophrenia whereas bipolar disorder type II (depressive and hypomanic episodes; ~17% of our cases) is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for bipolar disorder.

Published
2017
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36. International multi-site survey on the use of online support groups in bipolar disorder

Author

Mark Zetin, Jonas Gildebro, Sabine Choppin, Diego Hidalgo-Mazzei, Caterina Chillotti, Błażej Misiak, Alberto Bocchetta, Claire O'Donovan, Letizia Bossini, Yoshitaka Tatebayashi, René Ernst Nielsen, Guy M. Goodwin, Brett Sawchuk, Philipp Ritter, Jörn Conell, Amy C. Bilderbeck, Paul Grof, Scott Monteith, Vaisnvy Kapur, Hirohiko Harima, Chantal Henry, Martin Alda, Beny Lafer, Michael Bauer, Eric Yw Cheung, Ana González-Pinto, Julia Volkert, Maj Vinberg, Erik Roj Larsen, Michael Berk, Andrea Fagiolini, Patryk Piotrowski, Aleksandra Suwalska, Elon Schwartz, Rodrigo A. Munoz, Anne Duffy, Ângela Miranda Scippa, Maria Del Zompo, Angela Marianne Paredes Castro, Anne Hvenegaard Lund, Leonardo Tondo, Yamima Osher, Andreas Reif, Bernhard T. Baune, Peter Tam, Takako Nakanotani, Girish Kunigiri, Claire Slaney, Tasha Glenn, Rita Bauer, Eduard Vieta, Yuly Bersudsky, Biju Viswanath, Janusz K. Rybakowski, Julie Garnham, Miryam Fernández Hernandez, Rodrigo R. Dias, Raffaella Ardau, John R. Geddes, Ramus Licht, Ahmad Hatim Sulaiman, Peter C. Whybrow, Yasushi Okamura, Kemal Sagduyu, Kirsi Suominen, Stefanie Hassel, Ute Lewitzka, Seetal Dodd, and Bruno Etain

Subjects
Adult, Male, medicine.medical_specialty, Bipolar Disorder, Internationality, Online support groups, Peer support, online support groups, Self-help, 03 medical and health sciences, 0302 clinical medicine, Surveys and Questionnaires, Journal Article, medicine, Humans, survey, 030212 general & internal medicine, Bipolar disorder, self-help, Psychiatry, Generalized estimating equation, Internet, Descriptive statistics, business.industry, Information seeking, Psychiatry and Mental Health, Middle Aged, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Self-Help Groups, The Internet, Female, business, Psychology, Clinical psychology
Abstract

BACKGROUND: Peer support is an established component of recovery from bipolar disorder, and online support groups may offer opportunities to expand the use of peer support at the patient's convenience. Prior research in bipolar disorder has reported value from online support groups.AIMS: To understand the use of online support groups by patients with bipolar disorder as part of a larger project about information seeking.METHODS: The results are based on a one-time, paper-based anonymous survey about information seeking by patients with bipolar disorder, which was translated into 12 languages. The survey was completed between March 2014 and January 2016 and included questions on the use of online support groups. All patients were diagnosed by a psychiatrist. Analysis included descriptive statistics and general estimating equations to account for correlated data.RESULTS AND CONCLUSIONS: The survey was completed by 1222 patients in 17 countries. The patients used the Internet at a percentage similar to the general public. Of the Internet users who looked online for information about bipolar disorder, only 21.0% read or participated in support groups, chats, or forums for bipolar disorder (12.8% of the total sample). Given the benefits reported in prior research, clarification of the role of online support groups in bipolar disorder is needed. With only a minority of patients using online support groups, there are analytical challenges for future studies.

Published
2017

37. Erratum to:Online information seeking by patients with bipolar disorder: results from an international multisite survey

Author

Paul Grof, Claire Slaney, Martin Alda, Chantal Henry, Scott Monteith, Eric Yat Wo Cheung, Ana González-Pinto, Peter C. Whybrow, Guy M. Goodwin, Yamima Osher, Vaisnvy Kapur, Hirohiko Harima, Claire O'Donovan, Amy C. Bilderbeck, Anne Hvenegaard Lund, Yasushi Okamura, Kirsi Suominen, Ahmad Hatim Sulaiman, Rasmus Wentzer Licht, Biju Viswanath, Elon Schwartz, Julie Garnham, Brett Sawchuk, Jonas Gildebro, Sabine Choppin, Rodrigo A. Muñoz, Kemal Sagduyu, René Ernst Nielsen, Leonardo Tondo, Jörn Conell, Michael Bauer, Beny Lafer, Ângela Miranda Scippa, Michael Berk, Andrea Fagiolini, Janusz K. Rybakowski, Erik Roj Larsen, Takako Nakanotani, Rodrigo R. Dias, Andreas Reif, Ute Lewitzka, Maria Del Zompo, Seetal Dodd, Angela Marianne Paredes Castro, Maj Vinberg, Bernhard T. Baune, Aleksandra Suwalska, Chun Lam, Anne Duffy, Patryk Piotrowski, Stefanie Hassel, Bruno Etain, Yuly Bersudsky, John R. Geddes, Philipp Ritter, Peter Tam, Raffaella Ardau, Eduard Vieta, Mark Zetin, Iñaki Zorrilla, Girish Kunigiri, Tasha Glenn, Rita Bauer, Julia Volkert, Diego Hidalgo-Mazzei, Alberto Bocchetta, Caterina Chillotti, Błażej Misiak, Letizia Bossini, and Yoshitaka Tatebayashi

Subjects
medicine.medical_specialty, Published Erratum, Information seeking, lcsh:QP351-495, medicine.disease, lcsh:RC321-571, 030227 psychiatry, 03 medical and health sciences, Psychiatry and Mental health, lcsh:Neurophysiology and neuropsychology, 0302 clinical medicine, medicine, Bipolar disorder, Erratum, Psychology, Psychiatry, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, 030217 neurology & neurosurgery, Biological Psychiatry, Clinical psychology
Abstract

Information seeking is an important coping mechanism for dealing with chronic illness. Despite a growing number of mental health websites, there is little understanding of how patients with bipolar disorder use the Internet to seek information.A 39 question, paper-based, anonymous survey, translated into 12 languages, was completed by 1222 patients in 17 countries as a convenience sample between March 2014 and January 2016. All patients had a diagnosis of bipolar disorder from a psychiatrist. Data were analyzed using descriptive statistics and generalized estimating equations to account for correlated data.976 (81 % of 1212 valid responses) of the patients used the Internet, and of these 750 (77 %) looked for information on bipolar disorder. When looking online for information, 89 % used a computer rather than a smartphone, and 79 % started with a general search engine. The primary reasons for searching were drug side effects (51 %), to learn anonymously (43 %), and for help coping (39 %). About 1/3 rated their search skills as expert, and 2/3 as basic or intermediate. 59 % preferred a website on mental illness and 33 % preferred Wikipedia. Only 20 % read or participated in online support groups. Most patients (62 %) searched a couple times a year. Online information seeking helped about 2/3 to cope (41 % of the entire sample). About 2/3 did not discuss Internet findings with their doctor.Online information seeking helps many patients to cope although alternative information sources remain important. Most patients do not discuss Internet findings with their doctor, and concern remains about the quality of online information especially related to prescription drugs. Patients may not rate search skills accurately, and may not understand limitations of online privacy. More patient education about online information searching is needed and physicians should recommend a few high quality websites.

Published
2017

38. Nonlinear dynamics of mood regulation in bipolar disorder

Author

Abigail Ortiz, Martin Alda, Kamil Bradler, Claire Slaney, and Julie Garnham

Subjects
Adult, Male, Bipolar Disorder, Visual Analog Scale, Visual analogue scale, Short-term memory, Anxiety, Self-Control, mental disorders, medicine, Humans, Bipolar disorder, Autoregressive integrated moving average, Biological Psychiatry, Autocorrelation, Middle Aged, medicine.disease, Cyclothymic Disorder, Affect, Psychiatry and Mental health, Mood, Nonlinear Dynamics, Mood disorders, Case-Control Studies, Female, medicine.symptom, Psychology, Clinical psychology
Abstract

Objectives We sought to study the underlying dynamic processes involved in mood regulation in subjects with bipolar disorder and healthy control subjects using time-series analysis and to then analyze the relation between anxiety and mood using cross-correlation techniques. Methods We recruited 30 healthy controls and 30 euthymic patients with bipolar disorder. Participants rated their mood, anxiety, and energy levels using a paper-based visual analog scale; and they also recorded their sleep and any life events. Information on these variables was provided over a three-month period on a daily basis, twice per day. We analyzed the data using Box–Jenkins time series analysis to obtain information on the autocorrelation of the series (for mood) and cross-correlation (mood and anxiety series). Results Throughout the study, we analyzed 10,170 data points. Self-ratings for mood, anxiety, and energy were normally distributed in both groups. Autocorrelation functions for mood in both groups were governed by the autoregressive integrated moving average (ARIMA) (1,1,0) model, which means that current values in the series were related to one previous point only. We also found a negative cross-correlation between mood and anxiety. Conclusions Mood can be considered a memory stochastic process; it is a flexible, dynamic process that has a ‘short memory’ both in healthy controls and euthymic patients with bipolar disorder. This process may be quite different in untreated patients or in those acutely ill. Our results suggest that nonlinear measures can be applied to the study of mood disorders.

Published
2014

39. Internet use by patients with bipolar disorder: Results from an international multisite survey

Author

Janusz K. Rybakowski, Julie Garnham, Mark Zetin, Peter C. Whybrow, Raffaella Ardau, Vaisnvy Kapur, Yasushi Okamura, Peter Tam, Claire O'Donovan, Rasmus Wentzer Licht, Hirohiko Harima, Chantal Henry, Girish Kunigiri, Jörn Conell, Bruno Etain, Anne Hvenegaard Lund, Tasha Glenn, Caterina Chillotti, Andreas Reif, Rita Bauer, Erik Roj Larsen, John R. Geddes, Ahmad Hatim Sulaiman, Miryam Fernández Hernandez, Leonardo Tondo, Scott Monteith, Błażej Misiak, Amy C. Bilderbeck, Seetal Dodd, Julia Volkert, Ana González-Pinto, Martin Alda, Eduard Vieta, Takako Nakanotani, René Ernst Nielsen, Letizia Bossini, Philipp Ritter, Elon Schwartz, Patryk Piotrowski, Brett Sawchuk, Angela Marianne Paredes Castro, Beny Lafer, Guy M. Goodwin, Jonas Gildebro, Sabine Choppin, Kemal Sagduyu, Rodrigo R. Dias, Yoshitaka Tatebayashi, Kirsi Suominen, Stefanie Hassel, Biju Viswanath, Maj Vinberg, Aleksandra Suwalska, Ute Lewitzka, Rodrigo A. Munoz, Anne Duffy, Diego Hidalgo-Mazzei, Michael Bauer, Michael Berk, Alberto Bocchetta, Andrea Fagiolini, Claire Slaney, Yamima Osher, Paul Grof, Eric Yat Wo Cheung, Ângela Miranda Scippa, Maria Del Zompo, Bernhard T. Baune, and Yuly Bersudsky

Subjects
Adult, Male, medicine.medical_specialty, Bipolar Disorder, Internationality, Adolescent, media_common.quotation_subject, education, World wide web, Information source, Odds, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Surveys and Questionnaires, mental disorders, medicine, Humans, Bipolar disorder, Young adult, Psychiatry, Internet, Psychiatry and Mental Health, Biological Psychiatry, media_common, Internet use, business.industry, Middle Aged, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Feeling, The Internet, Female, Self Report, Biological psychiatry, business, 030217 neurology & neurosurgery
Abstract

There is considerable international interest in online education of patients with bipolar disorder, yet little understanding of how patients use the Internet and other sources to seek information. 1171 patients with a diagnosis of bipolar disorder in 17 countries completed a paper-based, anonymous survey. 81% of the patients used the Internet, a percentage similar to the general public. Older age, less education, and challenges in country telecommunications infrastructure and demographics decreased the odds of using the Internet. About 78% of the Internet users looked online for information on bipolar disorder or 63% of the total sample. More years of education in relation to the country mean, and feeling very confident about managing life decreased the odds of seeking information on bipolar disorder online, while having attended support groups increased the odds. Patients who looked online for information on bipolar disorder consulted medical professionals plus a mean of 2.3 other information sources such as books, physician handouts, and others with bipolar disorder. Patients not using the Internet consulted medical professionals plus a mean of 1.6 other information sources. The percentage of patients with bipolar disorder who use the Internet is about the same as the general public. Other information sources remain important.

Published
2016

40. Online information seeking by patients with bipolar disorder: results from an international multisite survey

Author

Claire O'Donovan, Biju Viswanath, Beny Lafer, Raffaella Ardau, Kemal Sagduyu, Anne Hvenegaard Lund, Hirohiko Harima, Ahmad Hatim Sulaiman, Rasmus Wentzer Licht, Guy M. Goodwin, Scott Monteith, Vaisnvy Kapur, John R. Geddes, Paul Grof, Chantal Henry, Kirsi Suominen, Eduard Vieta, Ana González-Pinto, Claire Slaney, Stefanie Hassel, Caterina Chillotti, Leonardo Tondo, Yoshitaka Tatebayashi, Yuly Bersudsky, Erik Roj Larsen, Brett Sawchuk, Bruno Etain, Jörn Conell, Błażej Misiak, Patryk Piotrowski, Eric Yat Wo Cheung, Jonas Gildebro, Takako Nakanotani, Chun Lam, René Ernst Nielsen, Seetal Dodd, Amy C. Bilderbeck, Mark Zetin, Michael Bauer, Sabine Choppin, Letizia Bossini, Philipp Ritter, Rodrigo R. Dias, Michael Berk, Diego Hidalgo-Mazzei, Andrea Fagiolini, Ângela Miranda Scippa, Maj Vinberg, Rodrigo A. Munoz, Andreas Reif, Maria Del Zompo, Aleksandra Suwalska, Martin Alda, Anne Duffy, Alberto Bocchetta, Bernhard T. Baune, Yamima Osher, Julie Garnham, Janusz K. Rybakowski, Peter C. Whybrow, Yasushi Okamura, Julia Volkert, Elon Schwartz, Angela Marianne Paredes Castro, Peter Tam, Iñaki Zorrilla, Girish Kunigiri, Tasha Glenn, Rita Bauer, Ute Lewitzka, CHU Henri Mondor [Créteil], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Perception et Mémoire / Perception and Memory, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), CHU Henri Mondor, Perception et Mémoire, and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
Coping (psychology), medicine.medical_specialty, 020205 medical informatics, 02 engineering and technology, 03 medical and health sciences, 0302 clinical medicine, Journal Article, 0202 electrical engineering, electronic engineering, information engineering, medicine, 030212 general & internal medicine, Bipolar disorder, Psychiatry, Biological Psychiatry, Descriptive statistics, business.industry, Information seeking, Research, medicine.disease, Mental illness, Mental health, 3. Good health, Psychiatry and Mental health, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, The Internet, business, Psychology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Patient education
Abstract

Background Information seeking is an important coping mechanism for dealing with chronic illness. Despite a growing number of mental health websites, there is little understanding of how patients with bipolar disorder use the Internet to seek information. Methods A 39 question, paper-based, anonymous survey, translated into 12 languages, was completed by 1222 patients in 17 countries as a convenience sample between March 2014 and January 2016. All patients had a diagnosis of bipolar disorder from a psychiatrist. Data were analyzed using descriptive statistics and generalized estimating equations to account for correlated data. Results 976 (81 % of 1212 valid responses) of the patients used the Internet, and of these 750 (77 %) looked for information on bipolar disorder. When looking online for information, 89 % used a computer rather than a smartphone, and 79 % started with a general search engine. The primary reasons for searching were drug side effects (51 %), to learn anonymously (43 %), and for help coping (39 %). About 1/3 rated their search skills as expert, and 2/3 as basic or intermediate. 59 % preferred a website on mental illness and 33 % preferred Wikipedia. Only 20 % read or participated in online support groups. Most patients (62 %) searched a couple times a year. Online information seeking helped about 2/3 to cope (41 % of the entire sample). About 2/3 did not discuss Internet findings with their doctor. Conclusion Online information seeking helps many patients to cope although alternative information sources remain important. Most patients do not discuss Internet findings with their doctor, and concern remains about the quality of online information especially related to prescription drugs. Patients may not rate search skills accurately, and may not understand limitations of online privacy. More patient education about online information searching is needed and physicians should recommend a few high quality websites. Electronic supplementary material The online version of this article (doi:10.1186/s40345-016-0058-0) contains supplementary material, which is available to authorized users.

Published
2016

41. Genome-wide association study identifies 30 loci associated with bipolar disorder

Author

Euijung Ryu, Danfeng Chen, Allan H. Young, Olav B. Smeland, James McKay, Frank Bellivier, Qingqin S. Li, Yunpeng Wang, Tõnu Esko, Bertram Müller-Myhsok, Weiqing Wang, Thomas W. Weickert, Joanna M. Biernacka, Ralph W. Kupka, Claire O'Donovan, Josep Antoni Ramos-Quiroga, Marian L. Hamshere, Derek W. Morris, Douglas M. Ruderfer, Stephan Ripke, Nelson B. Freimer, Tatiana Foroud, Shaun Purcell, Ashley Dumont, Shawn Levy, Dominic Holland, Joanna Hauser, Anders D. Børglum, Liz Forty, Alan F. Schatzberg, Christine Fraser, Jennifer M. Whitehead Pavlides, William E. Bunney, Merete Nordentoft, Andres Metspalu, Gunnar Morken, Susanne Lucae, Roy H. Perlis, Anne T. Spijker, Richard A. Belliveau, Sarah E. Bergen, Fan Meng, Eduard Vieta, Cynthia Shannon Weickert, J. Raymond DePaulo, Martin Alda, Lina Martinsson, Melvin G. McInnis, Jacob Lawrence, Markus Leber, James A. Knowles, Franziska Degenhardt, Melissa J. Green, Jaqueline Goldstein, Amanda Dobbyn, Radhika Kandaswamy, Steve McCarroll, Katrin Gade, Jack D. Barchas, Christina M. Hultman, Sarah Kittel-Schneider, Martin Hautzinger, Maria Hipolito, Louise Frisén, Kari Stefansson, Michael Conlon O'Donovan, Markus M. Nöthen, Eline J. Regeer, Jens Treutlein, Robert Karlsson, Ian Jones, Nicholas G. Martin, William A. Scheftner, Caroline M. Nievergelt, Marta Ribasés, Simone de Jong, Szabolcs Szelinger, Thomas W. Mühleisen, Michele T. Pato, Manuel Mattheisen, Maciej Trzaskowski, Urs Heilbronner, Diane Gage, Jakob Grove, Ingrid Melle, Ole A. Andreassen, Claudia Giambartolomei, Kimberly Chambert, Arne E. Vaaler, William Coryell, Peter R. Schofield, Preben Bo Mortensen, Roel A. Ophoff, Fabian Streit, Manolis Kogevinas, Ingrid Agartz, John Strauss, James L. Kennedy, Anders M. Dale, Stefan Herms, Douglas Blackwood, Torbjørn Elvsåshagen, Bernhard T. Baune, Grant W. Montgomery, Andreas Reif, Fabio Rivas, Andrew McQuillin, Jordan W. Smoller, Chun Chieh Fan, James B. Potash, Jun Li, Ketil J. Oedegaard, David Curtis, Martin Schalling, John R. Kelsoe, Valentina Escott-Price, Sascha B. Fischer, Tatyana Shehktman, Jonathan R. I. Coleman, Stanley J. Watson, Donald J. MacIntyre, Tune H. Pers, Eystein Stordal, Richard M. Myers, Jose Guzman-Parra, Danielle Posthuma, John I. Nurnberger, William Lawson, Janet L. Sobell, Felecia Cerrato, Judith A. Badner, Elliot S. Gershon, Gerome Breen, Naomi R. Wray, Thomas Werge, Lilijana Oruc, Claire Slaney, Anil P.S. Ori, Alexander W. Charney, Marianne Giørtz Pedersen, Marie Bækvad-Hansen, Michael Boehnke, Marcella Rietschel, George Kirov, Aiden Corvin, Piotr M. Czerski, Peter Holmans, Michael Steffens, Margarita Rivera, Maria Grigoroiu-Serbanescu, René S. Kahn, Laura M. Huckins, Monika Budde, Michael Gill, Lili Milani, Christiaan de Leeuw, Peng Zhang, Nicholas Bass, Jana Strohmaier, John P. Rice, Wei Xu, Cristiana Cruceanu, Vassily Trubetskoy, Philip B. Mitchell, Helena Medeiros, Thomas Damm Als, Anna C. Koller, Huda Akil, Jessica S. Johnson, Toni-Kim Clarke, Janice M. Fullerton, Guy A. Rouleau, Fernando S. Goes, Weihua Guan, Wolfgang Maier, Pamela Sklar, Diego Albani, Laura J. Scott, Pamela B. Mahon, Anna Maaser, Katherine Gordon-Smith, Urban Ösby, Jurgen Del-Favero, Jolanta Lissowska, Howard J. Edenberg, Sven Cichon, Annelie Nordin Adolfsson, Julie Garnham, Josef Frank, Hoang T. Nguyen, Michael Bauer, Helmut Vedder, Vishwajit L. Nimgaonkar, Loes M. Olde Loohuis, Thomas G. Schulze, Cristina Sánchez-Mora, Udo Dannlowski, Rolf Adolfsson, Benjamin M. Neale, Verneri Antilla, Andrea Pfennig, John B. Vincent, Niamh Mullins, Per Hoffmann, Peter McGuffin, Erlend Bøen, Ney Alliey-Rodriguez, Adebayo Anjorin, Fermín Mayoral, Arianna Di Florio, Claire Churchhouse, David M. Hougaard, Nicholas J. Schork, Tiffany A. Greenwood, Carlos N. Pato, Thorgeir E. Thorgeirsson, Nicholas John Craddock, Stephanie H. Witt, Liam Abbott, Swapnil Awasthi, Miquel Casas, Jonas Bybjerg-Grauholm, Cathryn M. Lewis, Srdjan Djurovic, Bruno Etain, Margit Burmeister, Phil Lee, Elaine K. Green, Sara A. Paciga, Lena Backlund, Engilbert Sigurdsson, Patrick F. Sullivan, Amy Perry, Pablo Cervantes, Marco P. Boks, Catharina Lavebratt, Andrew M. McIntosh, Panos Roussos, Enda M. Byrne, Alexander Richards, Eli A. Stahl, Stéphane Jamain, Hreinn Stefansson, Ole Mors, Esben Agerbo, Susan L. McElroy, Wade H. Berrettini, Peter P. Zandi, Lisa Jones, Andreas J. Forstner, Alessandro Serretti, Céline S. Reinbold, Robert C. Thompson, Matthew Flickinger, William Byerley, Michael John Owen, Helena Gaspar, Francis J. McMahon, David St Clair, Mark A. Frye, Christine Søholm Hansen, Scott D. Gordon, Mikael Landén, Gustavo Turecki, Simon Xi, Evaristus A. Nwulia, Anders Juréus, James Boocock, Stacy Steinberg, Paul D. Shilling, David Craig, Mark J. Daly, Sarah E. Medland, Marion Leboyer, Chunyu Liu, Carsten Bøcker Pedersen, Sebastian Zöllner, APH - Mental Health, Psychiatry, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Stahl E.A., Breen G., Forstner A.J., McQuillin A., Ripke S., Trubetskoy V., Mattheisen M., Wang Y., Coleman J.R.I., Gaspar H.A., de Leeuw C.A., Steinberg S., Pavlides J.M.W., Trzaskowski M., Byrne E.M., Pers T.H., Holmans P.A., Richards A.L., Abbott L., Agerbo E., Akil H., Albani D., Alliey-Rodriguez N., Als T.D., Anjorin A., Antilla V., Awasthi S., Badner J.A., Baekvad-Hansen M., Barchas J.D., Bass N., Bauer M., Belliveau R., Bergen S.E., Pedersen C.B., Boen E., Boks M.P., Boocock J., Budde M., Bunney W., Burmeister M., Bybjerg-Grauholm J., Byerley W., Casas M., Cerrato F., Cervantes P., Chambert K., Charney A.W., Chen D., Churchhouse C., Clarke T.-K., Coryell W., Craig D.W., Cruceanu C., Curtis D., Czerski P.M., Dale A.M., de Jong S., Degenhardt F., Del-Favero J., DePaulo J.R., Djurovic S., Dobbyn A.L., Dumont A., Elvsashagen T., Escott-Price V., Fan C.C., Fischer S.B., Flickinger M., Foroud T.M., Forty L., Frank J., Fraser C., Freimer N.B., Frisen L., Gade K., Gage D., Garnham J., Giambartolomei C., Pedersen M.G., Goldstein J., Gordon S.D., Gordon-Smith K., Green E.K., Green M.J., Greenwood T.A., Grove J., Guan W., Guzman-Parra J., Hamshere M.L., Hautzinger M., Heilbronner U., Herms S., Hipolito M., Hoffmann P., Holland D., Huckins L., Jamain S., Johnson J.S., Jureus A., Kandaswamy R., Karlsson R., Kennedy J.L., Kittel-Schneider S., Knowles J.A., Kogevinas M., Koller A.C., Kupka R., Lavebratt C., Lawrence J., Lawson W.B., Leber M., Lee P.H., Levy S.E., Li J.Z., Liu C., Lucae S., Maaser A., MacIntyre D.J., Mahon P.B., Maier W., Martinsson L., McCarroll S., McGuffin P., McInnis M.G., McKay J.D., Medeiros H., Medland S.E., Meng F., Milani L., Montgomery G.W., Morris D.W., Muhleisen T.W., Mullins N., Nguyen H., Nievergelt C.M., Adolfsson A.N., Nwulia E.A., O'Donovan C., Loohuis L.M.O., Ori A.P.S., Oruc L., Osby U., Perlis R.H., Perry A., Pfennig A., Potash J.B., Purcell S.M., Regeer E.J., Reif A., Reinbold C.S., Rice J.P., Rivas F., Rivera M., Roussos P., Ruderfer D.M., Ryu E., Sanchez-Mora C., Schatzberg A.F., Scheftner W.A., Schork N.J., Shannon Weickert C., Shehktman T., Shilling P.D., Sigurdsson E., Slaney C., Smeland O.B., Sobell J.L., Soholm Hansen C., Spijker A.T., St Clair D., Steffens M., Strauss J.S., Streit F., Strohmaier J., Szelinger S., Thompson R.C., Thorgeirsson T.E., Treutlein J., Vedder H., Wang W., Watson S.J., Weickert T.W., Witt S.H., Xi S., Xu W., Young A.H., Zandi P., Zhang P., Zollner S., Adolfsson R., Agartz I., Alda M., Backlund L., Baune B.T., Bellivier F., Berrettini W.H., Biernacka J.M., Blackwood D.H.R., Boehnke M., Borglum A.D., Corvin A., Craddock N., Daly M.J., Dannlowski U., Esko T., Etain B., Frye M., Fullerton J.M., Gershon E.S., Gill M., Goes F., Grigoroiu-Serbanescu M., Hauser J., Hougaard D.M., Hultman C.M., Jones I., Jones L.A., Kahn R.S., Kirov G., Landen M., Leboyer M., Lewis C.M., Li Q.S., Lissowska J., Martin N.G., Mayoral F., McElroy S.L., McIntosh A.M., McMahon F.J., Melle I., Metspalu A., Mitchell P.B., Morken G., Mors O., Mortensen P.B., Muller-Myhsok B., Myers R.M., Neale B.M., Nimgaonkar V., Nordentoft M., Nothen M.M., O'Donovan M.C., Oedegaard K.J., Owen M.J., Paciga S.A., Pato C., Pato M.T., Posthuma D., Ramos-Quiroga J.A., Ribases M., Rietschel M., Rouleau G.A., Schalling M., Schofield P.R., Schulze T.G., Serretti A., Smoller J.W., Stefansson H., Stefansson K., Stordal E., Sullivan P.F., Turecki G., Vaaler A.E., Vieta E., Vincent J.B., Werge T., Nurnberger J.I., Wray N.R., Di Florio A., Edenberg H.J., Cichon S., Ophoff R.A., Scott L.J., Andreassen O.A., Kelsoe J., Sklar P., eQTLGen Consortium, BIOS Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, and Complex Trait Genetics

Subjects
Male, Bipolar Disorder, Bipolar I disorder, Schizophrenia/genetics, LD SCORE REGRESSION, Genome-wide association study, VARIANTS, Bipolar II disorder, 0302 clinical medicine, SCHIZOPHRENIA, GWAS, Psychotic Disorders/genetics, Non-U.S. Gov't, RISK, Genetics, 0303 health sciences, HERITABILITY, Research Support, Non-U.S. Gov't, Systems Biology, Major/genetics, Single Nucleotide, 3. Good health, Schizophrenia, Major depressive disorder, Female, Case-Control Studie, Depressive Disorder, Major/genetics, Human, Psychosis, GENES, Biology, Psychotic Disorder, Research Support, Polymorphism, Single Nucleotide, Article, Bipolar Disorder/classification, N.I.H, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, Journal Article, POLYGENICITY, Humans, Genetic Predisposition to Disease, Bipolar disorder, Polymorphism, METAANALYSIS, 030304 developmental biology, Intramural, Depressive Disorder, Major, Depressive Disorder, Genetic heterogeneity, Research Support, N.I.H., Intramural, medicine.disease, INDIVIDUALS, Psychotic Disorders, Genetic Loci, Case-Control Studies, Human medicine, 030217 neurology & neurosurgery, Genome-Wide Association Study, Meta-Analysis
Abstract

This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar disorder working group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and to the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. The views expressed are those of the authors and not necessarily those of any funding or regulatory body. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org ) hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu)., Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P, This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr. Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs. Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M O'Neil and Betty C Lynch.

Published
2019

42. T2. Brain Age in Bipolar Disorders - Effects of Lithium Treatment

Author

Holly Van Gestel, Claire Slaney, Joanne Petite, Katja Franke, Tomas Hajek, Rudolf Uher, Julie Garnham, and Martin Alda

Subjects
medicine.medical_specialty, Endocrinology, Lithium (medication), business.industry, Internal medicine, medicine, business, Biological Psychiatry, medicine.drug
Published
2019

44. The Pharmacogenomics of Bipolar Disorder study (PGBD): Identification of genes for lithium response in a prospective sample

Author

Michael McCarthy, Susan G. Leckband, Keming Gao, Abesh Kumar Bhattacharjee, Ketil J. Oedegaard, Katherine E. Burdick, Anna DeModena, Jun Yao, Anit Anand, Kristen J. Brennand, Jerome Mertens, Yokesh Balaraman, Caroline M. Nievergelt, John I. Nurnberger, Petter Jakobsen, Szabolcs Szelinger, Helle K. Schoeyen, Mark A. Frye, Cynthia V. Calkin, Paul D. Shilling, Joseph R. Calabrese, Bruce Tarwater, David Craig, John R. Kelsoe, Ole A. Andreassen, Melvin G. McInnis, Son Pham, Ana M. Claasen, Martin Alda, Julie Garnham, Gunnar Morken, Adam X. Maihofer, Tatyana Shekhtman, William Coryell, Elliot S. Gershon, Fred H. Gage, Wade H. Berrettini, and Peter P. Zandi

Subjects
Male, Bipolar I disorder, Bipolar Disorder, Lithium (medication), Study Protocol, 0302 clinical medicine, Secondary Prevention, Psychology, GWAS, Prospective Studies, Prospective cohort study, Psychiatry, screening and diagnosis, Depression, Precision medicine, Mood stabilizer, Middle Aged, Antidepressive Agents, 3. Good health, Diagnostic and Statistical Manual of Mental Disorders, Detection, Psychiatry and Mental health, Mental Health, 6.1 Pharmaceuticals, Public Health and Health Services, Lithium Compounds, Female, Prospective trial, medicine.drug, 4.2 Evaluation of markers and technologies, medicine.medical_specialty, medicine.drug_class, Bipolar disorder, Clinical Sciences, Lithium, Relapse prevention, 03 medical and health sciences, Clinical Research, Internal medicine, Behavioral and Social Science, mental disorders, medicine, Genetics, Humans, Aged, Retrospective Studies, business.industry, Prevention, Valproic Acid, Human Genome, Evaluation of treatments and therapeutic interventions, Retrospective cohort study, medicine.disease, Personalized medicine, 030227 psychiatry, Brain Disorders, Pharmacogenetics, business, 030217 neurology & neurosurgery, Follow-Up Studies, Genome-Wide Association Study
Abstract

Background Bipolar disorder is a serious and common psychiatric disorder characterized by manic and depressive mood switches and a relapsing and remitting course. The cornerstone of clinical management is stabilization and prophylaxis using mood-stabilizing medications to reduce both manic and depressive symptoms. Lithium remains the gold standard of treatment with the strongest data for both efficacy and suicide prevention. However, many patients do not respond to this medication, and clinically there is a great need for tools to aid the clinician in selecting the correct treatment. Large genome wide association studies (GWAS) investigating retrospectively the effect of lithium response are in the pipeline; however, few large prospective studies on genetic predictors to of lithium response have yet been conducted. The purpose of this project is to identify genes that are associated with lithium response in a large prospective cohort of bipolar patients and to better understand the mechanism of action of lithium and the variation in the genome that influences clinical response. Methods/Design This study is an 11-site prospective non-randomized open trial of lithium designed to ascertain a cohort of 700 subjects with bipolar I disorder who experience protocol-defined relapse prevention as a result of treatment with lithium monotherapy. All patients will be diagnosed using the Diagnostic Interview for Genetic Studies (DIGS) and will then enter a 2-year follow-up period on lithium monotherapy if and when they exhibit a score of 1 (normal, not ill), 2 (minimally ill) or 3 (mildly ill) on the Clinical Global Impressions of Severity Scale for Bipolar Disorder (CGI-S-BP Overall Bipolar Illness) for 4 of the 5 preceding weeks. Lithium will be titrated as clinically appropriate, not to exceed serum levels of 1.2 mEq/L. The sample will be evaluated longitudinally using a wide range of clinical scales, cognitive assessments and laboratory tests. On relapse, patients will be discontinued or crossed-over to treatment with valproic acid (VPA) or treatment as usual (TAU). Relapse is defined as a DSM-IV manic, major depressive or mixed episode or if the treating physician decides a change in medication is clinically necessary. The sample will be genotyped for GWAS. The outcome for lithium response will be analyzed as a time to event, where the event is defined as clinical relapse, using a Cox Proportional Hazards model. Positive single nucleotide polymorphisms (SNPs) from past genetic retrospective studies of lithium response, the Consortium on Lithium Genetics (ConLiGen), will be tested in this prospective study sample; a meta-analysis of these samples will then be performed. Finally, neurons will be derived from pluripotent stem cells from lithium responders and non-responders and tested in vivo for response to lithium by gene expression studies. SNPs in genes identified in these cellular studies will also be tested for association to response. Discussion Lithium is an extraordinarily important therapeutic drug in the clinical management of patients suffering from bipolar disorder. However, a significant proportion of patients, 30–40 %, fail to respond, and there is currently no method to identify the good lithium responders before initiation of treatment. Converging evidence suggests that genetic factors play a strong role in the variation of response to lithium, but only a few genes have been tested and the samples have largely been retrospective or quite small. The current study will collect an entirely unique sample of 700 patients with bipolar disorder to be stabilized on lithium monotherapy and followed for up to 2 years. This study will produce useful information to improve the understanding of the mechanism of action of lithium and will add to the development of a method to predict individual response to lithium, thereby accelerating recovery and reducing suffering and cost. © 2016 Oedegaard et al.Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated

Published
2016

45. Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder

Author

Christina M. Hultman, Peter R. Schofield, J. Raymond DePaulo, Martin Alda, Szabolcs Szelinger, Susanne Bengesser, Stefan Herms, Alessio Squassina, Gustavo Turecki, Barbara König, Fabian Streit, Jana Strohmaier, Martin Schalling, Maren Lang, Michael McCarthy, Per Hoffmann, Sarah K. Tighe, William Byerley, Jean-Pierre Kahn, Bárbara Arias, Alfonso Tortorella, Francis J. McMahon, William Lawson, Gonzalo Laje, Wade H. Berrettini, Tatyana Shekhtman, Jean-Michel Aubry, Erin N. Smith, Peng Zhang, Stefanie Heilmann-Heimbach, Evaristus A. Nwulia, Thomas B. Barrett, Cinnamon S. Bloss, Nicholas J. Schork, Tatiana Foroud, Antonio Benabarre, Bernhard T. Baune, William Coryell, Giovanni Severino, Sébastien Gard, Michael Bauer, Layla Kassem, Judith A. Badner, Peter P. Zandi, Rebecca McKinney, Paul D. Shilling, Mazda Adli, Pablo Cervantes, John P. Rice, Nirmala Akula, Marcella Rietschel, Maria Grigoroiu-Serbanescu, Armin Birner, David Craig, Caterina Chillotti, Sebastian Kliwicki, Guy A. Rouleau, Alexandre Dayer, Claire Slaney, Thomas Stamm, Piotr M. Czerski, Pamela B. Mahon, Elliot S. Gershon, Susan L. McElroy, Andreas J. Forstner, Sarah E. Bergen, Peter Propping, Johannes Schumacher, Mikael Landén, Marion Leboyer, Janusz K. Rybakowski, Cristiana Cruceanu, Urs Heilbronner, Joanna Hauser, Fernando S. Goes, Howard J. Edenberg, Markus M. Nöthen, Adam Wright, Chunyu Liu, Daniel L. Koller, James B. Potash, Elise T. Bui, Julie Garnham, Caroline M. Nievergelt, William A. Scheftner, Lina Martinsson, Janice M. Fullerton, Maria Del Zompo, Shashi Hitturlingappa, Mirko Manchia, Andreas Reif, Andrea Pfennig, Thomas G. Schulze, Eduard Vieta, Jie Song, Liping Hou, Maria Hipolito, John I. Nurnberger, Louise Frisén, Anna Maaser, Wolfgang Maier, Thomas W. Mühleisen, Andrea Hofmann, Philip B. Mitchell, Clara Brichant-Petitjean, Raffaella Ardau, Joanna M. Biernacka, N. Lackner, Eva Z. Reininghaus, Francesc Colom, Catharina Lavebratt, Francis M. Mondimore, Urban Ösby, Esther Jiménez, Abesh Kumar Bhattacharjee, Marina Mitjans, Tiffany A. Greenwood, Peter Falkai, Stephanie H. Witt, Stéphane Jamain, Sven Cichon, Julia Volkert, Bruno Etain, Lena Backlund, Tomas Novak, Sarah Kittel-Schneider, Franziska Degenhardt, Barbara W. Schweizer, Mark A. Frye, Christian Simhandl, John R. Kelsoe, Sebastian Zöllner, Frank Bellivier, Palmiero Monteleone, Tony Davis, Susan G. Leckband, Mario Maj, Melvin G. McInnis, and Pavla Stopkova

Subjects
Genetics, 0303 health sciences, Genome-wide association study, Odds ratio, Biology, Heritability, medicine.disease, Mental illness, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Intergenic region, Mood, medicine, Bipolar disorder, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87×10−9; odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10−9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.

Published
2016
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46. Genetic variants associated with response to lithium treatment in bipolar disorder:a genome-wide association study

Author

Ryota Hashimoto, Andrea Hofmann, Gustavo Turecki, N. Lackner, Philip B. Mitchell, Bárbara Arias, Urban Ösby, J. Raymond DePaulo, Martin Alda, Julie Garnham, Esther Jiménez, Abesh Kumar Bhattacharjee, Peter P. Zandi, Clara Brichant-Petitjean, Frank Bellivier, Marina Mitjans, Palmiero Monteleone, Eduard Vieta, Liping Hou, Eva Z. Reininghaus, Raffaella Ardau, Paul D. Shilling, Mazda Adli, Armin Birner, Marion Leboyer, Lena Backlund, Andreas J. Forstner, David A. Cousins, Francesc Colom, Catharina Lavebratt, K Oliver Schubert, Barbara W. Schweizer, Mario Maj, Kazufumi Akiyama, Antoni Benabarre, Julia Volkert, Alessio Squassina, Marcella Rietschel, Stephanie H. Witt, Gonzalo Laje, Louise Frisén, Jordan W. Smoller, Paul Grof, Tomas Novak, L. Trevor Young, Sven Cichon, Bruno Etain, Ichiro Kusumi, Sarah K. Tighe, Sarah Kittel-Schneider, Florian Seemüller, Jean-Pierre Kahn, Markus M. Nöthen, Tadafumi Kato, Alexandre Dayer, Caroline M. Nievergelt, Mirko Manchia, Francis J. McMahon, Peter R. Schofield, Susanne Bengesser, Po-Hsiu Kuo, Stefan Herms, Scott R. Clark, Piotr M. Czerski, Oliver Gruber, Franziska Degenhardt, Mark A. Frye, Joanna M. Biernacka, Christian Simhandl, Guo-Bo Chen, Adam Wright, Sébastien Gard, Peter Falkai, Carlos Jaramillo, Stéphane Jamain, Roy H. Perlis, Andrea Pfennig, Tatyana Shekhtman, Maria Del Zompo, Clarissa de Rosalmeida Dantas, Thomas G. Schulze, Alfonso Tortorella, Francis M. Mondimore, John R. Kelsoe, Jean-Michel Aubry, Mikael Landén, Andreas Reif, Naomi R. Wray, Martin Schalling, Janice M. Fullerton, Nirmala Akula, Claudio E. M. Banzato, Elise T. Bui, Per Hoffmann, Sebastian Kliwicki, Guy A. Rouleau, Maria Grigoroiu-Serbanescu, Glenda MacQueen, Lina Martinsson, Giovanni Severino, Norio Ozaki, Daniela Reich-Erkelenz, Layla Kassem, Manuel Mattheisen, Pavla Stopkova, Michael Bauer, Caterina Chillotti, Kazutaka Shimoda, Bernhard T. Baune, Janusz K. Rybakowski, Thomas Stamm, Joanna Hauser, Fernando S. Goes, Urs Heilbronner, James B. Potash, Susan L. McElroy, Barbara König, Susan G. Leckband, Michael McCarthy, Hsi-Chung Chen, Claire Slaney, Cristiana Cruceanu, Pablo Cervantes, Hou, Liping, Heilbronner, Ur, Degenhardt, Franziska, Adli, Mazda, Akiyama, Kazufumi, Akula, Nirmala, Ardau, Raffaella, Arias, Bárbara, Backlund, Lena, Banzato, Claudio E M, Benabarre, Antoni, Bengesser, Susanne, Bhattacharjee, Abesh Kumar, Biernacka, Joanna M, Birner, Armin, Brichant-Petitjean, Clara, Bui, Elise T, Cervantes, Pablo, Chen, Guo-Bo, Chen, Hsi-Chung, Chillotti, Caterina, Cichon, Sven, Clark, Scott R, Colom, Francesc, Cousins, David A, Cruceanu, Cristiana, Czerski, Piotr M, Dantas, Clarissa R, Dayer, Alexandre, Étain, Bruno, Falkai, Peter, Forstner, Andreas J, Frisén, Louise, Fullerton, Janice M, Gard, Sébastien, Garnham, Julie S, Goes, Fernando S, Grof, Paul, Gruber, Oliver, Hashimoto, Ryota, Hauser, Joanna, Herms, Stefan, Hoffmann, Per, Hofmann, Andrea, Jamain, Stephane, Jiménez, Esther, Kahn, Jean-Pierre, Kassem, Layla, Kittel-Schneider, Sarah, Kliwicki, Sebastian, König, Barbara, Kusumi, Ichiro, Lackner, Nina, Laje, Gonzalo, Landén, Mikael, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G, Jaramillo, Carlos A López, Macqueen, Glenda, Manchia, Mirko, Martinsson, Lina, Mattheisen, Manuel, Mccarthy, Michael J, Mcelroy, Susan L, Mitjans, Marina, Mondimore, Francis M, Monteleone, Palmiero, Nievergelt, Caroline M, Nöthen, Markus M, Ösby, Urban, Ozaki, Norio, Perlis, Roy H, Pfennig, Andrea, Reich-Erkelenz, Daniela, Rouleau, Guy A, Schofield, Peter R, Schubert, K Oliver, Schweizer, Barbara W, Seemüller, Florian, Severino, Giovanni, Shekhtman, Tatyana, Shilling, Paul D, Shimoda, Kazutaka, Simhandl, Christian, Slaney, Claire M, Smoller, Jordan W, Squassina, Alessio, Stamm, Thoma, Stopkova, Pavla, Tighe, Sarah K, Tortorella, Alfonso, Turecki, Gustavo, Volkert, Julia, Witt, Stephanie, Wright, Adam, Young, L Trevor, Zandi, Peter P, Potash, James B, Depaulo, J Raymond, Bauer, Michael, Reininghaus, Eva Z, Novák, Toma, Aubry, Jean-Michel, Maj, Mario, Baune, Bernhard T, Mitchell, Philip B, Vieta, Eduard, Frye, Mark A, Rybakowski, Janusz K, Kuo, Po-Hsiu, Kato, Tadafumi, Grigoroiu-Serbanescu, Maria, Reif, Andrea, Del Zompo, Maria, Bellivier, Frank, Schalling, Martin, Wray, Naomi R, Kelsoe, John R, Alda, Martin, Rietschel, Marcella, Mcmahon, Francis J, and Schulze, Thomas G

Subjects
Male, Glial Cell Line-Derived Neurotrophic Factor Receptors, Bipolar Disorder, Genotype, Genome-wide association study, Single-nucleotide polymorphism, Bipolar Disorder/drug therapy/genetics, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, ddc:616.89, 0302 clinical medicine, Genetic variation, Medicine, Humans, Bipolar disorder, Prospective Studies, Allele, Polymorphism, Lithium Compounds/therapeutic use, Genetics, business.industry, Medicine (all), Genetic Variation, General Medicine, Single Nucleotide, Middle Aged, medicine.disease, Polymorphism, Single Nucleotide/genetics, 030227 psychiatry, 3. Good health, Phenotype, Treatment Outcome, Female, Genome-Wide Association Study, Lithium Compounds, business, 030217 neurology & neurosurgery, Imputation (genetics), Pharmacogenetics, Glial Cell Line-Derived Neurotrophic Factor Receptors/genetics
Abstract

BACKGROUND: Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified.METHODS: Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis.FINDINGS: A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0).INTERPRETATION: The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings.FUNDING: Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

Published
2016

47. Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder

Author

Philip B. Mitchell, Clara Brichant-Petitjean, Raffaella Ardau, Peter R. Schofield, Susanne Bengesser, Stefan Herms, Sebastian Zöllner, Christina M. Hultman, Shashi Hitturlingappa, Maria Hipolito, Louise Frisén, Thomas W. Mühleisen, Layla Kassem, Christian Simhandl, Urban Ösby, Frank Bellivier, Peter Falkai, Alessio Squassina, Jana Strohmaier, Esther Jiménez, Palmiero Monteleone, Caterina Chillotti, Stéphane Jamain, Peter P. Zandi, Abesh Kumar Bhattacharjee, Tony Davis, Sarah K. Tighe, William Byerley, Jean-Pierre Kahn, Michael Bauer, Nicholas J. Schork, Joanna Hauser, Andreas J. Forstner, Francis J. McMahon, Peter Propping, Marina Mitjans, Tiffany A. Greenwood, Alfonso Tortorella, Fernando S. Goes, Szabolcs Szelinger, Tomas Novak, Erin N. Smith, Andrea Pfennig, Susan G. Leckband, Pablo Cervantes, Sarah Kittel-Schneider, Sébastien Gard, Adam Wright, Tatiana Foroud, Joanna M. Biernacka, Jean-Michel Aubry, Marcella Rietschel, Elliot S. Gershon, Janusz K. Rybakowski, John R. Kelsoe, Stephanie H. Witt, Elise T. Bui, Sarah E. Bergen, Tatyana Shekhtman, Thomas G. Schulze, Sven Cichon, Julia Volkert, Thomas Stamm, Eduard Vieta, Jie Song, Liping Hou, Markus M. Nöthen, Bruno Etain, Mikael Landén, Caroline M. Nievergelt, Mirko Manchia, William Coryell, Howard J. Edenberg, Andreas Reif, Urs Heilbronner, Gonzalo Laje, Lena Backlund, Wade H. Berrettini, Martin Schalling, Franziska Degenhardt, Susan L. McElroy, Mario Maj, Francis M. Mondimore, Peng Zhang, Stefanie Heilmann-Heimbach, Janice M. Fullerton, Daniel L. Koller, James B. Potash, Michael McCarthy, Barbara W. Schweizer, Rebecca McKinney, Nirmala Akula, Sebastian Kliwicki, Guy A. Rouleau, N. Lackner, William Lawson, Melvin G. McInnis, Eva Z. Reininghaus, Maria Grigoroiu-Serbanescu, Pavla Stopkova, Francesc Colom, Catharina Lavebratt, Judith A. Badner, Mark A. Frye, Alexandre Dayer, Giovanni Severino, Maren Lang, John P. Rice, Per Hoffmann, William A. Scheftner, Lina Martinsson, Pamela B. Mahon, Piotr M. Czerski, Paul D. Shilling, Mazda Adli, Armin Birner, David Craig, Gustavo Turecki, Bárbara Arias, Evaristus A. Nwulia, Thomas B. Barrett, Cinnamon S. Bloss, Marion Leboyer, Chunyu Liu, Maria Del Zompo, Antonio Benabarre, Bernhard T. Baune, Fabian Streit, John I. Nurnberger, Barbara König, Anna Maaser, Wolfgang Maier, Julie Garnham, Claire Slaney, Johannes Schumacher, Cristiana Cruceanu, J. Raymond DePaulo, Martin Alda, Andrea Hofmann, Hou, Liping, Bergen, Sarah E., Akula, Nirmala, Song, Jie, Hultman, Christina M., Landén, Mikael, Adli, Mazda, Alda, Martin, Ardau, Raffaella, Arias, Barbara, Aubry, Jean-Michel, Backlund, Lena, Badner, Judith A., Barrett, Thomas B., Bauer, Michael, Baune, Bernhard T., Bellivier, Frank, Benabarre, Antonio, Bengesser, Susanne, Berrettini, Wade H., Bhattacharjee, Abesh Kumar, Biernacka, Joanna M., Birner, Armin, Bloss, Cinnamon S., Brichant-Petitjean, Clara, Bui, Elise T., Byerley, William, Cervantes, Pablo, Chillotti, Caterina, Cichon, Sven, Colom, Francesc, Coryell, William, Craig, David W., Cruceanu, Cristiana, Czerski, Piotr M., Davis, Tony, Dayer, Alexandre, Degenhardt, Franziska, Del Zompo, Maria, Depaulo, J. Raymond, Edenberg, Howard J., Étain, Bruno, Falkai, Peter, Foroud, Tatiana, Forstner, Andreas J., Frisén, Louise, Frye, Mark A., Fullerton, Janice M., Gard, Sébastien, Garnham, Julie S., Gershon, Elliot S., Goes, Fernando S., Greenwood, Tiffany A., Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Heilbronner, Ur, Heilmann-Heimbach, Stefanie, Herms, Stefan, Hipolito, Maria, Hitturlingappa, Shashi, Hoffmann, Per, Hofmann, Andrea, Jamain, Stephane, Jiménez, Esther, Kahn, Jean-Pierre, Kassem, Layla, Kelsoe, John R., Kittel-Schneider, Sarah, Kliwicki, Sebastian, Koller, Daniel L., König, Barbara, Lackner, Nina, Laje, Gonzalo, Lang, Maren, Lavebratt, Catharina, Lawson, William B., Leboyer, Marion, Leckband, Susan G., Liu, Chunyu, Maaser, Anna, Mahon, Pamela B., Maier, Wolfgang, Maj, Mario, Manchia, Mirko, Martinsson, Lina, Mccarthy, Michael J., Mcelroy, Susan L., Mcinnis, Melvin G., Mckinney, Rebecca, Mitchell, Philip B., Mitjans, Marina, Mondimore, Francis M., Monteleone, Palmiero, Mühleisen, Thomas W., Nievergelt, Caroline M., Nöthen, Markus M., Novák, Toma, Nurnberger, John I., Nwulia, Evaristus A., Ösby, Urban, Pfennig, Andrea, Potash, James B., Propping, Peter, Reif, Andrea, Reininghaus, Eva, Rice, John, Rietschel, Marcella, Rouleau, Guy A., Rybakowski, Janusz K., Schalling, Martin, Scheftner, William A., Schofield, Peter R., Schork, Nicholas J., Schulze, Thomas G., Schumacher, Johanne, Schweizer, Barbaraw., Severino, Giovanni, Shekhtman, Tatyana, Shilling, Paul D., Simhandl, Christian, Slaney, Claire M., Smith, Erin N., Squassina, Alessio, Stamm, Thoma, Stopkova, Pavla, Streit, Fabian, Strohmaier, Jana, Szelinger, Szabolc, Tighe, Sarah K., Tortorella, Alfonso, Turecki, Gustavo, Vieta, Eduard, Volkert, Julia, Witt, Stephanie H., Wright, Adam, Zandi, Peter P., Zhang, Peng, Zollner, Sebastian, and Mcmahon, Francis J.

Subjects
Male, 0301 basic medicine, Bipolar Disorder, Receptor, ErbB-2, Genome-wide association study, Single-nucleotide polymorphism, Biology, 03 medical and health sciences, ddc:616.89, 0302 clinical medicine, Genetic, Molecular Biology, Genetics, Genetics (clinical), medicine, Humans, Bipolar disorder, Genetic association, Chromosomes, Human, X, Association Studies Articles, Case-control study, General Medicine, Odds ratio, Heritability, medicine.disease, 3. Good health, 030104 developmental biology, Meta-analysis, Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P = 5.87 × 10 (-) (9); odds ratio (OR) = 1.12) and markers within ERBB2 (rs2517959, P = 4.53 × 10 (-) (9); OR = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.

Published
2016

49. Cross-prevalence of migraine and bipolar disorder

Author

Gustavo Turecki, Claire Slaney, Abigail Ortiz, Martin Alda, Julie Garnham, Gregorio Zlotnik, Caroline van de Velde, Pablo Cervantes, and Claire O'Donovan

Subjects
medicine.medical_specialty, education.field_of_study, Pediatrics, Generalized anxiety disorder, Panic disorder, Population, Schedule for Affective Disorders and Schizophrenia, medicine.disease, Comorbidity, Psychiatry and Mental health, Migraine, mental disorders, medicine, Bipolar disorder, Psychiatry, Psychology, education, Biological Psychiatry, Psychopathology
Abstract

Ortiz A, Cervantes P, Zlotnik G, van de Velde C, Slaney C, Garnham J, Turecki G, O’Donovan C, Alda M. Cross-prevalence of migraine and bipolar disorder. Bipolar Disord 2010: 12: 397–403. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objective: In two related studies, we explored the prevalence of migraine and its associated clinical characteristics in patients with bipolar disorder (BD) as well as psychiatric morbidity in patients treated for migraine. Method: The first study included 323 subjects with BD type I (BD I) or BD type II (BD II), diagnosed using the Schedule for Affective Disorders and Schizophrenia, Lifetime version (SADS-L) format, or the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID). Migraine history was assessed by means of a structured questionnaire. In a second sample of 102 migraine patients, we investigated current and lifetime psychiatric morbidity using the SADS-L. Statistical analyses were conducted using nonparametric analysis and log-linear models. Results: A total of 24.5% of BD patients had comorbid migraine; those with BD II had a higher prevalence (34.8%) compared to BD I (19.1%) (p < 0.005). BD patients with comorbid migraine had significantly higher rates of suicidal behaviour, social phobia, panic disorder, generalized anxiety disorder, and obsessive-compulsive disorder (all p < 0.05). In the sample of migraine patients, 34.3% had a current psychiatric diagnosis, and 73.5% had a lifetime psychiatric diagnosis. The prevalence of BD I was 4.9%, and 7.8% for BD II. Discussion: Migraine is prevalent within the BD population, particularly among BD II subjects. It is associated with an increased risk of suicidal behaviour and comorbid anxiety disorders. Conversely, migraine sufferers have high rates of current and lifetime psychopathology. A greater understanding of this comorbidity may contribute to our knowledge of the underlying mechanisms of BD.

Published
2010

50. Can body mass index help predict outcome in patients with bipolar disorder?

Author

Claire O'Donovan, Tomas Hajek, Martin Alda, Cynthia V. Calkin, Martina Růžičková, Caroline van de Velde, Claire Slaney, and Julie Garnham

Subjects
Adult, Male, medicine.medical_specialty, Bipolar Disorder, Bipolar I disorder, Adolescent, Statistics as Topic, Population, Comorbidity, Overweight, Article, Body Mass Index, Young Adult, Bipolar II disorder, Predictive Value of Tests, Internal medicine, Prevalence, medicine, Humans, Obesity, Bipolar disorder, education, Psychiatry, Biological Psychiatry, Aged, Aged, 80 and over, Psychiatric Status Rating Scales, Analysis of Variance, education.field_of_study, Models, Statistical, business.industry, Mental Disorders, Not Otherwise Specified, Middle Aged, medicine.disease, Psychiatry and Mental health, Female, medicine.symptom, business, Body mass index
Abstract

Obesity is common in patients with bipolar disor- der (BD), with a prevalence of 20% to 49% (1-3), compared to 18% in the general US population (4). There are a number of possible causes of obesity in BD, including lifestyle, medication exposure, binge-eating comorbidity, neuroendocrine and neurotransmitter dysfunctions, comorbid meta- bolic syndrome, and genetic predisposition. The growing evidence of obesity in patients with BD and its correlation with increased morbidity and mortality led us to study the association between the two disorders more systematically, with the hypothesis that body mass index (BMI) is related to prognosis and outcome. In this paper, we examine differences in sociodemographic, clinical, and medical characteristics of BD patients with elevated BMI. Calkin C, van de Velde C, RuzickovaM, Slaney C, Garnham J, Hajek T, ODonovan C, Alda M. Can body mass index help predict outcome in patients with bipolar disorder? Bipolar Disord 2009: 11: 650-656. a 2009 The Authors. Journal compilation a 2009 John Wiley & A ⁄ S. Objective: Several studies have reported higher prevalence of obesity in patients suffering from bipolar disorder (BD). To study the relation of elevated body mass index (BMI) in patients with BD more closely, we investigated differences in sociodemographic, clinical, and medical characteristics with respect to BMI, with the hypothesis that BMI is related to prognosis and outcome. Methods: We measured the BMI of 276 subjects of a tertiary care sample from the Maritime Bipolar Registry. Subjects were 16 to 83 years old, with psychiatric diagnoses of bipolar I disorder (n = 186), bipolar II disorder (n = 85), and BD not otherwise specified (n = 5). The registry included basic demographic data and details of the clinical presentation. We first examined the variables showing a significant association with BMI; subsequently, we modeled the relationship between BMI and psychiatric outcome using structural equation analysis. Results: The prevalence of obesity in our sample was 39.1%. We found higher BMI in subjects with a chronic course (p < 0.001) and longer duration of illness (p = 0.02), lower scores on the Global Assessment of Functioning Scale (p = 0.02), and on disability (p = 0.002). Overweight patients had more frequent comorbid subthreshold social (p = 0.02) and generalized anxiety disorders (p = 0.05), diabetes mellitus type II (p < 0.001), and hypertension (p = 0.001). Subjects who achieved complete remission of symptoms on lithium showed significantly lower BMI (p = 0.01). Conclusions: Our findings suggest that BMI is associated with the prognosis and outcome of BD. Whether this association is causal remains to be determined.

Published
2009

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