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1. Associations between behavioral and self-reported impulsivity, brain structure, and genetic influences in middle childhood

Author

Jodi M. Gilman, Jasmeen Kaur, Brenden Tervo-Clemmens, Kevin Potter, Brandon T. Sanzo, Randi M. Schuster, James M. Bjork, A. Eden Evins, Joshua L. Roffman, and Phil H. Lee

Subjects
Impulsivity, Genetic predictors, Brain structure, Cortical volume, Cortical area, Childhood, Neurophysiology and neuropsychology, QP351-495
Abstract

Impulsivity undergoes a normative developmental trajectory from childhood to adulthood and is thought to be driven by maturation of brain structure. However, few large-scale studies have assessed associations between impulsivity, brain structure, and genetic susceptibility in children. In 9112 children ages 9–10 from the ABCD study, we explored relationships among impulsivity (UPPS-P impulsive behavior scale; delay discounting), brain structure (cortical thickness (CT), cortical volume (CV), and cortical area (CA)), and polygenic scores for externalizing behavior (PGSEXT). Both higher UPPS-P total scores and more severe delay-discounting had widespread, low-magnitude associations with smaller CA in frontal and temporal regions. No associations were seen between impulsivity and CV or CT. Additionally, higher PGSEXT was associated with both higher UPPS-P scores and with smaller CA and CV in frontal and temporal regions, but in non-overlapping cortical regions, underscoring the complex interplay between genetics and brain structure in influencing impulsivity. These findings indicate that, within large-scale population data, CA is significantly yet weakly associated with each of these impulsivity measures and with polygenic risk for externalizing behaviors, but in distinct brain regions. Future work should longitudinally assess these associations through adolescence, and examine associated functional outcomes, such as future substance use and psychopathology.

Published
2024
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2. Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia

Author

Yu-Han H. Hsu, Greta Pintacuda, Ruize Liu, Eugeniu Nacu, April Kim, Kalliopi Tsafou, Natalie Petrossian, William Crotty, Jung Min Suh, Jackson Riseman, Jacqueline M. Martin, Julia C. Biagini, Daya Mena, Joshua K.T. Ching, Edyta Malolepsza, Taibo Li, Tarjinder Singh, Tian Ge, Shawn B. Egri, Benjamin Tanenbaum, Caroline R. Stanclift, Annie M. Apffel, Steven A. Carr, Monica Schenone, Jake Jaffe, Nadine Fornelos, Hailiang Huang, Kevin C. Eggan, Kasper Lage, Stephan Ripke, Benjamin M. Neale, Aiden Corvin, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Martin Begemann, Richard A. Belliveau, Jr., 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, Kimberley D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chan, Eric Y.H. Chen, Wei Cheng, Eric FC. 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, Franziska Degenhardt, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, 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, Ina Giegling, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, David M. Hougaard, 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, James A. Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee, 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, Patrik K.E. Magnusson, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Bela Melegh, Ingrid Melle, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W. Morris, Ole Mors, Kieran C. Murphy, Robin M. Murray, Inez Myin-Germeys, Bertram Müller-Myhsok, 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, Michele T. Pato, 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, Alan R. Sanders, Ulrich Schall, Christian R. Schubert, Thomas G. Schulze, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Jianxin Shi, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Jordan W. Smoller, Hon-Cheong So, Chris C.A. Spencer, Eli A. Stahl, 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, Rolf Adolfsson, Ole A. Andreassen, Douglas H.R. Blackwood, Elvira Bramon, Joseph D. Buxbaum, Anders D. Børglum, Sven Cichon, Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Tõnu Esko, Pablo V. Gejman, Michael Gill, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen V. Jablensky, Erik G. Jönsson, Kenneth S. Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F. Levinson, Qingqin S. Li, Jianjun Liu, Anil K. Malhotra, Steven A. McCarroll, Andrew McQuillin, Jennifer L. Moran, Preben B. Mortensen, Bryan J. Mowry, Markus M. Nöthen, Roel A. Ophoff, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Tracey L. Petryshen, Danielle Posthuma, Marcella Rietschel, Brien P. Riley, Dan Rujescu, Pak C. Sham, Pamela Sklar, David St Clair, Daniel R. Weinberger, Jens R. Wendland, Thomas Werge, Mark J. Daly, Patrick F. Sullivan, Michael C. O'Donovan, Shengying Qin, Akira Sawa, Rene Kahn, Kyung Sue Hong, Wenzhao Shi, Ming Tsuang, Masanari Itokawa, Gang Feng, Stephen J. Glatt, Xiancang Ma, Jinsong Tang, Yunfeng Ruan, Feng Zhu, Yasue Horiuchi, Byung Dae Lee, Eun-Jeong Joo, Woojae Myung, Kyooseob Ha, Hong-Hee Won, Ji Hyung Baek, Young Chul Chung, Sung-Wan Kim, Agung Kusumawardhani, Wei J. Chen, Hai-Gwo Hwu, Akitoyo Hishimoto, Ikuo Otsuka, Ichiro Sora, Tomoko Toyota, Takeo Yoshikawa, Hiroshi Kunugi, Kotaro Hattori, Sayuri Ishiwata, Shusuke Numata, Tetsuro Ohmori, Makoto Arai, Yuji Ozeki, Kumiko Fujii, Se Joo Kim, Heon-Jeong Lee, Yong Min Ahn, Se Hyun Kim, Kazufumi Akiyama, Kazutaka Shimoda, and Makoto Kinoshita

Subjects
Molecular interaction, Developmental neuroscience, Cellular neuroscience, Proteomics, Science
Abstract

Summary: Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.

Published
2023
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3. Neuroepigenetic signatures of age and sex in the living human brain

Author

Tonya M. Gilbert, Nicole R. Zürcher, Mary C. Catanese, Chieh-En J. Tseng, Maria A. Di Biase, Amanda E. Lyall, Baileigh G. Hightower, Anjali J. Parmar, Anisha Bhanot, Christine J. Wu, Matthew L. Hibert, Minhae Kim, Umar Mahmood, Steven M. Stufflebeam, Frederick A. Schroeder, Changning Wang, Joshua L. Roffman, Daphne J. Holt, Douglas N. Greve, Ofer Pasternak, Marek Kubicki, Hsiao-Ying Wey, and Jacob M. Hooker

Subjects
Science
Abstract

Gene transcription is known to vary with age and sex, although the underlying mechanisms are unresolved. Here, the authors show that epigenetic enzymes known as HDACs, which regulate gene transcription, are increasingly expressed with age in the living human brain, with sex differences also observed.

Published
2019
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4. Working memory load-dependent changes in cortical network connectivity estimated by machine learning

Author

Hamdi Eryilmaz, Kevin F. Dowling, Dylan E. Hughes, Anais Rodriguez-Thompson, Alexandra Tanner, Charlie Huntington, William G. Coon, and Joshua L. Roffman

Subjects
Working memory, Task load, Ventral attention network, Functional connectivity, Machine learning, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Working memory engages multiple distributed brain networks to support goal-directed behavior and higher order cognition. Dysfunction in working memory has been associated with cognitive impairment in neuropsychiatric disorders. It is important to characterize the interactions among cortical networks that are sensitive to working memory load since such interactions can also hint at the impaired dynamics in patients with poor working memory performance. Functional connectivity is a powerful tool used to investigate coordinated activity among local and distant brain regions. Here, we identified connectivity footprints that differentiate task states representing distinct working memory load levels. We employed linear support vector machines to decode working memory load from task-based functional connectivity matrices in 177 healthy adults. Using neighborhood component analysis, we also identified the most important connectivity pairs in classifying high and low working memory loads. We found that between-network coupling among frontoparietal, ventral attention and default mode networks, and within-network connectivity in ventral attention network are the most important factors in classifying low vs. high working memory load. Task-based within-network connectivity profiles at high working memory load in ventral attention and default mode networks were the most predictive of load-related increases in response times. Our findings reveal the large-scale impact of working memory load on the cerebral cortex and highlight the complex dynamics of intrinsic brain networks during active task states.

Published
2020
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5. The human cortex possesses a reconfigurable dynamic network architecture that is disrupted in psychosis

Author

Jenna M. Reinen, Oliver Y. Chén, R. Matthew Hutchison, B. T. Thomas Yeo, Kevin M. Anderson, Mert R. Sabuncu, Dost Öngür, Joshua L. Roffman, Jordan W. Smoller, Justin T. Baker, and Avram J. Holmes

Subjects
Science
Abstract

Temporal changes in brain dynamics are linked with cognitive abilities, but neither their stability nor relationship to psychosis is clear. Here, authors describe the dynamic neural architecture in healthy controls and patients with psychosis and find that they are stable over time and can predict psychotic symptoms.

Published
2018
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6. Neural determinants of human goal-directed vs. habitual action control and their relation to trait motivation

Author

Hamdi Eryilmaz, Anais Rodriguez-Thompson, Alexandra S. Tanner, Madeline Giegold, Franklin C. Huntington, and Joshua L. Roffman

Subjects
Medicine, Science
Abstract

Abstract Instrumental learning is mediated by goal-directed and habit systems in the brain. While rodent studies implicate distinct prefrontal/striatal regions in goal-directed and habit learning, neural systems underpinning these two processes in humans remain poorly understood. Here, using a validated discrimination learning task that distinguishes goal-directed learning from habit learning in 72 subjects in fMRI, we investigated the corticostriatal correlates of goal-directed learning and tested whether brain activation during learning is associated with trait motivation and behavioral performance in the post-learning test phase. Participants showed enhanced activation in medial prefrontal and posterior cingulate cortices during goal-directed action selection in the training phase, whereas habitual action selection activated bilateral insula, bilateral dorsal caudate and left precentral gyrus. In addition, early phase of learning was associated with increased activation in the frontoparietal control network and dorsal striatum, whereas default mode regions depicted increased activation in the late phase. Finally, avoidance motivation scores measured by Behavioral Inhibition/Activation System (BIS/BAS) correlated with accuracy during goal-directed learning and showed a nominally significant correlation with activation in dorsomedial prefrontal cortex during goal-directed acquisition of stimuli. These findings reveal the temporal dynamics of instrumental behavior and suggest that avoidance motivation predicts performance and brain activity during goal-directed learning.

Published
2017
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7. Novel genetic loci associated with hippocampal volume

Author

Derrek P. Hibar, Hieab H. H. Adams, Neda Jahanshad, Ganesh Chauhan, Jason L. Stein, Edith Hofer, Miguel E. Renteria, Joshua C. Bis, Alejandro Arias-Vasquez, M. Kamran Ikram, Sylvane Desrivières, Meike W. Vernooij, Lucija Abramovic, Saud Alhusaini, Najaf Amin, Micael Andersson, Konstantinos Arfanakis, Benjamin S. Aribisala, Nicola J. Armstrong, Lavinia Athanasiu, Tomas Axelsson, Ashley H. Beecham, Alexa Beiser, Manon Bernard, Susan H. Blanton, Marc M. Bohlken, Marco P. Boks, Janita Bralten, Adam M. Brickman, Owen Carmichael, M. Mallar Chakravarty, Qiang Chen, Christopher R. K. Ching, Vincent Chouraki, Gabriel Cuellar-Partida, Fabrice Crivello, Anouk Den Braber, Nhat Trung Doan, Stefan Ehrlich, Sudheer Giddaluru, Aaron L. Goldman, Rebecca F. Gottesman, Oliver Grimm, Michael E. Griswold, Tulio Guadalupe, Boris A. Gutman, Johanna Hass, Unn K. Haukvik, David Hoehn, Avram J. Holmes, Martine Hoogman, Deborah Janowitz, Tianye Jia, Kjetil N. Jørgensen, Nazanin Karbalai, Dalia Kasperaviciute, Sungeun Kim, Marieke Klein, Bernd Kraemer, Phil H. Lee, David C. M. Liewald, Lorna M. Lopez, Michelle Luciano, Christine Macare, Andre F. Marquand, Mar Matarin, Karen A. Mather, Manuel Mattheisen, David R. McKay, Yuri Milaneschi, Susana Muñoz Maniega, Kwangsik Nho, Allison C. Nugent, Paul Nyquist, Loes M. Olde Loohuis, Jaap Oosterlaan, Martina Papmeyer, Lukas Pirpamer, Benno Pütz, Adaikalavan Ramasamy, Jennifer S. Richards, Shannon L. Risacher, Roberto Roiz-Santiañez, Nanda Rommelse, Stefan Ropele, Emma J. Rose, Natalie A. Royle, Tatjana Rundek, Philipp G. Sämann, Arvin Saremi, Claudia L. Satizabal, Lianne Schmaal, Andrew J. Schork, Li Shen, Jean Shin, Elena Shumskaya, Albert V. Smith, Emma Sprooten, Lachlan T. Strike, Alexander Teumer, Diana Tordesillas-Gutierrez, Roberto Toro, Daniah Trabzuni, Stella Trompet, Dhananjay Vaidya, Jeroen Van der Grond, Sven J. Van der Lee, Dennis Van der Meer, Marjolein M. J. Van Donkelaar, Kristel R. Van Eijk, Theo G. M. Van Erp, Daan Van Rooij, Esther Walton, Lars T. Westlye, Christopher D. Whelan, Beverly G. Windham, Anderson M. Winkler, Katharina Wittfeld, Girma Woldehawariat, Christiane Wolf, Thomas Wolfers, Lisa R. Yanek, Jingyun Yang, Alex Zijdenbos, Marcel P. Zwiers, Ingrid Agartz, Laura Almasy, David Ames, Philippe Amouyel, Ole A. Andreassen, Sampath Arepalli, Amelia A. Assareh, Sandra Barral, Mark E. Bastin, Diane M. Becker, James T. Becker, David A. Bennett, John Blangero, Hans van Bokhoven, Dorret I. Boomsma, Henry Brodaty, Rachel M. Brouwer, Han G. Brunner, Randy L. Buckner, Jan K. Buitelaar, Kazima B. Bulayeva, Wiepke Cahn, Vince D. Calhoun, Dara M. Cannon, Gianpiero L. Cavalleri, Ching-Yu Cheng, Sven Cichon, Mark R. Cookson, Aiden Corvin, Benedicto Crespo-Facorro, Joanne E. Curran, Michael Czisch, Anders M. Dale, Gareth E. Davies, Anton J. M. De Craen, Eco J. C. De Geus, Philip L. De Jager, Greig I. De Zubicaray, Ian J. Deary, Stéphanie Debette, Charles DeCarli, Norman Delanty, Chantal Depondt, Anita DeStefano, Allissa Dillman, Srdjan Djurovic, Gary Donohoe, Wayne C. Drevets, Ravi Duggirala, Thomas D. Dyer, Christian Enzinger, Susanne Erk, Thomas Espeseth, Iryna O. Fedko, Guillén Fernández, Luigi Ferrucci, Simon E. Fisher, Debra A. Fleischman, Ian Ford, Myriam Fornage, Tatiana M. Foroud, Peter T. Fox, Clyde Francks, Masaki Fukunaga, J. Raphael Gibbs, David C. Glahn, Randy L. Gollub, Harald H. H. Göring, Robert C. Green, Oliver Gruber, Vilmundur Gudnason, Sebastian Guelfi, Asta K. Håberg, Narelle K. Hansell, John Hardy, Catharina A. Hartman, Ryota Hashimoto, Katrin Hegenscheid, Andreas Heinz, Stephanie Le Hellard, Dena G. Hernandez, Dirk J. Heslenfeld, Beng-Choon Ho, Pieter J. Hoekstra, Wolfgang Hoffmann, Albert Hofman, Florian Holsboer, Georg Homuth, Norbert Hosten, Jouke-Jan Hottenga, Matthew Huentelman, Hilleke E. Hulshoff Pol, Masashi Ikeda, Clifford R. Jack Jr, Mark Jenkinson, Robert Johnson, Erik G. Jönsson, J. Wouter Jukema, René S. Kahn, Ryota Kanai, Iwona Kloszewska, David S. Knopman, Peter Kochunov, John B. Kwok, Stephen M. Lawrie, Hervé Lemaître, Xinmin Liu, Dan L. Longo, Oscar L. Lopez, Simon Lovestone, Oliver Martinez, Jean-Luc Martinot, Venkata S. Mattay, Colm McDonald, Andrew M. McIntosh, Francis J. McMahon, Katie L. McMahon, Patrizia Mecocci, Ingrid Melle, Andreas Meyer-Lindenberg, Sebastian Mohnke, Grant W. Montgomery, Derek W. Morris, Thomas H. Mosley, Thomas W. Mühleisen, Bertram Müller-Myhsok, Michael A. Nalls, Matthias Nauck, Thomas E. Nichols, Wiro J. Niessen, Markus M. Nöthen, Lars Nyberg, Kazutaka Ohi, Rene L. Olvera, Roel A. Ophoff, Massimo Pandolfo, Tomas Paus, Zdenka Pausova, Brenda W. J. H. Penninx, G. Bruce Pike, Steven G. Potkin, Bruce M. Psaty, Simone Reppermund, Marcella Rietschel, Joshua L. Roffman, Nina Romanczuk-Seiferth, Jerome I. Rotter, Mina Ryten, Ralph L. Sacco, Perminder S. Sachdev, Andrew J. Saykin, Reinhold Schmidt, Helena Schmidt, Peter R. Schofield, Sigurdur Sigursson, Andrew Simmons, Andrew Singleton, Sanjay M. Sisodiya, Colin Smith, Jordan W. Smoller, Hilkka Soininen, Vidar M. Steen, David J. Stott, Jessika E. Sussmann, Anbupalam Thalamuthu, Arthur W. Toga, Bryan J. Traynor, Juan Troncoso, Magda Tsolaki, Christophe Tzourio, Andre G. Uitterlinden, Maria C. Valdés Hernández, Marcel Van der Brug, Aad van der Lugt, Nic J. A. van der Wee, Neeltje E. M. Van Haren, Dennis van ’t Ent, Marie-Jose Van Tol, Badri N. Vardarajan, Bruno Vellas, Dick J. Veltman, Henry Völzke, Henrik Walter, Joanna M. Wardlaw, Thomas H. Wassink, Michael E. Weale, Daniel R. Weinberger, Michael W. Weiner, Wei Wen, Eric Westman, Tonya White, Tien Y. Wong, Clinton B. Wright, Ronald H. Zielke, Alan B. Zonderman, Nicholas G. Martin, Cornelia M. Van Duijn, Margaret J. Wright, W. T. Longstreth, Gunter Schumann, Hans J. Grabe, Barbara Franke, Lenore J. Launer, Sarah E. Medland, Sudha Seshadri, Paul M. Thompson, and M. Arfan Ikram

Subjects
Science
Abstract

The hippocampus in mammalian brain varies in size across individuals. Here, Hibar and colleagues perform a genome-wide association meta-analysis to find six genetic loci with significant association to hippocampus volume.

Published
2017
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8. Multidimensional heritability analysis of neuroanatomical shape

Author

Tian Ge, Martin Reuter, Anderson M. Winkler, Avram J. Holmes, Phil H. Lee, Lee S. Tirrell, Joshua L. Roffman, Randy L. Buckner, Jordan W. Smoller, and Mert R. Sabuncu

Subjects
Science
Abstract

Neuroanatomical shape measurements are multidimensional geometric descriptions of brain structure. This study develops multivariate heritability analysis methods and examines structural brain MRI scans and genetic data to estimate the heritability of neuroanatomical shape.

Published
2016
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9. A Cross-Sectional Study of Dietary and Genetic Predictors of Blood Folate Levels in Healthy Young Adults

Author

Daniel Cummings, Kevin F. Dowling, Noah J. Silverstein, Alexandra S. Tanner, Hamdi Eryilmaz, Jordan W. Smoller, and Joshua L. Roffman

Subjects
FOLH1, dietary folate, RBC folate, folic acid, Nutrition. Foods and food supply, TX341-641
Abstract

Since 1998, the U.S. has mandated folic acid (FA) fortification of certain grain products to reduce the risk of neural tube defects. Folate intake and red blood cell (RBC) folate concentrations increased substantially post-intervention, although recent studies raise concerns about the level of ongoing benefit. This study investigated blood folate level determinants in healthy young adults, including intake of naturally occurring food folate, synthetic FA, and the interaction of naturally occurring food folate with a common missense variant in the FOLH1 gene thought to affect absorption. Participants (n = 265) completed the Diet History Questionnaire II, RBC folate testing, and were genotyped for the 484T>C FOLH1 variant. Men reported significantly greater intake of all folate sources except for supplemental FA, but RBC folate levels did not significantly differ by sex. Synthetic FA was a stronger predictor of RBC folate than naturally occurring food folate. In the largest racial group, synthetic FA and the interaction of FOLH1 genotype with naturally occurring food folate significantly predicted RBC folate, with the overall model accounting for 13.8% of the variance in RBC folate levels. Blood folate levels rely on a complex interaction of natural and synthetic folate intake as well as FOLH1 genotype.

Published
2017
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10. Genetic patterning for child psychopathology is distinct from that for adults and implicates fetal cerebellar development

Author

Dylan E. Hughes, Keiko Kunitoki, Safia Elyounssi, Mannan Luo, Oren M. Bazer, Casey E. Hopkinson, Kevin F. Dowling, Alysa E. Doyle, Erin C. Dunn, Hamdi Eryilmaz, Jodi M. Gilman, Daphne J. Holt, Eve M. Valera, Jordan W. Smoller, Charlotte A. M. Cecil, Henning Tiemeier, Phil H. Lee, Joshua L. Roffman, Department of Psychology, Education and Child Studies, Epidemiology, and Child and Adolescent Psychiatry / Psychology

Subjects
SDG 3 - Good Health and Well-being, General Neuroscience
Abstract

Childhood psychiatric symptoms are often diffuse but can coalesce into discrete mental illnesses during late adolescence. We leveraged polygenic scores (PGSs) to parse genomic risk for childhood symptoms and to uncover related neurodevelopmental mechanisms with transcriptomic and neuroimaging data. In independent samples (Adolescent Brain Cognitive Development, Generation R) a narrow cross-disorder neurodevelopmental PGS, reflecting risk for attention deficit hyperactivity disorder, autism, depression and Tourette syndrome, predicted psychiatric symptoms through early adolescence with greater sensitivity than broad cross-disorder PGSs reflecting shared risk across eight psychiatric disorders, the disorder-specific PGS individually or two other narrow cross-disorder (Compulsive, Mood-Psychotic) scores. Neurodevelopmental PGS-associated genes were preferentially expressed in the cerebellum, where their expression peaked prenatally. Further, lower gray matter volumes in cerebellum and functionally coupled cortical regions associated with psychiatric symptoms in mid-childhood. These findings demonstrate that the genetic underpinnings of pediatric psychiatric symptoms differ from those of adult illness, and implicate fetal cerebellar developmental processes that endure through childhood.

Published
2023

11. Distinct effects of interleukin-6 and interferon-γ on differentiating human cortical neurons

Author

Annie Kathuria, Kara Lopez-Lengowski, Joshua L. Roffman, and Rakesh Karmacharya

Subjects
Neurons, Pluripotent Stem Cells, Interferon-gamma, Behavioral Neuroscience, Folic Acid, Interleukin-6, Endocrine and Autonomic Systems, Immunology, Cytokines, Humans, Cell Differentiation, Article
Abstract

Translational evidence suggests that cytokines involved in maternal immune activation (MIA), such as interleukin-6 (IL-6) and interferon-γ (IFN-γ), can cross the placenta, injure fetal brain, and predispose to neuropsychiatric disorders. To elaborate developmental neuronal sequelae of MIA, we differentiated human pluripotent stem cells to cortical neurons over a two-month period, exposing them to IL-6 or IFN-γ. IL-6 impacted expression of genes regulating extracellular matrix, actin cytoskeleton and TGF-β signaling while IFN-γ impacted genes regulating antigen processing, major histocompatibility complex and endoplasmic reticulum biology. IL-6, but not IFN-γ, altered mitochondrial respiration while IFN-γ, but not IL-6, induced reduction in dendritic spine density. Pre-treatment with folic acid, which has known neuroprotective and anti-inflammatory properties, ameliorated IL-6 effects on mitochondrial respiration and IFN-γ effects on dendritic spine density. These findings suggest distinct mechanisms for how fetal IL-6 and IFN-γ exposure influence risk for neuropsychiatric disorders, and how folic acid can mitigate such risk.

Published
2022

12. Uncovering and mitigating bias in large, automated MRI analyses of brain development

Author

Safia Elyounssi, Keiko Kunitoki, Jacqueline A. Clauss, Eline Laurent, Kristina Kane, Dylan E. Hughes, Casey E. Hopkinson, Oren Bazer, Rachel Freed Sussman, Alysa E. Doyle, Hang Lee, Brenden Tervo-Clemmens, Hamdi Eryilmaz, Randy L. Gollub, Deanna M. Barch, Theodore D. Satterthwaite, Kevin F. Dowling, and Joshua L. Roffman

Abstract

Large, population-based MRI studies of adolescents promise transformational insights into neurodevelopment and mental illness risk1, 2. However, MRI studies of youth are especially susceptible to motion and other artifacts3, 4. These artifacts may go undetected by automated quality control (QC) methods that are preferred in high-throughput imaging studies,5and can potentially introduce non-random noise into clinical association analyses. Here we demonstrate bias in structural MRI analyses of children due to inclusion of lower quality images, as identified through rigorous visual quality control of 11,263 T1 MRI scans obtained at age 9-10 through the Adolescent Brain Cognitive Development (ABCD) Study6. Compared to the best-rated images (44.9% of the sample), lower-quality images generally associated with decreased cortical thickness and increased cortical surface area measures (Cohen’s d 0.14-2.84). Variable image quality led to counterintuitive patterns in analyses that associated structural MRI and clinical measures, as inclusion of lower-quality scans altered apparent effect sizes in ways that increased risk for both false positives and negatives. Quality-related biases were partially mitigated by controlling for surface hole number, an automated index of topological complexity that differentiated lower-quality scans with good specificity at Baseline (0.81-0.93) and in 1,000 Year 2 scans (0.88-1.00). However, even among the highest-rated images, subtle topological errors occurred during image preprocessing, and their correction through manual edits significantly and reproducibly changed thickness measurements across much of the cortex (d 0.15-0.92). These findings demonstrate that inadequate QC of youth structural MRI scans can undermine advantages of large sample size to detect meaningful associations.

Published
2023

13. Cortical thickness across the lifespan

Author

Simon E. Fisher, Eveline A. Crone, Dominik Grotegerd, Jilly Naaijen, Anders M. Dale, Sean N. Hatton, Ramona Baur-Streubel, Anthony A. James, Daniel Brandeis, Andrew J. Kalnin, Andreas Reif, Hans-Jörgen Grabe, Pieter J. Hoekstra, Lars Nyberg, Fleur M. Howells, Moji Aghajani, Randy L. Buckner, Daniel A. Rinker, Steven G. Potkin, Dennis van 't Ent, Rachel M. Brouwer, Sophia Frangou, Yang Wang, Nhat Trung Doan, Theodore D. Satterthwaite, Christine Lochner, Geraldo F. Busatto, Lars T. Westlye, Lara M. Wierenga, Calhoun Vd, Henry Brodaty, Carles Soriano-Mas, Annette Conzelmann, Christian K. Tamnes, Julian N. Trollor, Nicholas G. Martin, Neeltje E.M. van Haren, René S. Kahn, Irina Lebedeva, Philip Asherson, Suzanne C. Swagerman, John A. Joska, Theophilus N. Akudjedu, Kang Sim, Lachlan T. Strike, Patricia Gruner, Brenna C. McDonald, Thomas Frodl, Edith Pomarol-Clotet, Víctor Ortiz-García de la Foz, Margaret J. Wright, Norbert Hosten, Jean-Paul Fouche, Bernd Weber, Salvador Sarró, Wei Wen, Dag Alnæs, Greig I. de Zubicaray, Iris E. C. Sommer, Marise W. J. Machielsen, Knut Schnell, Dara M. Cannon, Paola Fuentes-Claramonte, Josiane Bourque, Andreas Meyer-Lindenberg, Anton Albajes-Eizagirre, Sarah Hohmann, Erin W. Dickie, Theo G.M. van Erp, Micael Andersson, Paul Pauli, Thomas Espeseth, Heather C. Whalley, Victoria Chubar, Ruben C. Gur, Tomohiro Nakao, Xavier Caseras, Alessandro Bertolino, Ignacio Martínez-Zalacaín, Katharina Wittfeld, Erick J. Canales-Rodríguez, David C. Glahn, Neda Jahanshad, Jiyang Jiang, Katie L. McMahon, Stefan Borgwardt, Erlend S. Dørum, Jaap Oosterlaan, Won Hee Lee, Alan Breier, Steven Williams, Aristotle N. Voineskos, Bernard Mazoyer, Jordan W. Smoller, Nancy C. Andreasen, Ilya M. Veer, Tiffany M. Chaim-Avancini, Sophie Maingault, Paul M. Thompson, Eco J. C. de Geus, Luisa Lázaro, Giulio Pergola, Efstathios Papachristou, Beng-Choon Ho, David Mataix-Cols, Esther Walton, Ben J. Harrison, Dirk J. Heslenfeld, Pablo Najt, Helena Fatouros-Bergman, Derrek P. Hibar, Gunter Schumann, Raymond Salvador, Lieuwe de Haan, Henry Völzke, Joaquim Radua, Henk Temmingh, Lianne Schmaal, Martine Hoogman, Daniel H. Wolf, Georg C. Ziegler, Marieke Klein, Barbara Franke, Erik G. Jönsson, Laura Koenders, Stefan Ehrlich, Oliver Gruber, Ingrid Agartz, Kun Yang, Ryota Kanai, Sarah Baumeister, Colm McDonald, Annabella Di Giorgio, Amanda Worker, Anne Uhlmann, Marcus V. Zanetti, Danai Dima, Matthew D. Sacchet, Sarah E. Medland, Aurora Bonvino, Benedicto Crespo-Facorro, Jan Egil Nordvik, Joshua L. Roffman, Yannis Paloyelis, Jessica A. Turner, T. P. Klyushnik, Christopher G. Davey, Rachel E. Gur, Ian B. Hickie, Christopher R.K. Ching, Jonna Kuntsi, Tobias Banaschewski, Chaim Huyser, Amirhossein Modabbernia, John D. West, Fabrice Crivello, Núria Bargalló, Patricia J. Conrod, Nic J.A. van der Wee, Mauricio H. Serpa, Thomas H. Wassink, Kathryn I. Alpert, Dick J. Veltman, Andrew J. Saykin, Genevieve McPhilemy, Perminder S. Sachdev, Vincent P. Clark, Ian H. Gotlib, Susanne Erk, Henrik Walter, Dennis van den Meer, Simon Cervenka, Oliver Grimm, Andrew M. McIntosh, Alexander Tomyshev, Francisco X. Castellanos, Bernd Kramer, Klaus-Peter Lesch, Odile A. van den Heuvel, Sophia I. Thomopoulos, Diana Tordesillas-Gutiérrez, Terry L. Jernigan, Yulyia Yoncheva, Anouk den Braber, Jim Lagopoulos, Maria J. Portella, Ole A. Andreassen, Gaelle E. Doucet, Avram J. Holmes, Nynke A. Groenewold, Pedro G.P. Rosa, Hilleke E. Hulshoff Pol, Sanne Koops, José M. Menchón, Jan K. Buitelaar, Dan J. Stein, Dorret I. Boomsma, Lei Wang, C.A. Hartman, Pascual Sánchez-Juan, Andreas Heinz, European Commission, National Institute of Child Health and Human Development (US), QIMR Berghofer Medical Research Institute (Australia), University of Queensland, National Cancer Institute (US), Dutch Research Council, Netherlands Organisation for Health Research and Development, National Institute of Mental Health (US), European Research Council, National Center for Advancing Translational Sciences (US), Medical Research Council (UK), Fundación Marques de Valdecilla, Instituto de Salud Carlos III, Swedish Research Council, South-Eastern Norway Regional Health Authority, Research Council of Norway, Icahn School of Medicine at Mount Sinai, South London and Maudsley NHS Foundation Trust, NHS Foundation Trust, National Institute for Health Research (UK), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Movement Disorder (MD), Developmental Neuroscience in Society, Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, APH - Mental Health, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, Child Psychiatry, ANS - Cellular & Molecular Mechanisms, General Paediatrics, ARD - Amsterdam Reproduction and Development, Karolinska Schizophrenia Project (KaSP), Ontwikkelingspsychologie (Psychologie, FMG), Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Epidemiology and Data Science, Neurology, Amsterdam Neuroscience - Neurodegeneration, Pediatric surgery, Anatomy and neurosciences, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Brain Imaging, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Biological Psychology, APH - Methodology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Educational and Family Studies, Cognitive Psychology, IBBA, Clinical Neuropsychology, Faculty of Behavioural and Movement Sciences, and APH - Personalized Medicine

Subjects
Male, Aging, Neurologi, Audiology, Trajectories, 0302 clinical medicine, 130 000 Cognitive Neurology & Memory, diagnostic imaging [Cerebral Cortex], Child, Research Articles, Cerebral Cortex, Psychiatry, Aged, 80 and over, Radiological and Ultrasound Technology, Fractional polynomial, 05 social sciences, Radiology, Nuclear Medicine & Medical Imaging, 1. No poverty, Cognition, Middle Aged, Cerebral cortex, Regression, 3. Good health, Escorça cerebral, Neurology, Radiology Nuclear Medicine and imaging, Healthy individuals, Child, Preschool, anatomy & histology [Cerebral Cortex], Female, Analysis of variance, Anatomy, Life Sciences & Biomedicine, Trajectorie, Research Article, Neuroinformatics, Adult, medicine.medical_specialty, Adolescent, Human Development, Clinical Neurology, BF, Neuroimaging, Biology, Development, 050105 experimental psychology, Psykiatri, Cortical thickness, 03 medical and health sciences, Young Adult, Neuroimaging genetics, Envelliment, medicine, Humans, trajectories, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, ddc:610, development, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Science & Technology, Brain morphometry, aging, Neurosciences, cortical thickness, Cross-Sectional Studies, RC0321, Neurology (clinical), Neurosciences & Neurology, 030217 neurology & neurosurgery, physiology [Human Development]
Abstract

Special Issue: The ENIGMA Consortium: the first 10 years., Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes., European Community's Seventh Framework Programme, Grant/Award Numbers: 278948, 602450, 603016, 602805; US National Institute of Child Health and Human Development, Grant/Award Numbers: RO1HD050735, 1009064, 496682; QIMR Berghofer Medical Research Institute and the Centre for Advanced Imaging, University of Queensland; ICTSI NIH/NCRR, Grant/Award Number: RR025761; European Community's Horizon 2020 Programme, Grant/Award Numbers: 667302, 643051; Vici Innovation Program, Grant/Award Numbers: #91619115, 016-130-669; NWO Brain & Cognition Excellence Program, Grant/Award Number: 433-09-229; Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL); Spinozapremie, Grant/Award Number: NWO-56-464-14192; Biobanking and Biomolecular Resources Research Infrastructure, Grant/Award Numbers: 184.033.111, 184.021.007; Netherlands Organization for Health Research and Development (ZonMW), Grant/Award Numbers: 480-15-001/674, 024.001.003, 911-09-032, 056-32-010, 481-08-011, 016-115-035, 31160008, 400-07-080, 400-05-717, 451-04-034, 463-06-001, 480-04-004, 904-61-193, 912-10-020, 985-10-002, 904-61-090; NIMH, Grant/Award Number: R01 MH090553; Geestkracht programme of the Dutch Health Research Council, Grant/Award Number: 10-000-1001; FP7 Ideas: European Research Council; Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Grant/Award Numbers: NWO/SPI 56-464-14192, NWO-MagW 480-04-004, 433-09-220, NWO 51.02.062, NWO 51.02.061; National Center for Advancing Translational Sciences, National Institutes of Health, Grant/Award Number: UL1 TR000153; National Center for Research Resources; National Center for Research Resources at the National Institutes of Health, Grant/Award Numbers: NIH 1U24 RR025736-01, NIH 1U24 RR021992; NIH Institutes contributing to the Big Data to Knowledge; U.S. National Institutes of Health, Grant/Award Numbers: R01 CA101318, P30 AG10133, R01 AG19771; Medical Research Council, Grant/Award Numbers: U54EB020403, G0500092; National Institute of Mental Health, Grant/Award Numbers: R01MH117014, R01MH042191; Fundación Instituto de Investigación Marqués de Valdecilla, Grant/Award Numbers: API07/011, NCT02534363, NCT0235832; Instituto de Salud Carlos III, Grant/Award Numbers: PI14/00918, PI14/00639, PI060507, PI050427, PI020499; Swedish Research Council, Grant/Award Numbers: 523-2014-3467, 2017-00949, 521-2014-3487; South-Eastern Norway Health Authority; the Research Council of Norway, Grant/Award Number: 223273; South Eastern Norway Regional Health Authority, Grant/Award Numbers: 2017-112, 2019107; Icahn School of Medicine at Mount Sinai; Seventh Framework Programme (FP7/2007-2013), Grant/Award Number: 602450; National Institutes of Health, Grant/Award Numbers: R01 MH116147, R01 MH113619, R01 MH104284; South London and Maudsley NHS Foundation Trust; the National Institute for Health Research (NIHR)

Published
2022

14. Greater male than female variability in regional brain structure across the lifespan

Author

Erick J. Canales-Rodríguez, Hans J. Grabe, Dirk J. Heslenfeld, Erik G. Jönsson, Oliver Gruber, Daniel Brandeis, Yang Wang, Henry Brodaty, Ruben C. Gur, Iris E. C. Sommer, Paul M. Thompson, Knut K. Kolskår, Christopher G. Davey, Dick J. Veltman, Eco J. C. de Geus, Tobias Banaschewski, Greig I. Zubicaray, Xavier Caseras, Sarah Baumeister, Raquel E. Gur, Vincent P. Clark, Maria J. Portella, Simon E. Fisher, Christopher R.K. Ching, Lars T. Westlye, Laura Koenders, Vince D. Calhoun, Carles Soriano-Mas, Nicholas G. Martin, Stefan Ehrlich, Fleur M. Howells, Catharina A. Hartman, Matthew D. Sacchet, Ole A. Andreassen, Josiane Bourque, Fabrice Crivello, Annette Conzelmann, Jaap Oosterlaan, Brenna C. McDonald, Gaelle E. Doucet, Avram J. Holmes, José M. Menchón, Danai Dima, Moji Aghajani, Joshua L. Roffman, Steven Williams, Lei Wang, David Mataix-Cols, Philip R. Szeszko, Bernd Weber, Tiril P. Gurholt, Sarah Hohmann, Ian H. Gotlib, Patricia Gruner, Anthony C. James, Paul Pauli, Lara M. Wierenga, Andrew M. McIntosh, Andrew J. Kalnin, Jim Lagopoulos, Henrik Walter, Andreas Reif, Andrew Simmons, Norbert Hosten, Pieter J. Hoekstra, Aristotle Voineskos, Alexander Tomyshev, Anton Albajes-Eizagirre, Jean-Paul Fouche, Dara M. Cannon, Ignacio Martínez‐Zalacaín, Geneviève Richard, Theophilus N. Akudjedu, David C. Glahn, Patricia J. Conrod, Ben J. Harrison, Alan Anticevic, Martine Hoogman, Francisco X. Castellanos, Bernd Kramer, Neda Jahanshad, Lieuwe de Haan, Dennis van der Meer, John D. West, Alan Breier, Jordan W. Smoller, P. G. P. Rosa, Katharina Wittfeld, Dan J. Stein, Jiyang Jiang, Jilly Naaijen, Christine Lochner, Dorret I. Boomsma, Alessandro Bertolino, Marise W. J. Machielsen, Hilleke E. Hulshoff Pol, Henry Völzke, Christian K. Tamnes, Ingrid Agartz, Georg C. Ziegler, Marieke Klein, Lars Nyberg, Perminder S. Sachdev, Philip Asherson, I.M. Veer, Sean N. Hatton, Núria Bargalló, Annabella Di Giorgio, Henk Temmingh, John A. Joska, Odile A. van den Heuvel, Wei Wen, Eveline A Crone, Kang Sim, Kathryn I. Alpert, Dennis van 't Ent, Jan K. Buitelaar, Joaquim Radua, Julian N. Trollor, B Mazoyer, Chaim Huyser, H. C. Whalley, Irina Lebedeva, Erin W. Dickie, Marcus Vinicus Zanetti, Stefan Borgwardt, Theodore D. Satterthwaite, Daniel H Wolf, Sophia I. Thomopoulos, Giulio Pergola, Luisa Lazaro, Ramona Baur-Streubel, Beathe Haatveit, Yannis Paloyelis, Ian B. Hickie, Jonna Kuntsi, Sophia Frangou, R. Salvador, Geraldo F. Busatto, Margaret J. Wright, Aurora Bonvino, Edith Pomarol-Clotet, Anouk den Braber, Lachlan T. Strike, Phil Lee, Anne Uhlmann, Yuliya N. Yoncheva, Mauricio H. Serpa, Dag Alnæs, Paola Fuentes-Claramonte, Katie L. McMahon, Andrew J. Saykin, Genevieve McPhilemy, Tiffany M. Chaim-Avancini, Sophie Maingault, Barbara Franke, Colm McDonald, Rachel M. Brouwer, Salvador Sarró, Department of Psychology, Education and Child Studies, Biological Psychology, APH - Mental Health, APH - Methodology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, AMS - Ageing & Vitality, AMS - Sports, APH - Personalized Medicine, Cognitive Psychology, Clinical Neuropsychology, IBBA, Karolinska Schizophrenia Project (KaSP) Consortium, Adult Psychiatry, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, Child Psychiatry, ANS - Cellular & Molecular Mechanisms, ANS - Amsterdam Neuroscience, General Paediatrics, ARD - Amsterdam Reproduction and Development, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Movement Disorder (MD), Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Neurology, Amsterdam Neuroscience - Neurodegeneration, Anatomy and neurosciences, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Pediatric surgery, and Amsterdam Neuroscience - Brain Imaging

Subjects
Male, Netherlands Twin Register (NTR), SEGMENTATION, Vulnerability, Disease, HM, 0302 clinical medicine, Anàlisi de variància, 130 000 Cognitive Neurology & Memory, diagnostic imaging [Cerebral Cortex], sexual characteristics, Analysis of variance, nuclear magnetic resonance imaging, Cervell, Research Articles, Cerebral Cortex, Sex Characteristics, Radiological and Ultrasound Technology, 05 social sciences, Brain, clinical trial, Brain Structure, Magnetic Resonance Imaging, Early life, Adolescence, medicine.anatomical_structure, Neurology, Cerebral cortex, Healthy individuals, X-CHROMOSOME, anatomy & histology [Cerebral Cortex], Evolution of the brain, Female, Anatomy, Neurovetenskaper, Research Article, Radiology, Nuclear Medicine and Medical Imaging, Neuroinformatics, SEX-DIFFERENCES, diagnostic imaging, brain, Human Development, BF, Neuroimaging, SURFACE-AREA, Evolució del cervell, Regional area, Biology, MULTISAMPLE, 050105 experimental psychology, brain cortex, 03 medical and health sciences, CEREBRAL-CORTEX, Sex differences, medicine, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, human, ddc:610, Cortical surface, GENERAL INTELLIGENCE, diagnostic imaging [Brain], METAANALYSIS, biological variation, HUMAN HIPPOCAMPUS, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], physiology [Biological Variation, Population], Neurosciences, Gender, Brain Cortical Thickness, multicenter study, Biological Variation, Population, Diferències entre sexes, physiology, RC0321, Radiologi och bildbehandling, Neurology (clinical), anatomy & histology [Brain], 170 000 Motivational & Cognitive Control, 030217 neurology & neurosurgery, anatomy and histology, meta analysis, physiology [Human Development], Demography
Abstract

Contains fulltext : 248376.pdf (Publisher’s version ) (Open Access) For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.

Published
2022

16. Normative Modeling of Brain Morphometry Across the Lifespan using CentileBrain: Algorithm Benchmarking and Model Optimization

Author

Ruiyang Ge, Yuetong Yu, Yi Xuan Qi, Yunan Vera Fan, Shiyu Chen, Chuntong Gao, Shalaila S Haas, Amirhossein Modabbernia, Faye New, Ingrid Agartz, Philip Asherson, Rosa Ayesa-Arriola, Nerisa Banaj, Tobias Banaschewski, Sarah Baumeister, Alessandro Bertolino, Dorret I Boomsma, Stefan Borgwardt, Josiane Bourque, Daniel Brandeis, Alan Breier, Henry Brodaty, Rachel M Brouwer, Randy Buckner, Jan K Buitelaar, Dara M Cannon, Xavier Caseras, Simon Cervenka, Patricia J Conrod, Benedicto Crespo-Facorro, Fabrice Crivello, Eveline A Crone, Liewe de Haan, Greig I de Zubicaray, Annabella Di Giorgio, Susanne Erk, Simon E Fisher, Barbara Franke, Thomas Frodl, David C Glahn, Dominik Grotegerd, Oliver Gruber, Patricia Gruner, Raquel E Gur, Ruben C Gur, Ben J Harrison, Sean N Hatton, Ian Hickie, Fleur M Howells, Hilleke E Hulshoff Pol, Chaim Huyser, Terry L Jernigan, Jiyang Jiang, John A Joska, Rene S Kahn, Andrew J Kalnin, Nicole A Kochan, Sanne Koops, Jonna Kuntsi, Jim Lagopoulos, Luisa Lazaro, Irina S Lebedeva, Christine Lochner, Nicholas G Martin, Bernard Mazoyer, Brenna C McDonald, Colm McDonald, Katie L McMahon, Tomohiro Nakao, Lars Nyberg, Fabrizio Piras, Maria J Portella, Jiang Qiu, Joshua L Roffman, Perminder S Sachdev, Nicole Sanford, Andrew J Saykin, Theodore D Satterthwaite, Sophia I Thomopolous, Carl M Sellgren, Kang Sim, Jordan W Smoller, Jair Soares, Iris E Sommer, Gianfranco Spalletta, Dan J Stein, Christian K Tamnes, Alexander S Tomyshev, Theo GM van Erp, Diana Tordesillas-Gutierrez, Julian N Trollor, Dennis van 't Ent, Odile A van den Heuvel, Neeltje EM van Haren, Daniela Vecchio, Dick J Veltman, Dongtao Wei, Henrik Walter, Yang Wang, Bernd Weber, Margaret J Wright, Wei Wen, Lars T Westlye, Lara M Wierenga, Paul M Thompson, Steven CR Williams, Sarah Medland, Mon-Ju Wu, Kevin Yu, Neda Jahanshad, and Sophia Frangou

Abstract

Background: Normative modeling is a statistical approach to quantify the degree to which a particular individual-level measure deviates from the pattern observed in a normative reference population. When applied to human brain morphometric measures it has the potential to inform about the significance of normative deviations for health and disease. Normative models can be implemented using a variety of algorithms that have not been systematically appraised. Methods: To address this gap, eight algorithms were compared in terms of performance and computational efficiency using brain regional morphometric data from 37,407 healthy individuals (53% female; aged 3-90 years) collated from 87 international MRI datasets. Performance was assessed with the mean absolute error (MAE) and computational efficiency was inferred from central processing unit (CPU) time. The algorithms evaluated were Ordinary Least Squares Regression (OLSR), Bayesian Linear Regression (BLR), Generalized Additive Models for Location, Scale, and Shape (GAMLSS), Parametric Lambda, Mu, Sigma (LMS), Gaussian Process Regression (GPR), Warped Bayesian Linear Regression (WBLG), Hierarchical Bayesian Regression (HBR), and Multivariable Fractional Polynomial Regression (MFPR). Model optimization involved testing nine covariate combinations pertaining to acquisition features, parcellation software versions, and global neuroimaging measures (i.e., total intracranial volume, mean cortical thickness, and mean cortical surface area). Findings: Statistical comparisons across models at PFDR

Published
2023

18. Network hub centrality and working memory performance in schizophrenia

Author

Hamdi Eryilmaz, Melissa Pax, Alexandra G. O’Neill, Mark Vangel, Ibai Diez, Daphne J. Holt, Joan A. Camprodon, Jorge Sepulcre, and Joshua L. Roffman

Abstract

Cognitive impairment, and working memory deficits in particular, are debilitating, treatment-resistant aspects of schizophrenia. Dysfunction of brain network hubs, putatively related to altered neurodevelopment, is thought to underlie the cognitive symptoms associated with this illness. Here, we used weighted degree, a robust graph theory metric representing the number of weighted connections to a node, to quantify centrality in cortical hubs in 29 patients with schizophrenia and 29 age- and gender-matched healthy controls and identify the critical nodes that underlie working memory performance. In both patients and controls, elevated weighted degree in the default mode network (DMN) was generally associated with poorer performance (accuracy and reaction time). Higher degree in the ventral attention network (VAN) nodes in the right superior temporal cortex was associated with better performance (accuracy) in patients. Degree in several prefrontal and parietal areas was associated with cognitive performance only in patients. In regions that are critical for sustained attention, these correlations were primarily driven by between-network connectivity in patients. Moreover, a cross-validated prediction analysis showed that a linear model using a summary degree score can be used to predict an individual’s working memory accuracy (r = 0.35). Our results suggest that schizophrenia is associated with dysfunctional hubs in the cortical systems supporting internal and external cognition and highlight the importance of topological network analysis in the search of biomarkers for cognitive deficits in schizophrenia.

Published
2022

19. Altered temporal, but intact spatial, features of transient network dynamics in psychosis

Author

Amy Farabaugh, Joshua L. Roffman, Hesheng Liu, Hamdi Eryilmaz, Xiaolong Peng, Danhong Wang, Natasza Orlov, Maurizio Fava, Avram J. Holmes, Daphne J. Holt, Andrea Pelletier-Baldelli, and Shahin Nasr

Subjects
Psychosis, Salience (language), Adolescent, Brain activity and meditation, media_common.quotation_subject, Brain, medicine.disease, Network dynamics, Magnetic Resonance Imaging, Article, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Brain state, Environmental risk, Psychotic Disorders, Schizophrenia, Perception, medicine, Humans, Psychology, Molecular Biology, Neuroscience, media_common
Abstract

Contemporary models of psychosis suggest that a continuum of severity of psychotic symptoms exists, with subthreshold psychotic experiences (PEs) potentially reflecting some genetic and environmental risk factors shared with clinical psychosis. Thus, identifying abnormalities in brain activity that manifest across this continuum can shed new light on the pathophysiology of psychosis. Here, we investigated the moment-to-moment engagement of brain networks (“states”) in individuals with schizophrenia (SCZ) and PEs and identified features of these states that are associated with psychosis-spectrum symptoms. Transient brain states were defined by clustering “single snapshots” of blood oxygen level-dependent images, based on spatial similarity of the images. We found that individuals with SCZ (n = 35) demonstrated reduced recruitment of three brain states compared to demographically matched healthy controls (n = 35). Of these three illness-related states, one specific state, involving primarily the visual and salience networks, also occurred at a lower rate in individuals with persistent PEs (n = 22), compared to demographically matched healthy youth (n = 22). Moreover, the occurrence rate of this marker brain state was negatively correlated with the severity of PEs (r = −0.26, p = 0.003, n = 130). In contrast, the spatial map of this state appeared to be unaffected in the SCZ or PE groups. Thus, reduced engagement of a brain state involving the visual and salience networks was demonstrated across the psychosis continuum, suggesting that early disruptions of perceptual and affective function may underlie some of the core symptoms of the illness.

Published
2021

21. In vivo human brain expression of histone deacetylases in bipolar disorder

Author

Hannah E. Brown, Changning Wang, Minhae Kim, Jacob M. Hooker, Amy T. Peters, Anjali J. Parmar, Joshua L. Roffman, Baileigh G. Hightower, Tonya M. Gilbert, Nicole R. Zürcher, Roy H. Perlis, Mary C. Catanese, and Chieh-En Jane Tseng

Subjects
Behavioral epigenetics, Bipolar Disorder, Prefrontal Cortex, Molecular neuroscience, Article, Histone Deacetylases, lcsh:RC321-571, Cellular and Molecular Neuroscience, Neuroimaging, Epigenetics and behaviour, medicine, Humans, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Martinostat, business.industry, Brain, Human brain, medicine.disease, Magnetic Resonance Imaging, Dorsolateral prefrontal cortex, Psychiatry and Mental health, medicine.anatomical_structure, Schizophrenia, Positron-Emission Tomography, Orbitofrontal cortex, Histone deacetylase, business, Neuroscience
Abstract

The etiology of bipolar disorder (BD) is unknown and the neurobiological underpinnings are not fully understood. Both genetic and environmental factors contribute to the risk of BD, which may be linked through epigenetic mechanisms, including those regulated by histone deacetylase (HDAC) enzymes. This study measures in vivo HDAC expression in individuals with BD for the first time using the HDAC-specific radiotracer [11C]Martinostat. Eleven participants with BD and 11 age- and sex-matched control participants (CON) completed a simultaneous magnetic resonance – positron emission tomography (MR-PET) scan with [11C]Martinostat. Lower [11C]Martinostat uptake was found in the right amygdala of BD compared to CON. We assessed uptake in the dorsolateral prefrontal cortex (DLPFC) to compare previous findings of lower uptake in the DLPFC in schizophrenia and found no group differences in BD. Exploratory whole-brain voxelwise analysis showed lower [11C]Martinostat uptake in the bilateral thalamus, orbitofrontal cortex, right hippocampus, and right amygdala in BD compared to CON. Furthermore, regional [11C]Martinostat uptake was associated with emotion regulation in BD in fronto-limbic areas, which aligns with findings from previous structural, functional, and molecular neuroimaging studies in BD. Regional [11C]Martinostat uptake was associated with attention in BD in fronto-parietal and temporal regions. These findings indicate a potential role of HDACs in BD pathophysiology. In particular, HDAC expression levels may modulate attention and emotion regulation, which represent two core clinical features of BD.

Published
2020

22. 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

24. Association of Maternal Stress and Social Support During Pregnancy With Growth Marks in Children’s Primary Tooth Enamel

Author

Rebecca V. Mountain, Joshua L. Roffman, Alexandre A. Lussier, Erin C. Dunn, Olivia R. Pickett, Felicitas B. Bidlack, Jill M. Goldstein, and Yiwen Zhu

Subjects
Adult, Male, medicine.medical_specialty, Longitudinal study, Mothers, Prenatal care, Anxiety, Young Adult, stomatognathic system, Pregnancy, Risk Factors, Epidemiology, Medicine, Humans, Longitudinal Studies, Tooth, Deciduous, Prospective cohort study, Child, Dental Enamel, Original Investigation, Psychiatry, business.industry, Obstetrics, Depression, Research, General Medicine, Neonatal line, medicine.disease, stomatognathic diseases, Online Only, England, Prenatal Exposure Delayed Effects, Birth Cohort, Female, business, Psychosocial, Stress, Psychological, Cohort study
Abstract

Key Points Question Can exfoliated primary teeth be used to identify children exposed to psychosocial risk and protective factors during their prenatal and perinatal life? Findings This cohort study of 70 children from the Avon Longitudinal Study of Parents and Children birth cohort found evidence that teeth may record early-life events. Children exposed to prenatal maternal depression or anxiety had wider neonatal lines, a marker of enamel growth, and children with perinatal maternal social support had narrower neonatal lines. Meaning Exfoliated primary teeth, specifically neonatal line width, may be associated with prenatal and perinatal life experiences., Importance Exposure to maternal psychosocial stressors during the prenatal and perinatal periods can have major long-term mental health consequences for children. However, valid and inexpensive biomarkers are currently unavailable to identify children who have been exposed to psychosocial stress and the buffers of stress exposure. Objective To assess whether a growth mark in tooth enamel, the neonatal line, is associated with exposure to prenatal and perinatal maternal psychosocial factors. Design, Setting, and Participants This prospective cohort study used exfoliated primary canine teeth and epidemiological survey data from 70 children enrolled in the Avon Longitudinal Study of Parents and Children, a birth cohort based in Bristol, England. Exfoliated teeth were collected from children at 5 to 7 years of age. Data were collected from January 1, 1991, to December 31, 1998, and were analyzed from January 1, 2019, to August 10, 2021. Exposures Four types of prenatal and perinatal maternal psychosocial factors were studied: stressful life events, psychopathological history, neighborhood disadvantage, and social support. Data were collected from mailed-in questionnaires completed during and shortly after pregnancy. Main Outcomes and Measures Neonatal line width measured within 3 portions of the tooth crown (the cuspal, middle, and innermost third) in exfoliated primary canines. Results A total of 70 children (34 of 70 [48.7%] male; 63 of 67 [94.0%] White) were studied. Most children were born full term (57 [83.8%]) and to mothers of typical child-bearing age (60 [88.2%]). Neonatal lines were wider in the canines of children born to mothers who self-reported severe lifetime depression (β = 3.35; 95% CI, 1.48-5.23; P = .001), any lifetime psychiatric problems (β = 2.66; 95% CI, 0.92-4.41; P = .003), or elevated anxiety or depressive symptoms at 32 weeks’ gestation (β = 2.29; 95% CI, 0.38-4.20; P = .02). By contrast, neonatal lines were narrower in children born to mothers who self-reported high social support shortly after birth (β = −2.04; 95% CI, −3.70 to −0.38; P = .02). The magnitude of these associations was large, up to 1.2 SD unit differences, and persisted after adjusting for other risk factors. Conclusions and Relevance In this cohort study, neonatal line width was associated with exposure to maternal perinatal psychosocial factors. Replication and validation of these findings can further evaluate teeth as possible new biomarkers., This cohort study examines whether the teeth of children exposed to common prenatal and perinatal maternal stressors have wider neonatal lines, a marker of tooth enamel growth, compared with children without such exposure.

Published
2021

25. Neuroepigenetic signatures of age and sex in the living human brain

Author

Jacob M. Hooker, Matthew Louis Hibert, Umar Mahmood, Changning Wang, Joshua L. Roffman, Maria A Di Biase, Nicole R. Zürcher, Minhae Kim, Baileigh G. Hightower, Tonya M. Gilbert, Anisha Bhanot, Amanda E. Lyall, Douglas N. Greve, Ofer Pasternak, Marek Kubicki, Mary C. Catanese, Frederick A. Schroeder, Chieh-En Jane Tseng, Christine J. Wu, Hsiao-Ying Wey, Steven M. Stufflebeam, Anjali J. Parmar, and Daphne J. Holt

Subjects
Male, 0301 basic medicine, Emotions, Histone Deacetylase 2, General Physics and Astronomy, Hippocampus, Adamantane, Histone Deacetylase 1, 02 engineering and technology, Hydroxamic Acids, Epigenesis, Genetic, Carbon Radioisotopes, Epigenetics in the nervous system, lcsh:Science, Sex Characteristics, Martinostat, Multidisciplinary, biology, Histone deacetylase 2, Age Factors, Brain, Human brain, Middle Aged, 021001 nanoscience & nanotechnology, White Matter, Tissue Donors, medicine.anatomical_structure, Histone, Female, 0210 nano-technology, Sex characteristics, Adult, medicine.medical_specialty, Adolescent, Science, Article, General Biochemistry, Genetics and Molecular Biology, White matter, Young Adult, 03 medical and health sciences, Internal medicine, medicine, Humans, Epigenetics, Aged, General Chemistry, 030104 developmental biology, Endocrinology, biology.protein, lcsh:Q, Positron-emission tomography
Abstract

Age- and sex-related alterations in gene transcription have been demonstrated, however the underlying mechanisms are unresolved. Neuroepigenetic pathways regulate gene transcription in the brain. Here, we measure in vivo expression of the epigenetic enzymes, histone deacetylases (HDACs), across healthy human aging and between sexes using [11C]Martinostat positron emission tomography (PET) neuroimaging (n = 41). Relative HDAC expression increases with age in cerebral white matter, and correlates with age-associated disruptions in white matter microstructure. A post mortem study confirmed that HDAC1 and HDAC2 paralogs are elevated in white matter tissue from elderly donors. There are also sex-specific in vivo HDAC expression differences in brain regions associated with emotion and memory, including the amygdala and hippocampus. Hippocampus and white matter HDAC expression negatively correlates with emotion regulation skills (n = 23). Age and sex are associated with HDAC expression in vivo, which could drive age- and sex-related transcriptional changes and impact human behavior., Gene transcription is known to vary with age and sex, although the underlying mechanisms are unresolved. Here, the authors show that epigenetic enzymes known as HDACs, which regulate gene transcription, are increasingly expressed with age in the living human brain, with sex differences also observed.

Published
2019

26. Risk tolerance measured by probability discounting among individuals with primary mood and psychotic disorders

Author

Hannah E. Brown, Roy H. Perlis, Joshua L. Roffman, and Kamber L. Hart

Subjects
Adult, Male, Elementary cognitive task, Bipolar Disorder, Schizoaffective disorder, Neuropsychological Tests, Article, 050105 experimental psychology, Cognition, Risk-Taking, Reward, medicine, Humans, 0501 psychology and cognitive sciences, Bipolar disorder, Depressive Disorder, Major, Cambridge Neuropsychological Test Automated Battery, 05 social sciences, Middle Aged, medicine.disease, Neuropsychology and Physiological Psychology, Mood, Psychotic Disorders, Schizophrenia, Major depressive disorder, Female, Psychology, Psychopathology, Clinical psychology
Abstract

Objective Change in risk tolerance is a feature of multiple psychiatric disorders and may contribute to adverse outcomes. We used a probability discounting (PD) task to measure risk-taking behavior among individuals with bipolar disorder (BPAD), major depressive disorder (MDD), schizoaffective disorder (SCAD), and schizophrenia (SCZ). Method A PD task was administered to 117 patients and 88 healthy controls (HCs), along with a cognitive battery using the Cambridge Neuropsychological Test Automated Battery, and relevant symptomatology scales. We examined differences in PD rates between diagnostic groups, and compared with HCs, while controlling for potential confounding factors including measures of cognitive functioning. Results Individuals with a diagnosis of BPAD or SCAD/SCZ prefer smaller, more guaranteed rewards rather than larger, less likely rewards as compared with healthy controls (p = .002 and p = .034, respectively). There was no effect of performance on cognitive tasks, antipsychotic treatment, or symptomatology on the rate of probability discounting. Conclusion This study supports the transdiagnostic measurement of risk-taking behaviors, even when such behaviors are not the primary area of psychopathology. Quantifying risk-taking may enable targeted therapeutic strategies across disorders. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Published
2019

27. PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia

Author

Stephen J. Haggarty, Roy H. Perlis, Jacob M. Hooker, Baileigh G. Hightower, Minhae Kim, Tonya M. Gilbert, Anisha Bhanot, Joshua L. Roffman, Marco L. Loggia, Hsiao-Ying Wey, Thomas M. Morin, Changning Wang, Frederick A. Schroeder, Daphne J. Holt, Daniel S. Albrecht, Kamber L. Hart, Nicole R. Zürcher, Steven M. Stufflebeam, Amelia M. Pellegrini, Hannah E. Brown, Misha M. Riley, Anais Rodriguez-Thompson, and Christine J. Wu

Subjects
Adult, Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Prefrontal Cortex, Neuroimaging, Schizoaffective disorder, Gene Expression Regulation, Enzymologic, Histone Deacetylases, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Effects of sleep deprivation on cognitive performance, Martinostat, business.industry, Cognition, General Medicine, Middle Aged, medicine.disease, Dorsolateral prefrontal cortex, 030104 developmental biology, medicine.anatomical_structure, Psychotic Disorders, Schizophrenia, Case-Control Studies, Positron-Emission Tomography, Female, Histone deacetylase, business, 030217 neurology & neurosurgery, Research Article
Abstract

BACKGROUND. Patients with schizophrenia (SCZ) experience chronic cognitive deficits. Histone deacetylases (HDACs) are enzymes that regulate cognitive circuitry; however, the role of HDACs in cognitive disorders, including SCZ, remains unknown in humans. We previously determined that HDAC2 mRNA levels were lower in dorsolateral prefrontal cortex (DLPFC) tissue from donors with SCZ compared with controls. Here we investigated the relationship between in vivo HDAC expression and cognitive impairment in patients with SCZ and matched healthy controls using [(11)C]Martinostat positron emission tomography (PET). METHODS. In a case-control study, relative [((11))C]Martinostat uptake was compared between 14 patients with SCZ or schizoaffective disorder (SCZ/SAD) and 17 controls using hypothesis-driven region-of-interest analysis and unbiased whole brain voxel-wise approaches. Clinical measures, including the MATRICS consensus cognitive battery, were administered. RESULTS. Relative HDAC expression was lower in the DLPFC of patients with SCZ/SAD compared with controls, and HDAC expression positively correlated with cognitive performance scores across groups. Patients with SCZ/SAD also showed lower relative HDAC expression in the dorsomedial prefrontal cortex and orbitofrontal gyrus, and higher relative HDAC expression in the cerebral white matter, pons, and cerebellum compared with controls. CONCLUSIONS. These findings provide in vivo evidence of HDAC dysregulation in patients with SCZ and suggest that altered HDAC expression may impact cognitive function in humans. FUNDING. National Institute of Mental Health (NIMH), Brain and Behavior Foundation, Massachusetts General Hospital (MGH), Athinoula A. Martinos Center for Biomedical Imaging, National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH Shared Instrumentation Grant Program.

Published
2018

28. Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years

Author

Tiffany M. Chaim-Avancini, Suzanne C. Swagerman, Sophie Maingault, Mauricio H. Serpa, Kang Sim, Patricia Gruner, Dara M. Cannon, Esther Walton, Gunter Schumann, Christopher R.K. Ching, Simon E. Fisher, Tomohiro Nakao, Nhat Trung Doan, Sophia I. Thomopoulos, Diana Tordesillas-Gutiérrez, Ilya M. Veer, Lieuwe de Haan, Paul Pauli, Derrek P. Hibar, Kun Yang, Dan J. Stein, Dominik Grotegerd, Víctor Ortiz-García de la Foz, Daniel Brandeis, Sarah Baumeister, Xavier Caseras, Fabrice Crivello, Vincent P. Clark, Maria J. Portella, Salvador Sarró, Dorret I. Boomsma, Henry Völzke, Daniel H. Wolf, Lianne Schmaal, Yannis Paloyelis, Barbara Franke, Matthew D. Sacchet, Anne Uhlmann, Yulyia Yoncheva, Ole A. Andreassen, Erick J. Canales-Rodríguez, Ingrid Agartz, Anouk den Braber, Colm McDonald, Edith Pomarol-Clotet, Anders M. Dale, Calhoun Vd, David Mataix-Cols, Ignacio Martínez-Zalacaín, Joshua L. Roffman, Andrew J. Kalnin, Anton Albajes-Eizagirre, Andreas Reif, Won Hee Lee, Gaelle E. Doucet, Hans-Jörgen Grabe, Pieter J. Hoekstra, Avram J. Holmes, Theophilus N. Akudjedu, Ian H. Gotlib, Fleur M. Howells, Andrew J. Saykin, Genevieve McPhilemy, Moji Aghajani, David C. Glahn, Rachel M. Brouwer, Núria Bargalló, Knut Schnell, Katharina Wittfeld, Thomas Frodl, Josiane Bourque, Ryota Kanai, Raymond Salvador, Sean N. Hatton, Terry L. Jernigan, Helena Fatouros-Bergman, Oliver Grimm, Marise W. J. Machielsen, Victoria Chubar, Henk Temmingh, Andrew M. McIntosh, Georg C. Ziegler, Marieke Klein, T. P. Klyushnik, Iris E. C. Sommer, Heather C. Whalley, Rachel E. Gur, Alan Breier, Jordan W. Smoller, Kathryn I. Alpert, Dick J. Veltman, Neda Jahanshad, Sophia Frangou, Jiyang Jiang, Jessica A. Turner, Eveline A. Crone, Thomas Espeseth, Alexander Tomyshev, Christine Lochner, Anthony A. James, Aristotle N. Voineskos, Julian N. Trollor, Efstathios Papachristou, Beng-Choon Ho, Pablo Najt, Christian K. Tamnes, Geraldo F. Busatto, Stefan Borgwardt, Andreas Meyer-Lindenberg, Philip Asherson, Francisco X. Castellanos, Bernd Kramer, Jim Lagopoulos, Marcus V. Zanetti, Joaquim Radua, John A. Joska, Giulio Pergola, Nynke A. Groenewold, Erlend S. Dørum, Henrik Walter, Jan Egil Nordvik, Alessandro Bertolino, Wei Wen, Klaus-Peter Lesch, Ian B. Hickie, Pedro G.P. Rosa, Randy L. Buckner, Daniel A. Rinker, Hilleke E. Hulshoff Pol, Steven G. Potkin, Odile A. van den Heuvel, Nancy C. Andreasen, Sanne Koops, Amanda Worker, Susanne Erk, Lei Wang, Norbert Hosten, Jean-Paul Fouche, Dennis van 't Ent, Jonna Kuntsi, Dennis van den Meer, Simon Cervenka, C.A. Hartman, Nicholas G. Martin, Carles Soriano-Mas, Neeltje E.M. van Haren, Pascual Sánchez-Juan, Andreas Heinz, Brenna C. McDonald, Thomas H. Wassink, José M. Menchón, Katie L. McMahon, Jan K. Buitelaar, Sarah E. Medland, Aurora Bonvino, Patricia J. Conrod, Nic J.A. van der Wee, Paul M. Thompson, Micael Andersson, Perminder S. Sachdev, Lars Nyberg, Eco J. C. de Geus, Ramona Baur-Streubel, Lachlan T. Strike, Dag Alnæs, Paola Fuentes-Claramonte, Ben J. Harrison, Martine Hoogman, Lars T. Westlye, Annette Conzelmann, Annabella Di Giorgio, Benedicto Crespo-Facorro, Sarah Hohmann, Jilly Naaijen, Yang Wang, Henry Brodaty, Greig I. de Zubicaray, Laura Koenders, Ruben C. Gur, Stefan Ehrlich, Danai Dima, Christopher G. Davey, Tobias Banaschewski, Amirhossein Modabbernia, Dirk J. Heslenfeld, Erik G. Jönsson, Oliver Gruber, Theodore D. Satterthwaite, René S. Kahn, Margaret J. Wright, Jaap Oosterlaan, Steven Williams, Bernard Mazoyer, Lara M. Wierenga, Bernd Weber, Luisa Lázaro, Irina Lebedeva, Erin W. Dickie, Chaim Huyser, John D. West, Theo G.M. van Erp, National Institute of Mental Health (US), Karolinska Institute, Stockholm County Council, South-Eastern Norway Regional Health Authority, German Centre for Cardiovascular Research, Siemens Healthcare, University of Queensland, Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), National Health and Medical Research Council (Australia), National Institute on Drug Abuse (US), Indiana State Department of Health, Parents of children with epilepsy, Epilepsy Therapy Project, Fight Against Childhood Epilepsy and Seizures, Epilepsy Foundation, American Epilepsy Society, Knut and Alice Wallenberg Foundation, European Commission, Dutch Research Council, Netherlands Organization for Scientific Research, Netherlands Brain Foundation, Utrecht University, European Research Council, National Center for Advancing Translational Sciences (US), National Institutes of Health (US), National Center for Research Resources (US), Fundación Marques de Valdecilla, Instituto de Salud Carlos III, Swedish Research Council, Kings College London, South London and Maudsley NHS Foundation Trust, NIHR Biomedical Research Centre (UK), National Institute for Health Research (UK), RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Karolinska Schizophrenia Project (KaSP), Biological Psychology, APH - Mental Health, APH - Methodology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Educational and Family Studies, Cognitive Psychology, IBBA, Clinical Neuropsychology, Faculty of Behavioural and Movement Sciences, APH - Personalized Medicine, Developmental Neuroscience in Society, Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, Child Psychiatry, ANS - Cellular & Molecular Mechanisms, General Paediatrics, ARD - Amsterdam Reproduction and Development, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Movement Disorder (MD), Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Neurology, Amsterdam Neuroscience - Neurodegeneration, Pediatric surgery, Anatomy and neurosciences, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, and Amsterdam Neuroscience - Brain Imaging

Subjects
Male, diagnostic imaging [Corpus Striatum], Physiology, Hippocampus, Edat, Morfologia (Biologia), Lateral ventricles, anatomy & histology [Corpus Striatum], 0302 clinical medicine, Thalamus, 130 000 Cognitive Neurology & Memory, Basal ganglia, diagnostic imaging [Amygdala], Child, Cervell, Research Articles, diagnostic imaging [Hippocampus], Aged, 80 and over, Radiological and Ultrasound Technology, Putamen, Radiology, Nuclear Medicine & Medical Imaging, 05 social sciences, ENIGMA, Multisi, Brain, Middle Aged, Amygdala, 3. Good health, Neurology, Child, Preschool, Brain size, Female, Anatomy, Life Sciences & Biomedicine, Neurovetenskaper, Research Article, Neuroinformatics, Adult, Adolescent, anatomy & histology [Hippocampus], Human Development, multisite, BF, Neuroimaging, Nucleus accumbens, Biology, Brain morphometry, Morphology (Biology), 050105 experimental psychology, Young Adult, 03 medical and health sciences, Age, Longitudinal trajectories, brain morphometry, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, ddc:610, anatomy & histology [Thalamus], Aged, diagnostic imaging [Thalamus], Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Science & Technology, Neurosciences, Corpus Striatum, nervous system, anatomy & histology [Amygdala], RC0321, Neurosciences & Neurology, longitudinal trajectories, Neurology (clinical), 030217 neurology & neurosurgery, physiology [Human Development]
Abstract

Special Issue: The ENIGMA Consortium: the first 10 years.-- Karolinska Schizophrenia Project (KaSP)., Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3–90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns., National Institute of Mental Health, Grant/Award Numbers: MH104284, MH116147, R01MH113619, R01 MH090553, R01MH117014, R01MH042191; Karolinska Institutet; Stockholm County Council; Southern and Eastern Norway Regional Health Authority; German Centre for Cardiovascular Research; DZHK; Siemens Healthineers; University of Queensland; US National Institute of Child Health and Human Development, Grant/Award Number: RO1HD050735; Australian National Health and Medical Research Council; Eunice Kennedy Shriver National Institute of Child Health & Human Development; National Institute on Drug Abuse, Grant/Award Numbers: UL1 TR000153, 1 U24 RR025736-01, 1 U24 RR021992; Brain Injury Fund Research Grant Program; Indiana State Department of Health Spinal Cord; Parents Against Childhood Epilepsy; Epilepsy Therapy Project, Fight Against Childhood Epilepsy and Seizures; Epilepsy Foundation; American Epilepsy Society; Knut and Alice Wallenberg Foundation; European Community's Horizon 2020 Programme; Vici Innovation Program; NWO Brain & Cognition Excellence Program; Netherlands Organization for Scientific Research; Hersenstichting Nederland; Netherlands Organization for Health Research and Development; Geestkracht Programme of the Dutch Health Research Council, Grant/Award Number: 10-000-1001; Universiteit Utrecht; FP7 Ideas: European Research Council; Nederlandse Organisatie voor Wetenschappelijk Onderzoek; National Center for Advancing Translational Sciences; National Institutes of Health; National Center for Research Resources; Consortium grant, Grant/Award Number: U54 EB020403; U.S. National Institutes of Health, Grant/Award Numbers: R01 CA101318, P30 AG10133, R01 AG19771; Medical Research Council, Grant/Award Number: G0500092; Fundación Instituto de Investigación Marqués de Valdecilla, Grant/Award Numbers: API07/011, NCT02534363, NCT0235832; Instituto de Salud Carlos III, Grant/Award Numbers: PI14/00918, PI14/00639, PI060507, PI050427, PI020499; the Research Council, Grant/Award Number: 223273; South Eastern Norway Regional Health Authority, Grant/Award Numbers: 2017-112, 2019107; Swedish Research Council; European Community's Seventh Framework Programme, Grant/Award Number: 602450; King's College London; South London and Maudsley NHS Foundation Trust; Biomedical Research Centre; National Institute for Health Research.

Published
2021

29. A Comparison of Ten Polygenic Score Methods for Psychiatric Disorders Applied Across Multiple Cohorts

Author

Guiyan Ni, Jian Zeng, Joana A. Revez, Ying Wang, Zhili Zheng, Tian Ge, Restuadi Restuadi, Jacqueline Kiewa, Dale R. Nyholt, Jonathan R.I. Coleman, Jordan W. Smoller, Jian Yang, Peter M. Visscher, Naomi R. Wray, Stephan Ripke, Benjamin M. Neale, Aiden Corvin, 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, Martin Begemann, 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, Kimberley 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, Michael Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, 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, Ina Giegling, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, David M. Hougaard, 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, James A. Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee, 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, Patrik K.E. Magnusson, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Bela Melegh, Ingrid Melle, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W. Morris, Ole Mors, Kieran C. Murphy, Robin M. Murray, Inez Myin-Germeys, Bertram Müller-Myhsok, 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, Psychosis Endophenotypes International Consortium, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Michele T. Pato, 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, Alan R. Sanders, Ulrich Schall, Christian R. Schubert, Thomas G. Schulze, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Jianxin Shi, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Hon-Cheong So, Chris C.A. Spencer, Eli A. Stahl, 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, Kari Stefansson, Wellcome Trust Case-Control Consortium, Rolf Adolfsson, Ole A. Andreassen, Douglas H.R. Blackwood, Elvira Bramon, Joseph D. Buxbaum, Anders D. Børglum, Sven Cichon, Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Tõnu Esko, Pablo V. Gejman, Michael Gill, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen V. Jablensky, Erik G. Jönsson, Kenneth S. Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F. Levinson, Qingqin S. Li, Jianjun Liu, Anil K. Malhotra, Steven A. McCarroll, Andrew McQuillin, Jennifer L. Moran, Preben B. Mortensen, Bryan J. Mowry, Markus M. Nöthen, Roel A. Ophoff, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Tracey L. Petryshen, Danielle Posthuma, Marcella Rietschel, Brien P. Riley, Dan Rujescu, Pak C. Sham, Pamela Sklar, David St Clair, Daniel R. Weinberger, Jens R. Wendland, Thomas Werge, Mark J. Daly, Patrick F. Sullivan, Michael C. O’Donovan, Maciej Trzaskowski, Enda M. Byrne, Abdel Abdellaoui, Mark J. Adams, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Toni-Kim Clarke, 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, Andreas J. Forstner, Héléna A. Gaspar, Fernando S. Goes, Scott D. Gordon, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas F. Hansen, Ian B. Hickie, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, 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, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Peter McGuffin, Sarah E. Medland, Divya Mehta, Christel M. Middeldorp, Evelin Mihailov, Yuri Milaneschi, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Niamh Mullins, Matthias Nauck, Bernard Ng, Michel G. Nivard, Paul F. O’Reilly, Hogni Oskarsson, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Jorge A. Quiroz, Per Qvist, John P. Rice, Margarita Rivera, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Stanley I. Shyn, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Fabian Streit, 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, Sandra Van der Auwera, Albert M. van Hemert, Alexander Viktorin, Yunpeng Wang, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Yang Wu, Hualin S. Xi, Futao Zhang, Volker Arolt, Bernhard T. Baune, Klaus Berger, Dorret I. Boomsma, Udo Dannlowski, E.J.C. de Geus, J. Raymond DePaulo, Katharina Domschke, Hans J. Grabe, Steven P. Hamilton, Caroline Hayward, Andrew C. Heath, Stefan Kloiber, Glyn Lewis, Susanne Lucae, Pamela A.F. Madden, Patrik K. Magnusson, Nicholas G. Martin, Preben Bo Mortensen, Merete Nordentoft, Sara A. Paciga, Nancy L. Pedersen, Adult Psychiatry, APH - Mental Health, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, Ni, Guiyan, Zeng, Jian, Revez, Joana A., Wang, Ying, Zhili, Zheng, Ge, Tian, Restuadi, Restuadi, Kiewa, Jacqueline, Nyholt, Dale R, Coleman, Jonathan RI, Smoller, Jordan W, Lee, S Hong, APH - Methodology, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Econometrics, Psychiatry, Department of Technology and Operations Management, Child and Adolescent Psychiatry / Psychology, Epidemiology, Erasmus MC other, Urology, Internal Medicine, Medical Informatics, Immunology, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep

Subjects
0301 basic medicine, Multifactorial Inheritance, medicine.medical_specialty, LDpred2, BF, Genomics, Disease, Major depressive disorder, risk prediction, 03 medical and health sciences, 0302 clinical medicine, MegaPRS, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Genetic risk, Psychiatry, Biological Psychiatry, Genetic association, Depressive Disorder, Major, business.industry, Mental Disorders, medicine.disease, Genetic architecture, Polygenic scores, Risk prediction, polygenic scores, PRS-CS, psychiatric disorders, 030104 developmental biology, SBayesR, Schizophrenia, Cohort, Lassosum, RC0321, business, Psychiatric disorders, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

BACKGROUND: Polygenic scores (PGSs), which assess the genetic risk of individuals for a disease, are calculated as a weighted count of risk alleles identified in genome-wide association studies. PGS methods differ in which DNA variants are included and the weights assigned to them; some require an independent tuning sample to help inform these choices. PGSs are evaluated in independent target cohorts with known disease status. Variability between target cohorts is observed in applications to real data sets, which could reflect a number of factors, e.g., phenotype definition or technical factors.METHODS: The Psychiatric Genomics Consortium Working Groups for schizophrenia and major depressive disorder bring together many independently collected case-control cohorts. We used these resources (31,328 schizophrenia cases, 41,191 controls; 248,750 major depressive disorder cases, 563,184 controls) in repeated application of leave-one-cohort-out meta-analyses, each used to calculate and evaluate PGS in the left-out (target) cohort. Ten PGS methods (the baseline PC+T method and 9 methods that model genetic architecture more formally: SBLUP, LDpred2-Inf, LDpred-funct, LDpred2, Lassosum, PRS-CS, PRS-CS-auto, SBayesR, MegaPRS) were compared.RESULTS: Compared with PC+T, the other 9 methods gave higher prediction statistics, MegaPRS, LDPred2, and SBayesR significantly so, explaining up to 9.2% variance in liability for schizophrenia across 30 target cohorts, an increase of 44%. For major depressive disorder across 26 target cohorts, these statistics were 3.5% and 59%, respectively.CONCLUSIONS: Although the methods that more formally model genetic architecture have similar performance, MegaPRS, LDpred2, and SBayesR rank highest in most comparisons and are recommended in applications to psychiatric disorders.

Published
2021

31. Cortical Thickness Trajectories across the Lifespan: Data from 17,075 healthy individuals aged 3-90 years

Author

Stefan Ehrlich, Danai Dima, Nhat Trung Doan, Simon E. Fisher, Dominik Grotegerd, Nicholas G. Martin, Tiffany M. Chaim-Avancini, Sophie Maingault, Sean N. Hatton, Derrek P. Hibar, Vincent P. Clark, Anders M. Dale, Iris E. C. Sommer, Ben J. Harrison, Annabella Di Giorgio, Benedicto Crespo-Facorro, Ian H. Gotlib, Andrew J. Kalnin, Andreas Reif, Edith Pomarol-Clotet, Thomas Espeseth, Theodore D. Satterthwaite, Pieter J. Hoekstra, René S. Kahn, Margaret J. Wright, Núria Bargalló, Maria J. Portella, Thomas Frodl, Lianne Schmaal, Chaim Huyser, Sophia I. Thomopoulos, Odille A van den Heuvel, Rachel M. Brouwer, Rachel E. Gur, Stefan Borgwardt, Marise W. J. Machielsen, Kathryn I. Alpert, Dick J. Veltman, Sim Kang, Irina V. Lebedeva, Marcus V. Zanetti, Anne Uhlmann, Christopher R.K. Ching, John D. West, Paul Pauli, Susanne Erk, Xavier Caseras, Kun Yang, Randy L. Buckner, Julian N. Trollor, Katharina Wittfeld, Fabrice Crivello, Theo G.M. van Erp, Luisa Lázaro, Jan Egil Nordvik, Sarah Baumeister, Steven G. Potkin, Calhoun Vd, Ian B. Hickie, Giulio Pergola, Henrik Walter, Katie L. McMahon, Theophilus N. Akudjedu, Patricia J. Conrod, Nic J.A. van der Wee, Won Hee Lee, Dennis van 't Ent, Barbara Franke, Knut Schnell, Josiane Bourque, Matthew D. Sacchet, Perminder S. Sachdev, Esther Walton, Raymond Salvador, Colm McDonald, Gunter Schumann, Paul M. Thompson, Georg C. Ziegler, Erin W. Dickie, Christine Lochner, Andreas Meyer-Lindenberg, Eco J. C. de Geus, Ole A. Andreassen, Joshua L. Roffman, Oliver Grimm, Andrew M. McIntosh, Ryota Kanai, Mauricio H. Serpa, Dennis van den Meer, Jessica A. Turner, Simon Cervenka, Alexander Tomyshev, Lara M. Wierenga, Francisco X. Castellanos, Bernd Kramer, Erlend S. Dørum, Alessandro Bertolino, P. G. P. Rosa, Avram J. Holmes, Klaus-Peter Lesch, Norbert Hosten, Hilleke E. Hulshoff Pol, Jean-Paul Fouche, Neda Jahanshad, Daniel Brandeis, José M. Menchón, Jiyang Jiang, Jan K. Buitelaar, Andrew J. Saykin, Genevieve McPhilemy, Efstathios Papachristou, Hans-Jörgen Grabe, Bernd Weber, Beng-Choon Ho, Pablo Najt, Fleur M. Howells, Yannis Paloyelis, Lieuwe de Haan, Lachlan T. Strike, Dag Alnæs, David Mataix-Cols, Henry Völzke, Daniel H. Wolf, Suzanne C. Swagerman, Paola Fuentes-Claramonte, Marieke Klein, Patricia Gruner, Anthony A. James, Ingrid Agartz, Dara M. Cannon, Jim Lagopoulos, Geraldo F. Busatto, Tomohiro Nakao, Dan J. Stein, Gaelle E Doucet, Erick J. Canales-Rodríguez, Cristopher Davey, Tatyana P Klushnik, Jaap Oosterlaan, Ilya M. Veer, Steven Williams, Bernard Mazoyer, Helena Fatouros-Bergman, Yulyia Yoncheva, Ramona Baur-Streubel, Anouk den Braber, Nynke A. Groenewold, Salvador Sarró, Ignacio Martínez-Zalacaín, Sanne Koops, M. Aghajani, Lei Wang, Sarah E. Medland, C.A. Hartman, Aurora Bonvino, Pascual Sánchez-Juan, Andreas Heinz, Tobias Banaschewski, Amirhossein Modabbernia, Jilly Naaijen, Yang Wang, Sophia Frangou, Henry Brodaty, Henk Temmingh, Greig I. de Zubicaray, Nancy C. Andreasen, Carles Soriano-Mas, Neeltje E.M. van Haren, Brenna C. McDonald, Ruben C. Gur, Micael Andersson, Dorret I. Boomsma, Dirk J. Heslenfeld, Erik G. Jönsson, Oliver Gruber, Víctor Ortiz-García de la Foz, Anton Albajes-Eizagirre, David C. Glahn, Alan Breier, Heather C. Whalley, Jordan W. Smoller, Joaquim Radua, Christian K. Tamnes, Eveline A. Crone, Philip Asherson, John A. Joska, Wei Wen, Jonna Kuntsi, Lars Nyberg, Thomas H. Wassink, Diana Tordesillas-Gutiérrez, Martine Hoogman, Lars T. Westlye, Annette Conzelmann, Sarah Hohmann, and Laura Koenders

Subjects
0303 health sciences, medicine.medical_specialty, Fractional polynomial, Cognition, Audiology, Biology, Regression, Pooling data, 03 medical and health sciences, 0302 clinical medicine, Neuroimaging genetics, Healthy individuals, medicine, General pattern, Analysis of variance, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Delineating age-related cortical trajectories in healthy individuals is critical given the association of cortical thickness with cognition and behaviour. Previous research has shown that deriving robust estimates of age-related brain morphometric changes requires large-scale studies. In response, we conducted a large-scale analysis of cortical thickness in 17,075 individuals aged 3-90 years by pooling data through the Lifespan Working group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium. We used fractional polynomial (FP) regression to characterize age-related trajectories in cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma (LMS) method. Inter-individual variability was estimated using meta-analysis and one-way analysis of variance. Overall, cortical thickness peaked in childhood and had a steep decrease during the first 2-3 decades of life; thereafter, it showed a gradual monotonic decrease which was steeper in men than in women particularly in middle-life. Notable exceptions to this general pattern were entorhinal, temporopolar and anterior cingulate cortices. Inter-individual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results reconcile uncertainties about age-related trajectories of cortical thickness; the centile values provide estimates of normative variance in cortical thickness, and may assist in detecting abnormal deviations in cortical thickness, and associated behavioural, cognitive and clinical outcomes.

Published
2020

32. Subcortical Volume Trajectories across the Lifespan: Data from 18,605 healthy individuals aged 3-90 years

Author

Lara M. Wierenga, Iris E. C. Sommer, Edith Pomarol-Clotet, Erick J. Canales-Rodríguez, van Erp Tg, Lars T. Westlye, van Haren Ne, Francisco X. Castellanos, P. G. P. Rosa, Kang S, van der Wee Nj, Joaquim Radua, Jim Lagopoulos, José M. Menchón, Helena Fatouros-Bergman, Jan K. Buitelaar, Bernd Weber, Annette Conzelmann, Núria Bargalló, S. E. Medland, Maria J. Portella, Patricia J. Conrod, Amanda Worker, Klaus-Peter Lesch, Jonna Kuntsi, S.G. Potkin, R. Salvador, Knut Schnell, Stefan Borgwardt, Katharina Wittfeld, Kathryn I. Alpert, Dick J. Veltman, de Geus Ej, Ole A. Andreassen, Sophia Frangou, Di Giorgio A, Avram J. Holmes, Rachel M. Brouwer, Thomas Frodl, Lachlan T. Strike, Anton Albajes-Eizagirre, Giulio Pergola, van den Heuvel Oa, Perminder S. Sachdev, Esther Walton, Josiane Bourque, Dag Alnæs, David C. Glahn, Ramona Baur-Streubel, Laura Koenders, Christian K. Tamnes, Alan Breier, Jordan W. Smoller, Yulyia Yoncheva, Marise W. J. Machielsen, Sarah Hohmann, Magnus Andersson, Paola Fuentes-Claramonte, David Mataix-Cols, Salvador Sarró, Stefan Ehrlich, John A. Joska, Marieke Klein, Mauricio H. Serpa, den Braber A, Henry Völzke, Jilly Naaijen, de Haan L, Thomas H. Wassink, Daniel H. Wolf, Thomas Espeseth, Yang Wang, Henrik Walter, Wei Wen, Calhoun, Dan J. Stein, Simon E. Fisher, Eveline A. Crone, Ingrid Agartz, Susanne Erk, Oliver Grimm, Andrew M. McIntosh, Dominik Grotegerd, Henry Brodaty, Katie L. McMahon, Jaap Oosterlaan, Danai Dima, Aurora Bonvino, Anders M. Dale, Alexander Tomyshev, Ignacio Martínez-Zalacaín, Anthony A. James, Andrew J. Kalnin, Barbara Franke, Theophilus N. Akudjedu, Andreas Reif, Pieter J. Hoekstra, Nordvik Je, Lars Nyberg, Bernard Mazoyer, Paul M. Thompson, Andrew J. Saykin, Genevieve McPhilemy, Nhat Trung Doan, Geraldo F. Busatto, Colm McDonald, van ’t Ent D, Sophia I. Thomopoulos, Derrek P. Hibar, Neda Jahanshad, Norbert Hosten, Ryota Kanai, Ruben C. Gur, D.I. Boomsma, Lianne Schmaal, Jean-Paul Fouche, Anne Uhlmann, Jessica A. Turner, Fabrice Crivello, P. Asherson, de la Foz Vo, Heather C. Whalley, C.A. Hartman, Ching Cr, Dirk J. Heslenfeld, Jiyang Jiang, Pascual Sánchez-Juan, Andreas Heinz, Simon Cervenka, Irina V. Lebedeva, Nancy C. Andreasen, Erik G. Jönsson, Oliver Gruber, Ben J. Harrison, Tiffany M. Chaim-Avancini, Sophie Maingault, Efstathios Papachristou, Beng-Choon Ho, Marcus V. Zanetti, Doucet Ge, Nynke A. Groenewold, Sacchet, Andreas Meyer-Lindenberg, Bernhard K. Krämer, M. Aghajani, Diana Tordesillas-Gutiérrez, Martine Hoogman, Lu Wang, Pablo Najt, van den Meer D, Christopher G. Davey, Theodore D. Satterthwaite, René S. Kahn, Margaret J. Wright, N. G. Martin, G. Schumann, Tobias Banaschewski, Amirhossein Modabbernia, Benedicto Crespo-Facorro, Ian B. Hickie, Alessandro Bertolino, Sanne Koops, Sean N. Hatton, Georg C. Ziegler, Carles Soriano-Mas, Kun Yang, Brenna C. McDonald, Sarah Baumeister, Scr Williams, Julian N. Trollor, Paul Pauli, Joshua L. Roffman, Xavier Caseras, Won Hee Lee, Henk Temmingh, Rachel E. Gur, Randy L. Buckner, Vincent P. Clark, Daniel Brandeis, Ian H. Gotlib, Hulshoff Pol He, Hans-Jörgen Grabe, Fleur M. Howells, Christine Lochner, Yannis Paloyelis, Erlend S. Dørum, Suzanne C. Swagerman, Patricia Gruner, Dara M. Cannon, Tomohiro Nakao, Tatyana P Klushnik, Ilya M. Veer, de Zubicaray Gi, Chaim Huyser, John D. West, Luisa Lázaro, and Erin W. Dickie

Subjects
0303 health sciences, Putamen, Thalamus, Brain morphometry, Hippocampus, Nucleus accumbens, Biology, 03 medical and health sciences, Lateral ventricles, 0302 clinical medicine, nervous system, Brain size, Basal ganglia, Neuroscience, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalised on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine the age-related morphometric trajectories of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum early in life; the volume of the basal ganglia showed a gradual monotonic decline thereafter while the volumes of the thalamus, amygdala and the hippocampus remained largely stable (with some degree of decline in thalamus) until the sixth decade of life followed by a steep decline thereafter. The lateral ventricles showed a trajectory of continuous enlargement throughout the lifespan. Significant age-related increase in inter-individual variability was found for the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to derive risk predictions for the early identification of diverse clinical phenotypes.

Published
2020

34. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Author

Patricia T. Michie, Franziska Degenhardt, Brandon Wormley, Paola Giusti-Rodríguez, Mark J. Daly, Raquelle I. Mesholam-Gately, Ingrid Melle, Sibylle G. Schwab, Andrew McQuillin, Benjamin M. Neale, Joshua L. Roffman, Abraham Reichenberg, Pamela Sklar, Diana O. Perkins, Jennifer L. Moran, Donald W. Black, Per Hoffmann, A. Hofman, Hailiang Huang, John L. Waddington, Giulio Genovese, Aaron R. Wolen, Deborah L. Levy, David Curtis, Digby Quested, Carlos N. Pato, Nicholas John Craddock, Stephanie Williams, Kung Yee Liang, Zhouzhi Wang, Tracey L. Petryshen, Ann E. Pulver, Randy L. Buckner, Stephan Ripke, Roel A. Ophoff, Danielle Posthuma, Lili Milani, Jacques Mallet, Menachem Fromer, Christian R. Marshall, Jaana Suvisaari, Jana Strohmaier, Richard Bruggeman, Marcella Rietschel, Ayman H. Fanous, Andrew M. McIntosh, James T.R. Walters, Dimitris Dikeos, Panos Roussos, Veikko Salomaa, Aiden Corvin, Carin J. Meijer, Tiina Paunio, Assen Jablensky, Sarah E. Bergen, Nancy G. Buccola, Annelie Nordin, Wolfgang Maier, Srdjan Djurovic, Naomi R. Wray, Aniket Shetty, Joel Eriksson, Dan Rujescu, Jouko Lönnqvist, Brian Kelly, Wenting Wu, Alexander Richards, Frans Henskens, Rich Belliveau, Bryan J. Mowry, Elodie Drapeau, Andreas J. Forstner, Silviu Alin Bacanu, Jubao Duan, Tõnu Esko, Bernard Lerer, Carmel M. Loughland, Olli Pietiläinen, Michael Conlon O'Donovan, Shaun M. Purcell, Michael Gill, Thomas G. Schulze, Douglas S. Greer, Stephen W. Scherer, Eli A. Stahl, Markus M. Nöthen, Guiqing Cai, William M. Brandler, Kristin K. Nicodemus, Dominique Campion, David A. Collier, Farooq Amin, Joel N. Hirschhorn, Robin M. Murray, Timothy G. Dinan, Mark Reimers, Murray J. Cairns, Rodney J. Scott, Aarno Palotie, Robert Freedman, Nelson B. Freimer, Joshua R. Atkins, Gary Donohoe, Ann Olincy, Jonathan Sebat, Colm McDonald, Srinivas Thirumalai, John Powell, Jo Knight, Vahram Haroutunian, Dieter B. Wildenauer, Tim B. Bigdeli, Lieuwe de Haan, Peter Eichhammer, James J. Crowley, Lynn E. DeLisi, Ulrich Schall, Rolf Adolfsson, Marcelo Bertalan, Thomas Hansen, Eric Strengman, Michael Davidson, Dheeraj Malhotra, Manuel Mattheisen, Jeffrey A. Lieberman, Benedicto Crespo-Facorro, Stephanie Godard, Edward M. Scolnick, Jonathan Pimm, Bertram Müller-Myhsok, Qingqin Li, Michele T. Pato, Wiepke Cahn, Christos Pantelis, Ingrid Agartz, Brendan Bulik-Sullivan, Madhusudan Gujral, Martilias S. Farrell, Brady J. Maher, Laurent Essioux, Karin V Fuentes Fajarado, Andres Metspalu, Stephanie H. Witt, Patrick F. Sullivan, Mark Weiser, Younes Mokrab, Kai How Farh, Line Olsen, Dermot Walsh, Peter Holmans, Hugh Gurling, Joseph I. Friedman, Andrew Pocklington, Daniel P. Howrigan, Lude Franke, Tune H. Pers, Larry J. Seidman, Pablo V. Gejman, Dalila Pinto, Michael John Owen, Inez Myin-Germeys, Steven A. McCarroll, Wei Cheng, Jackie Goldstein, C. Robert Cloninger, Elliot S. Gershon, Deborah A. Nertney, Thomas Werge, Noa Carrera, Kieran C. Murphy, Rita M. Cantor, Ariel Darvasi, Mark Hansen, Annette M. Hartmann, Ole A. Andreassen, Bradley T. Webb, Henrik B. Rasmussen, David Cohen, Elvira Bramon, Erik G. Jönsson, Vaughan J. Carr, Pui Y. Lee, Masashi Ikeda, Daniele Merico, Danny Antaki, Brien P. Riley, Stefan Herms, Igor Nenadic, Bettina Konte, Kimberley D. Chambert, Jurgen Del Favero, George Kirov, Matthew C. Keller, Jacob Gratten, Douglas F. Levinson, Luba Kalaydjieva, Bhooma Thiruvahindrapuram, Alan R. Sanders, Sang-Yun Oh, Alkes L. Price, Vihra Milanova, Juha Veijola, Erik Söderman, Dragan M. Svrakic, David H. Kavanagh, Patrik K. E. Magnusson, Douglas Blackwood, Nakao Iwata, Jim van Os, Jeremy M. Silverman, Elena Parkhomenko, Kenneth L. Davis, Jing Qin Wu, Eadbhard O'Callaghan, Chris C. A. Spencer, Juha Karjalainen, Anna K. Kähler, Clement C. Zai, Nigel Williams, Joseph D. Buxbaum, Jin P. Szatkiewicz, Laura Nisenbaum, Sang Hong Lee, Yunjung Kim, Colm O'Dushlaine, René S. Kahn, Morten Mattingsdal, Inge Joa, Marian L. Hamshere, Frank Dudbridge, Ina Giegling, Sandra Meier, Derek W. Morris, Robert W. McCarley, Douglas M. Ruderfer, Paul Cormican, Lyudmila Georgieva, Sven Cichon, Josef Frank, Jianxin Shi, George N. Papadimitriou, Kenneth S. Kendler, Margot Albus, Enrico Domenici, Claudine Laurent, Francis A. O'Neill, Adam Savitz, Jordan W. Smoller, James L. Kennedy, Peter M. Visscher, Valentina Escott-Price, Christina M. Hultman, T. Scott Stroup, Elizabeth Bevilacqua, James A. Knowles, William Byerley, Paul A. Tooney, Madeline Alexander, Stanley V. Catts, David St Clair, Sophie E. Legge, Gerald Nestadt, Michelle S. Maile, Perceptual and Cognitive Neuroscience (PCN), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Stem Cell Aging Leukemia and Lymphoma (SALL), Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, MUMC+: Hersen en Zenuw Centrum (3), MUMC+: MA Psychiatrie (3), Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, ANS - Complex Trait Genetics, Adult Psychiatry, Other departments, Marshall, Christian R, Howrigan, Daniel P, Merico, Daniele, Thiruvahindrapuram, Bhooma, Lee, S Hong, Sebat, Jonathan, Psychosis Endophenotypes International Consortium, CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium, CNV, Schizophrenia Working Grp, Psychosis Endophenotypes, Rehabilitation Medicine, and Child and Adolescent Psychiatry / Psychology

Subjects
0301 basic medicine, Male, 16P11.2, Duplication, Autism, Rearrangement, Genome-wide association study, Copy number variant, Gene, Medical and Health Sciences, 0302 clinical medicine, DUPLICATIONS, Risk Factors, Gene duplication, Genotype, Disorder, Copy-number variation, Genetics, Genetics & Heredity, RISK, copy number variation, REARRANGEMENTS, Biological Sciences, 16p11.2, 3. Good health, Phenotype, Female, Risk, CNVS, Genetic Markers, genetic etiology, CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium, DNA Copy Number Variations, DISORDERS, CNV, Non-allelic homologous recombination, PHENOTYPES, Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, genomics, Journal Article, Humans, Comparative Study, Genetic Predisposition to Disease, AUTISM, Psychosis Endophenotypes International Consortium, MUTATIONS, Case-control study, Odds ratio, R1, GENE, 030104 developmental biology, genetics research, Genetic marker, Genetic Loci, Case-Control Studies, Mutation, Schizophrenia, Human medicine, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 x 10(-15)), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 x 10(-6)). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 x 10(-11)) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 x 10(-5)). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination. Refereed/Peer-reviewed

Published
2017

35. Endophenotype Research in Psychiatry-The Grasshopper Grows Up

Author

Joshua L. Roffman

Subjects
Psychiatry, medicine.medical_specialty, biology, Endophenotypes, Schizophrenia (object-oriented programming), MEDLINE, Genome-wide association study, Grasshoppers, biology.organism_classification, Psychiatry and Mental health, Endophenotype, mental disorders, medicine, Schizophrenia, Animals, Humans, Grasshopper, Psychology, Genome-Wide Association Study, Original Investigation
Abstract

IMPORTANCE: The Consortium on the Genetics of Schizophrenia (COGS) uses quantitative neurophysiological and neurocognitive endophenotypes with demonstrated deficits in schizophrenia as a platform from which to explore the underlying neural circuitry and genetic architecture. Many of these endophenotypes are associated with poor functional outcome in schizophrenia. Some are also endorsed as potential treatment targets by the US Food and Drug Administration. OBJECTIVE: To build on prior assessments of heritability, association, and linkage in the COGS phase 1 (COGS-1) families by reporting a genome-wide association study (GWAS) of 11 schizophrenia-related endophenotypes in the independent phase 2 (COGS-2) cohort of patients with schizophrenia and healthy comparison participants (HCPs). DESIGN, SETTING, AND PARTICIPANTS: A total of 1789 patients with schizophrenia and HCPs of self-reported European or Latino ancestry were recruited through a collaborative effort across the COGS sites and genotyped using the PsychChip. Standard quality control filters were applied, and more than 6.2 million variants with a genotyping call rate of greater than 0.99 were available after imputation. Association was performed for data sets stratified by diagnosis and ancestry using linear regression and adjusting for age, sex, and 5 principal components, with results combined through weighted meta-analysis. Data for COGS-1 were collected from January 6, 2003, to August 6, 2008; data for COGS-2, from June 30, 2010, to February 14, 2014. Data were analyzed from October 28, 2016, to May 4, 2018. MAIN OUTCOMES AND MEASURES: A genome-wide association study was performed to evaluate association for 11 neurophysiological and neurocognitive endophenotypes targeting key domains of schizophrenia related to inhibition, attention, vigilance, learning, working memory, executive function, episodic memory, and social cognition. RESULTS: The final sample of 1533 participants included 861 male participants (56.2%), and the mean (SD) age was 41.8 (13.6) years. In total, 7 genome-wide significant regions (P

Published
2019

38. Functional connectomics of affective and psychotic pathology

Author

Dost Öngür, Daniel G. Dillon, Justin T. Baker, Avram J. Holmes, Joshua L. Roffman, Lauren M. Patrick, Roscoe O. Brady, and Diego A. Pizzagalli

Subjects
Adult, Male, Connectomics, Psychosis, Pathology, medicine.medical_specialty, Rest, Social Sciences, Schizoaffective disorder, 03 medical and health sciences, resting-state connectivity, 0302 clinical medicine, medicine, Connectome, Humans, Bipolar disorder, Default mode network, bipolar disorder, Depressive Disorder, Major, Multidisciplinary, major depressive disorder, business.industry, Mood Disorders, Brain, Middle Aged, Biological Sciences, medicine.disease, functional connectome, Magnetic Resonance Imaging, 030227 psychiatry, schizophrenia, Psychotic Disorders, PNAS Plus, Schizophrenia, Psychological and Cognitive Sciences, Major depressive disorder, Female, Nerve Net, business, 030217 neurology & neurosurgery, Neuroscience
Abstract

Significance Historically, most research on the biological origins of psychiatric illness has focused on individual diagnostic categories, studied in isolation. Mounting evidence indicates that nominally distinct psychiatric diagnoses are not separated by clear neurobiological boundaries. Here, we derive functional connectomic signatures in over 1,000 individuals, including patients presenting with different categories of impairment (psychosis), clinical diagnoses, and severity of illness as reflected in treatment seeking. Our analyses reveal features of connectome functioning that are commonly disrupted across distinct forms of pathology, scaling with clinical severity. Conversely, other aspects of network connectivity were preferentially disrupted in patients with psychotic illness. These data have important implications for the establishment of functional connectome fingerprints of severe mental disease., Converging evidence indicates that groups of patients with nominally distinct psychiatric diagnoses are not separated by sharp or discontinuous neurobiological boundaries. In healthy populations, individual differences in behavior are reflected in variability across the collective set of functional brain connections (functional connectome). These data suggest that the spectra of transdiagnostic symptom profiles observed in psychiatric patients may map onto detectable patterns of network function. To examine the manner through which neurobiological variation might underlie clinical presentation, we obtained fMRI data from over 1,000 individuals, including 210 diagnosed with a primary psychotic disorder or affective psychosis (bipolar disorder with psychosis and schizophrenia or schizoaffective disorder), 192 presenting with a primary affective disorder without psychosis (unipolar depression, bipolar disorder without psychosis), and 608 demographically matched healthy comparison participants recruited through a large-scale study of brain imaging and genetics. Here, we examine variation in functional connectomes across psychiatric diagnoses, finding striking evidence for disease connectomic “fingerprints” that are commonly disrupted across distinct forms of pathology and appear to scale as a function of illness severity. The presence of affective and psychotic illnesses was associated with graded disruptions in frontoparietal network connectivity (encompassing aspects of dorsolateral prefrontal, dorsomedial prefrontal, lateral parietal, and posterior temporal cortices). Conversely, other properties of network connectivity, including default network integrity, were preferentially disrupted in patients with psychotic illness, but not patients without psychotic symptoms. This work allows us to establish key biological and clinical features of the functional connectomes of severe mental disease.

Published
2019

39. A New Era for the Harvard Review of Psychiatry

Author

Joshua L. Roffman

Subjects
Mental Health Services, Psychiatry and Mental health, Psychoanalysis, Humans, Periodicals as Topic, Psychology, Editorial Policies
Published
2019

40. Functional connectomics of affective and psychotic pathology

Author

Diego A. Pizzagalli, Avram J. Holmes, Dost Öngür, Lauren M. Patrick, Daniel G. Dillon, Justin T. Baker, Roscoe O. Brady, and Joshua L. Roffman

Subjects
0303 health sciences, Connectomics, Psychosis, Pathology, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Schizoaffective disorder, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Neuroimaging, Schizophrenia, Connectome, Medicine, Bipolar disorder, business, Functional magnetic resonance imaging, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Converging evidence indicates that groups of patients with nominally distinct psychiatric diagnoses are not separated by sharp or discontinuous neurobiological boundaries. In healthy populations, individual differences in behavior are reflected in variability across the collective set of functional brain connections (functional connectome). These data suggest that the spectra of transdiagnostic symptom profiles observed in psychiatric patients may map onto detectable patterns of network function. To examine the manner through which neurobiological variation might underlie clinical presentation we obtained functional magnetic resonance imaging (fMRI) data from over 1,000 individuals, including 210 diagnosed with a primary psychotic disorder or affective psychosis (bipolar disorder with psychosis and schizophrenia or schizoaffective disorder), 192 presenting with a primary affective disorder without psychosis (unipolar depression, bipolar disorder without psychosis), and 608 demographically and data-quality matched healthy comparison participants recruited through a large-scale study of brain imaging and genetics. Here, we examine variation in functional connectomes across psychiatric diagnoses, finding striking evidence for disease connectomic “fingerprints” that are commonly disrupted across distinct forms of pathology and appear to scale as a function of illness severity. Conversely, other properties of network connectivity were preferentially disrupted in patients with psychotic illness, but not patients without psychotic symptoms. This work allows us to establish key biological and clinical features of the functional connectomes of severe mental disease.SIGNIFICANCE STATEMENTHistorically, most research on the biological origins of psychiatric illness has focused on individual diagnostic categories, studied in isolation. Mounting evidence suggests nominally distinct psychiatric diagnoses are not separated by clear neurobiological boundaries. Here, we derive functional connectomic signatures in over 1,000 individuals including patients presenting with specific categories of impairment (psychosis), clinical diagnoses, or severity of illness as reflected in treatment seeking. Our analyses revealed features of connectome functioning that are commonly disrupted across distinct forms of pathology, scaling with clinical severity. Conversely, other aspects of network connectivity were preferentially disrupted in patients with psychotic illness, but not patients without psychotic symptoms. These data have important implications for the establishment of functional connectome fingerprints of severe mental disease.

Published
2018

43. Partitioning heritability analysis reveals a shared genetic basis of brain anatomy and schizophrenia

Author

Joshua Faskowitz, Y. Cruz, Dara S. Manoach, Margaret J. Wright, Derrek P. Hibar, Jordan W. Smoller, Tian Ge, Jae-Yoon Jung, Dost Öngür, G.I. de Zubicaray, N. H. Martin, Randy L. Buckner, Katie L. McMahon, Phil Lee, Paul M. Thompson, Avram J. Holmes, Justin T. Baker, Joshua L. Roffman, and Neda Jahanshad

Subjects
Adult, Male, 0301 basic medicine, Adolescent, Schizophrenia (object-oriented programming), Population, Biology, Polymorphism, Single Nucleotide, Article, Brain anatomy, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Neurodevelopmental disorder, Neuroimaging, Risk Factors, medicine, Humans, Dementia, SNP, Genetic Predisposition to Disease, Gray Matter, education, Molecular Biology, education.field_of_study, Basis (linear algebra), Brain, Heritability, medicine.disease, Magnetic Resonance Imaging, Psychiatry and Mental health, 030104 developmental biology, Evolutionary biology, Behavioral medicine, Schizophrenia, Female, Psychology, Neuroscience, Neurocognitive, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Schizophrenia is a devastating neurodevelopmental disorder with a complex genetic etiology. Widespread cortical gray matter loss has been observed in patients and prodromal samples. However, it remains unresolved whether schizophrenia-associated cortical structure variations arise due to disease etiology or secondary to the illness. Here we address this question using a partitioning-based heritability analysis of genome-wide single-nucleotide polymorphism (SNP) and neuroimaging data from 1750 healthy individuals. We find that schizophrenia-associated genetic variants explain a significantly enriched proportion of trait heritability in eight brain phenotypes (false discovery rate=10%). In particular, intracranial volume and left superior frontal gyrus thickness exhibit significant and robust associations with schizophrenia genetic risk under varying SNP selection conditions. Cross-disorder comparison suggests that the neurogenetic architecture of schizophrenia-associated brain regions is, at least in part, shared with other psychiatric disorders. Our study highlights key neuroanatomical correlates of schizophrenia genetic risk in the general population. These may provide fundamental insights into the complex pathophysiology of the illness, and a potential link to neurocognitive deficits shaping the disorder.

Published
2016

44. Emerging Treatments in Schizophrenia

Author

Joshua L. Roffman and Hannah E. Brown

Subjects
medicine.medical_specialty, medicine.medical_treatment, Treatment outcome, Anti-Inflammatory Agents, Antipsychotic treatment, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Excitatory Amino Acid Agents, Psychiatry, Antipsychotic, Randomized Controlled Trials as Topic, Cognitive Symptoms, business.industry, Vitamins, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Treatment Outcome, Schizophrenia, Drug Therapy, Combination, Antipsychotic Medications, Prevention trials, business, 030217 neurology & neurosurgery, Antipsychotic Agents
Abstract

In this column we examine the recent literature regarding adjunctive antipsychotic treatment of schizophrenia. We provide a brief introduction outlining the urgent need for new therapeutics, particularly for the treatment of negative and cognitive symptoms of schizophrenia. We then address (by mechanism of action) the most extensively studied adjunctive antipsychotic treatments. We conclude that adjunctive treatments targeting glutamatergic modulation, as well as supplementation with certain vitamins, have the strongest evidence for use in the treatment of schizophrenia. Further, larger randomized, controlled trials are needed, focusing on certain subgroups of patients and specific antipsychotic medications.

Published
2016

46. The human cortex possesses a reconfigurable dynamic network architecture that is disrupted in psychosis

Author

Justin T. Baker, R. Matthew Hutchison, Jenna Reinen, Joshua L. Roffman, Oliver Y. Chén, Dost Öngür, B.T. Thomas Yeo, Kevin M. Anderson, Mert R. Sabuncu, Jordan W. Smoller, and Avram J. Holmes

Subjects
Adult, Male, 0301 basic medicine, Psychosis, Bipolar Disorder, Dynamic network analysis, Adolescent, Science, Population, General Physics and Astronomy, Disease, Brain mapping, Article, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, Cognition, 0302 clinical medicine, Neural Pathways, medicine, Humans, Bipolar disorder, lcsh:Science, education, Cerebral Cortex, Brain Mapping, education.field_of_study, Multidisciplinary, General Chemistry, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Cerebral cortex, Schizophrenia, Female, lcsh:Q, Psychology, Neuroscience, 030217 neurology & neurosurgery
Abstract

Higher-order cognition emerges through the flexible interactions of large-scale brain networks, an aspect of temporal coordination that may be impaired in psychosis. Here, we map the dynamic functional architecture of the cerebral cortex in healthy young adults, leveraging this atlas of transient network configurations (states), to identify state- and network-specific disruptions in patients with schizophrenia and psychotic bipolar disorder. We demonstrate that dynamic connectivity profiles are reliable within participants, and can act as a fingerprint, identifying specific individuals within a larger group. Patients with psychotic illness exhibit intermittent disruptions within cortical networks previously associated with the disease, and the individual connectivity profiles within specific brain states predict the presence of active psychotic symptoms. Taken together, these results provide evidence for a reconfigurable dynamic architecture in the general population and suggest that prior reports of network disruptions in psychosis may reflect symptom-relevant transient abnormalities, rather than a time-invariant global deficit., Temporal changes in brain dynamics are linked with cognitive abilities, but neither their stability nor relationship to psychosis is clear. Here, authors describe the dynamic neural architecture in healthy controls and patients with psychosis and find that they are stable over time and can predict psychotic symptoms.

Published
2018

47. Functional connectivity between anterior insula and key nodes of frontoparietal executive control and salience networks distinguish bipolar depression from unipolar depression and healthy controls

Author

Joshua L. Roffman, Navneet Kaur, Jared P. Zimmerman, Kristen K. Ellard, Joan A. Camprodon, Thilo Deckersbach, Darin D. Dougherty, Koene R. A. Van Dijk, and Andrew A. Nierenberg

Subjects
Adult, Male, Bipolar Disorder, Rest, Cognitive Neuroscience, Neuroimaging, behavioral disciplines and activities, Article, 03 medical and health sciences, Executive Function, 0302 clinical medicine, Salience (neuroscience), Parietal Lobe, mental disorders, medicine, Humans, Radiology, Nuclear Medicine and imaging, Bipolar disorder, Biological Psychiatry, Default mode network, Cerebral Cortex, Brain Mapping, Depressive Disorder, Major, medicine.diagnostic_test, business.industry, Mood Disorders, Inferior parietal lobule, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Healthy Volunteers, 030227 psychiatry, Mood, Mood disorders, Female, Neurology (clinical), Functional magnetic resonance imaging, business, Neuroscience, Insula, 030217 neurology & neurosurgery, Biomarkers
Abstract

Background Patients with bipolar depression are characterized by dysregulation across the full spectrum of mood, differentiating them from patients with unipolar depression. The ability to switch neural resources among the default mode network, salience network, and executive control network (ECN) has been proposed as a key mechanism for adaptive mood regulation. The anterior insula is implicated in the modulation of functional network switching. Differential connectivity between anterior insula and functional networks may provide insights into pathophysiological differences between bipolar and unipolar mood disorders, with implications for diagnosis and treatment. Methods Resting-state functional magnetic resonance imaging data were collected from 98 subjects (35 unipolar, 24 bipolar, and 39 healthy control subjects). Pearson correlations were computed between bilateral insula seed regions and a priori defined target regions from the default mode network, salience network, and ECN. After r-to-z transformation, a one-way multivariate analysis of covariance was conducted to identify significant differences in connectivity between groups. Post hoc pairwise comparisons were conducted and Bonferroni corrections were applied. Receiver-operating characteristics were computed to assess diagnostic sensitivity. Results Patients with bipolar depression evidenced significantly altered right anterior insula functional connectivity with the inferior parietal lobule of the ECN relative to patients with unipolar depression and control subjects. Right anterior insula–inferior parietal lobule connectivity significantly discriminated patients with bipolar depression. Conclusions Impaired functional connectivity between the anterior insula and the inferior parietal lobule of the ECN distinguishes patients with bipolar depression from those with unipolar depression and healthy control subjects. This finding highlights a pathophysiological mechanism with potential as a therapeutic target and a clinical biomarker for bipolar disorder, exhibiting reasonable sensitivity and specificity.

Published
2018

48. S-Adenosyl Methionine and Transmethylation Pathways in Neuropsychiatric Diseases Throughout Life

Author

Catherine M. Cahill, Jack T. Rogers, Joshua L. Roffman, Xudong Huang, Maurizio Fava, Jin Gao, Stefania Lamon-Fava, and David Mischoulon

Subjects
0301 basic medicine, S-Adenosylmethionine, Biology, Methylation, Epigenesis, Genetic, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Animals, Humans, Pharmacology (medical), S-Adenosyl methionine, Pharmacology, Methionine, Mental Disorders, Neurodegenerative Diseases, Protein phosphatase 2, DNA Methylation, 030104 developmental biology, Histone, chemistry, Biochemistry, Current Perspectives, DNA methylation, biology.protein, Neurology (clinical), Signal transduction, Transmethylation, 030217 neurology & neurosurgery, Signal Transduction
Abstract

S-Adenosyl methionine (SAMe), as a major methyl donor, exerts its influence on central nervous system function through cellular transmethylation pathways, including the methylation of DNA, histones, protein phosphatase 2A, and several catecholamine moieties. Based on available evidence, this review focuses on the lifelong range of severe neuropsychiatric and neurodegenerative diseases and their associated neuropathologies, which have been linked to the deficiency/load of SAMe production or/and the disturbance in transmethylation pathways. Also included in this review are the present-day applications of SAMe in the treatment in these diseases in each age group.

Published
2018

49. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: a collaborative cognitive and neuroimaging genetics project

Author

Paul G. Nestor, James Lee, Vince D. Calhoun, Lynn E. DeLisi, Antje A. T. S. Reinders, Kang Sim, Neeltje E.M. van Haren, Robert W. McCarley, Anthony S. David, Wiepke Cahn, Timothea Toulopoulou, Martha E. Shenton, Paola Dazzan, Rick P.F. Wolthusen, Annette M. Hartmann, Bettina Konte, Randy L. Gollub, Jianjun Liu, Todd Lencz, Matcheri S. Keshavan, Erin W. Dickie, Jordan W. Smoller, Derek W. Morris, Lisa Osiecki, Esther Walton, Aristotle N. Voineskos, Sonja de Zwarte, Larry J. Seidman, Jill M. Goldstein, Stefan Ehrlich, New Fei Ho, Tiago Reis Marques, Marta Di Forti, Marek Kubicki, Daphne J. Holt, M. Aurora Falcone, Manuela Russo, Joey W. Trampush, Simone Ciufolini, Anil K. Malhotra, Joshua L. Roffman, Jessica A. Turner, S. Charles Schulz, Dara S. Manoach, Max Lam, René S. Kahn, Aiden Corvin, James T.R. Walters, Shaun Purcell, Elisabetta C. del Re, Jorge Jovicich, Valeria Mondelli, Ina Giegling, Elvira Bramon, Raquelle I. Mesholam-Gately, Donald C. Goff, Nasim Maleki, Michael Gill, Gary Donohoe, Dan Rujescu, Richard S.E. Keefe, Stephen L. Buka, Evangelos Vassos, Nicolas Crossley, Donna Cosgrove, Scott R. Sponheim, Sara Cherkerzian, Tracey L. Petryshen, Robin M. Murray, Marco Picchioni, Zora Kikinis, Gabriëlla A.M. Blokland, Heidi W. Thermenos, Sinead Kelly, and Toulopoulou, Timothea

Subjects
cognition, Male, neuropsychology, rare variant association, population, Genome-wide association study, heritability, Neuropsychological Tests, 0302 clinical medicine, Cognition, Image Processing, Computer-Assisted, genetics, phenotypes b-snip, Child, bipolar disorder, Aged, 80 and over, Genetics, education.field_of_study, neuroimaging, Neuropsychology, Middle Aged, Magnetic Resonance Imaging, Psychiatry and Mental health, Female, Sample collection, Psychology, metaanalysis, MRI, Adult, medicine.medical_specialty, Psychosis, polygenic risk, Adolescent, Genotype, Endophenotypes, Schizophrenia (object-oriented programming), Population, Neuroimaging, Polymorphism, Single Nucleotide, Article, Statistics, Nonparametric, Young Adult, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, education, Psychiatry, mri, Biological Psychiatry, Aged, brain structure, syndrome scale panss, medicine.disease, 030227 psychiatry, Endophenotype, genome-wide association, Schizophrenia, Cognition Disorders, 030217 neurology & neurosurgery
Abstract

Background: Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. Methods: We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. Results: Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p < 1 × 10− 10). Data from a diversity of neuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other. Conclusions: The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of > 10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia. We are grateful for the support of all study staff and participants. Acknowledgements for each sample are provided in the Supplementary Materials. Data processing and analyses (of the legacy data) at the central site was supported by the National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH) grant number R01MH092380 to T.L.P. supporting the Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium, and NIMH grant R21MH109819 to E.D.R. Appendix A

Published
2018

50. Correspondence of DNA Methylation Between Blood and Brain Tissue and Its Application to Schizophrenia Research

Author

Stefan Ehrlich, Esther Walton, Johanna Hass, Jingyu Liu, Matthias Kirsch, Vince D. Calhoun, Gabriele Schackert, Veit Roessner, Joshua L. Roffman, and Fabio Bernardoni

Subjects
0301 basic medicine, Biology, Bioinformatics, Epigenesis, Genetic, Temporal lobe, 03 medical and health sciences, 0302 clinical medicine, Biopsy, medicine, Humans, Epigenetics, Gene, Genetics, medicine.diagnostic_test, Brain, Regular Article, Human brain, Methylation, DNA Methylation, Psychiatry and Mental health, 030104 developmental biology, medicine.anatomical_structure, CpG site, DNA methylation, Schizophrenia, CpG Islands, Biomarkers, 030217 neurology & neurosurgery
Abstract

Given the difficulty of procuring human brain tissue, a key question in molecular psychiatry concerns the extent to which epigenetic signatures measured in more accessible tissues such as blood can serve as a surrogate marker for the brain. Here, we aimed (1) to investigate the blood-brain correspondence of DNA methylation using a within-subject design and (2) to identify changes in DNA methylation of brain-related biological pathways in schizophrenia.We obtained paired blood and temporal lobe biopsy samples simultaneously from 12 epilepsy patients during neurosurgical treatment. Using the Infinium 450K methylation array we calculated similarity of blood and brain DNA methylation for each individual separately. We applied our findings by performing gene set enrichment analyses (GSEA) of peripheral blood DNA methylation data (Infinium 27K) of 111 schizophrenia patients and 122 healthy controls and included only Cytosine-phosphate-Guanine (CpG) sites that were significantly correlated across tissues.Only 7.9% of CpG sites showed a statistically significant, large correlation between blood and brain tissue, a proportion that although small was significantly greater than predicted by chance. GSEA analysis of schizophrenia data revealed altered methylation profiles in pathways related to precursor metabolites and signaling peptides.Our findings indicate that most DNA methylation markers in peripheral blood do not reliably predict brain DNA methylation status. However, a subset of peripheral data may proxy methylation status of brain tissue. Restricting the analysis to these markers can identify meaningful epigenetic differences in schizophrenia and potentially other brain disorders.

Published
2015

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