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1. Novel neuronal surface autoantibodies in plasma of patients with depression and anxiety

Author: Shenghua Zong, Carolin Correia-Hoffmann, Marina Mané-Damas, Nils Kappelmann, Peter C. Molenaar, Gerard van Grootheest, Brenda W. J. H. Penninx, Rob P. W. Rouhl, Mario Losen, and Pilar Martinez-Martinez
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Abstract Neuronal surface autoantibodies (NSAbs) against various antigens cause autoimmune encephalitis. Some of these antigens are also involved in the pathology of depression and anxiety. To study whether NSAbs are more common in plasma of individuals with depression and anxiety than in controls, and to investigate if NSAbs correlate with disease status, plasma samples of 819 individuals with a current diagnosis of depression and/or anxiety, 920 in remission and 492 individuals without these disorders were included in this study. Samples were tested by a combination of immunohistochemistry (IHC), staining on live rat hippocampus neurons and cell-based assay (CBA). By IHC, 50 (2.2%) samples showed immunoreactivity to rat brain tissue, with no significant differences between the aforementioned groups (22/819 vs 18/920 vs 11/492, P > 0.99). In addition, eight IHC positive samples were positive for NSAbs on live neurons (7/819 vs 0/920 vs 1/492, P = 0.006). The IHC-staining patterns of these eight samples were atypical for autoimmune encephalitis and accordingly, they tested negative for known NSAbs by CBA. No obvious difference in the clinical characteristics between individuals with or without NSAbs was observed. In conclusion, novel NSAbs were rare but predominately found in patients with current anxiety or depression indicating they might affect mental health in a small group of patients.
Published: 2020
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2. A randomized controlled trial comparing the clinical efficacy and cost-effectiveness of eye movement desensitization and reprocessing (EMDR) and integrated EMDR-Dialectical Behavioural Therapy (DBT) in the treatment of patients with post-traumatic stress disorder and comorbid (Sub)clinical borderline personality disorder: study design

Author: Aishah Snoek, Aartjan T. F. Beekman, Jack Dekker, Inga Aarts, Gerard van Grootheest, Matthijs Blankers, Chris Vriend, Odile van den Heuvel, and Kathleen Thomaes
Subjects: EMDR, PTSD, Dialectical behaviour therapy, Borderline personality disorder, Psychiatry, RC435-571
Abstract: Abstract Background Comorbidity between Posttraumatic Stress Disorder (PTSD) and Borderline Personality Disorder (BPD) is high. There is growing motivation among clinicians to offer PTSD treatments – such as Eye Movement Desensitization and Reprocessing (EMDR) - to patients with PTSD and comorbid BPD. However, a large subgroup with comorbid BPD does not sufficiently respond to PTSD treatment and is more likely to be excluded or to dropout from treatment. Dialectical Behaviour Therapy (DBT) for BPD is well established and although there is some evidence that DBT combined with DBT Prolonged Exposure (DBT + DBT PE) is twice as effective in reducing PTSD symptoms than DBT alone, the comparative efficacy of integrated PTSD-DBT and PTSD-only treatment has not been investigated yet. The current study will therefore evaluate the comparative clinical efficacy and cost-effectiveness of EMDR-DBT and EMDR-only in patients with PTSD and comorbid (sub)clinical BPD. Moreover, it is not clear yet what treatment works best for which individual patient. The current study will therefore evaluate neurobiological predictors and mediators of the individual response to treatment. Method A randomized controlled trial comparing the clinical efficacy and cost-effectiveness of integrated EMDR-DBT (n = 63) and EMDR-only (n = 63) in treatment-seeking adult patients with PTSD and comorbid (sub)clinical BPD. In addition, neurobiological predictors and mediators of treatment outcome, such as hair cortisol, FKBP5 and BDNF protein levels and FKBP5 and BDNF methylation status, are measured through hair and blood samples. Discussion This is the first study to compare the clinical efficacy and cost-effectiveness of integrated EMDR-DBT and EMDR-only in patients with PTSD and comorbid (sub)clinical BPD, while simultaneously identifying individual predictors and mediators of treatment response. Results will reveal which treatment works best for which individual patient, thereby guiding individual treatment choices and personalizing psychiatry. Trial registration Clinical Trials, NCT03833453 . Retrospectively registered, 15 March 2019.
Published: 2020
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3. Overweight and obese individuals with depressive symptoms from the MooDFOOD prevention trial: Role of sociodemographic, somatic health, and weight related factors

Author: Ezgi Dogan-Sander, Sabrina Baldofski, Nicole Mauche, Mariska Bot, Ingeborg A. Brouwer, Mieke Cabout, Margarita Gili, Gerard van Grootheest, Ulrich Hegerl, Matthew Owens, Brenda W.J.H. Penninx, Miquel Roca, Marjolein Visser, Ed Watkins, and Elisabeth Kohls
Subjects: Depressive disorder, Depressive symptoms, Overweight, Obesity, Sociodemographics, Mental healing, RZ400-408
Abstract: Background: Major depression disorder (MDD)11 Abbreviations: BMI: Body mass index; MDD: Major depressive disorder; WHR: wait-to-hip-ratio and obesity are among the most common public health problems. The majority of epidemiological studies demonstrated a strong relationship between sociodemographic factors like age and socioeconomic status and depression. Also, a bidirectional link between depression and obesity is discussed. However, differences regarding sociodemographic factors and obesity between participants with and without lifetime MDD might occur, but potentially not in all individuals. This study intends to contribute to this discussion by investigating whether or not sociodemographic factors, chronic illness status, and overweight differ between individuals with and without lifetime MDD. Methods: In the MooDFOOD depression prevention trial, 1025 overweight or obese participants with subsyndromal symptoms of depression were recruited. Lifetime history of MDD, number of lifetime MDD episodes, sociodemographic data, and chronic illness were assessed via clinical interview, also standardized anthropometric measures (body mass index [BMI], waist-to-hip ratio [WHR]). Results: A lifetime MDD diagnosis was present in 33.5% of the sample. Individuals with lifetime MDD and individuals who never suffered from MDD did not differ regarding sex, age, marital status, educational level, employment status, and income. Further, there were no significant differences in BMI, WHR, and number of chronic illnesses between participants with and without lifetime MDD. Limitations: The cross-sectional nature of the data prohibited causal inferences. Conclusion: Sociodemographic variables, chronic illness status and anthropometric measures seem not to be related to the status of having suffered from MDD in the past vs. not having suffered from MDD in people who are currently overweight or obese.
Published: 2021
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4. Toxoplasma gondii seropositivity in patients with depressive and anxiety disorders

Author: Nienke J. de Bles, Juliette E.H. van der Does, Laetitia M. Kortbeek, Agnetha Hofhuis, Gerard van Grootheest, Albert M. Vollaard, Robert A. Schoevers, Albert M. van Hemert, Brenda W.J.H. Penninx, Nathaly Rius-Ottenheim, and Erik J. Giltay
Subjects: Toxoplasma gondii, Depression, Anxiety, Cognitive reactivity, Suicidality, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Introduction: Toxoplasma gondii (T. gondii) is an obligate intracellular parasite that is estimated to be carried by one-third of the world population. Latent T. gondii infection has been linked to several neuropsychiatric mood disorders and behaviors. The aim of the present study was to examine whether T. gondii seropositivity is associated with affective disorders, as well as with aggression reactivity and suicidal thoughts. Methods: In the Netherlands Study of Depression and Anxiety (NESDA), T. gondii antibodies were assessed in patients with current depressive (n = 133), anxiety (n = 188), comorbid depressive and anxiety (n = 148), and remitted disorders (n = 889), as well as in healthy controls (n = 373) based on DSM-IV criteria. Seropositivity was analyzed in relation to disorder status, aggression reactivity and suicidal thoughts using multivariate analyses of covariance and regression analyses. Results: Participants were on average 51.2 years (SD = 13.2), and 64.4% were female. Seropositivity was found in 673 participants (38.9%). A strong positive association between T. gondii seropositivity and age was observed. No significant associations were found between T. gondii seropositivity and disorder status, aggression reactivity and suicidal thoughts. The adjusted odds ratio (OR) for any remitted disorder versus controls was 1.13 (95% CI: 0.87-1.49), and for any current disorder versus controls was 0.94 (95% CI: 0.69-1.28). Conclusions: No evidence was found for a relationship between affective disorders and T. gondii infection in the current sample.
Published: 2021
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5. Acceptability and feasibility of two interventions in the MooDFOOD Trial: a food-related depression prevention randomised controlled trial in overweight adults with subsyndromal symptoms of depression

Author: Ulrich Hegerl, Edward Watkins, Miquel Roca, Matthew Owens, Mariska Bot, Ingeborg Annemarie Brouwer, Elisabeth Kohls, Brenda Penninx, Gerard van Grootheest, Mieke Cabout, Margalida Gili, Marjolein Visser, Bep Verkerk, Nadine Paans, Carisha Thesing, Deborah Gibson-Smith, Melany Horsfall, Lena Weiss, Amy Romijn, Hannah Bunce, Owain Winfield, Harriet Bunker-Smith, Fern Durbridge, Caterina Versari Molinares, Atikah Sapar, Miquel Tortella, Clara Homar Covas, M Angeles Pérez-Ara, Adoración Castro Gracia, José Luis Reig, Jana Hoesel, Ezgi Dogan, Sabrina Baldofski, and Nicole Mauche
Subjects: Medicine
Abstract: Objectives We report on the acceptability, feasibility, dose-response relationship and adherence of two nutritional strategies to improve mood (multinutrient supplements; food-related behavioural activation (F-BA)) studied in a randomised controlled depression prevention trial (the Multi‐country cOllaborative project on the rOle of Diet, Food‐related behaviour, and Obesity in the prevention of Depression (MooDFOOD) Trial). We also assessed baseline determinants of adherence and assessed whether better adherence resulted in lower depressive symptoms.Design Randomised controlled trial with a 2×2 factorial design conducted between 2015 and 2017.Setting Germany, the Netherlands, UK and Spain.Participants Community sample of 1025 overweight adults with elevated depressive symptoms without a current episode of major depressive disorder. Main eligibility criteria included age (18–75 years), being overweight or obese, and having at least mild depressive symptoms, shown by a Patient Health Questionnaire Score of ≥5. A total of 76% of the sample was retained at the 12-month follow-up.Interventions Daily nutritional supplements versus pill placebo or an F-BA therapy, delivered in individual and group sessions versus no behavioural intervention over a 1-year period.Primary and secondary outcome measures Primary outcome: self-reported acceptability of the interventions. Secondary outcomes: adherence and self-reported depressive symptoms.Results Most participants reported that the F-BA was acceptable (83.61%), feasible to do (65.91%) and would recommend it to a friend (84.57%). Individual F-BA sessions (88.10%) were significantly more often rated as positive than group F-BA sessions (70.17%) and supplements (28.59%). There were statistically significant reductions in depressive symptoms for those who both adhered to the F-BA intervention and had a history of depression (B=−0.08, SE=0.03, p=0.012) versus those who had no history of depression. Supplement intake had no effect on depressive symptoms irrespective of adherence.Conclusions F-BA may have scope for development as a depression prevention intervention and public health strategy but further refinement and testing are needed.Trial registration number NCT02529423.
Published: 2020
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6. Integrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder

Author: Hyun Ji Noh, Ruqi Tang, Jason Flannick, Colm O’Dushlaine, Ross Swofford, Daniel Howrigan, Diane P. Genereux, Jeremy Johnson, Gerard van Grootheest, Edna Grünblatt, Erik Andersson, Diana R. Djurfeldt, Paresh D. Patel, Michele Koltookian, Christina M. Hultman, Michele T. Pato, Carlos N. Pato, Steven A. Rasmussen, Michael A. Jenike, Gregory L. Hanna, S. Evelyn Stewart, James A. Knowles, Stephan Ruhrmann, Hans-Jörgen Grabe, Michael Wagner, Christian Rück, Carol A. Mathews, Susanne Walitza, Daniëlle C. Cath, Guoping Feng, Elinor K. Karlsson, and Kerstin Lindblad-Toh
Subjects: Science
Abstract: Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder with symptoms including intrusive thoughts and time-consuming repetitive behaviors. Here Noh and colleagues identify genes enriched for functional variants associated with increased risk of OCD.
Published: 2017
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7. Depressive Symptom Clusters in Relation to Body Weight Status: Results From Two Large European Multicenter Studies

Author: Sabrina Baldofski, Nicole Mauche, Ezgi Dogan-Sander, Mariska Bot, Ingeborg A. Brouwer, Nadine P. G. Paans, Mieke Cabout, Margarita Gili, Gerard van Grootheest, Ulrich Hegerl, Matthew Owens, Miquel Roca, Marjolein Visser, Ed Watkins, Brenda W. J. H. Penninx, and Elisabeth Kohls
Subjects: depression, depressive symptoms, obesity, overweight, body mass index, Psychiatry, RC435-571
Abstract: Background: There is strong evidence for a bidirectional association between depression and obesity. Several biological, psychological, and behavior-related factors may influence this complex association. Clinical impression and preliminary evidence suggest that patients with a diagnosis of major depressive disorder may endorse very different depressive symptom patterns depending on their body weight status. Until now, little is known about potential differences in depressive symptoms in relation to body weight status.Objective: The aim of this analysis is the investigation of potential differences in depressive symptom clusters (mood symptoms, somatic/vegetative symptoms, and cognitive symptoms) in relation to body weight status.Methods: Cross-sectional baseline data were derived from two large European multicenter studies: the MooDFOOD Trial and the NESDA cohort study, including persons with overweight and obesity and normal weight reporting subthreshold depressive symptoms (assessment via Inventory of Depressive Symptomatology Self-Report, IDS-SR30). Different measures for body weight status [waist-to-hip ratio (WHR) and body mass index (BMI)] were examined. Propensity score matching was performed and multiple linear regression analyses were conducted.Results: A total of n = 504 individuals (73.0% women) were analyzed. Results show that more somatic/vegetative depressive symptoms, such as pain, change in appetite and weight, gastrointestinal symptoms, and arousal-related symptoms, were significantly associated with both a higher BMI and higher WHR, respectively. In addition, being male and older age were significantly associated with higher WHR. Mood and cognitive depressive symptoms did not yield significant associations for both body weight status measures.Conclusions: Somatic/vegetative symptoms and not mood and cognitive symptoms of depression are associated with body weight status. Thus, the results support previous findings of heterogeneous depressive symptoms in relation to body weight status. In addition to BMI, other body weight status measures for obesity should be taken into account in future studies.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT02529423.
Published: 2019
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8. Correction: Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

Author: Mariaelisa Graff, Robert A Scott, Anne E Justice, Kristin L Young, Mary F Feitosa, Llilda Barata, Thomas W Winkler, Audrey Y Chu, Anubha Mahajan, David Hadley, Luting Xue, Tsegaselassie Workalemahu, Nancy L Heard-Costa, Marcel den Hoed, Tarunveer S Ahluwalia, Qibin Qi, Julius S Ngwa, Frida Renström, Lydia Quaye, John D Eicher, James E Hayes, Marilyn Cornelis, Zoltan Kutalik, Elise Lim, Jian'an Luan, Jennifer E Huffman, Weihua Zhang, Wei Zhao, Paula J Griffin, Toomas Haller, Shafqat Ahmad, Pedro M Marques-Vidal, Stephanie Bien, Loic Yengo, Alexander Teumer, Albert Vernon Smith, Meena Kumari, Marie Neergaard Harder, Johanne Marie Justesen, Marcus E Kleber, Mette Hollensted, Kurt Lohman, Natalia V Rivera, John B Whitfield, Jing Hua Zhao, Heather M Stringham, Leo-Pekka Lyytikäinen, Charlotte Huppertz, Gonneke Willemsen, Wouter J Peyrot, Ying Wu, Kati Kristiansson, Ayse Demirkan, Myriam Fornage, Maija Hassinen, Lawrence F Bielak, Gemma Cadby, Toshiko Tanaka, Reedik Mägi, Peter J van der Most, Anne U Jackson, Jennifer L Bragg-Gresham, Veronique Vitart, Jonathan Marten, Pau Navarro, Claire Bellis, Dorota Pasko, Åsa Johansson, Søren Snitker, Yu-Ching Cheng, Joel Eriksson, Unhee Lim, Mette Aadahl, Linda S Adair, Najaf Amin, Beverley Balkau, Juha Auvinen, John Beilby, Richard N Bergman, Sven Bergmann, Alain G Bertoni, John Blangero, Amélie Bonnefond, Lori L Bonnycastle, Judith B Borja, Søren Brage, Fabio Busonero, Steve Buyske, Harry Campbell, Peter S Chines, Francis S Collins, Tanguy Corre, George Davey Smith, Graciela E Delgado, Nicole Dueker, Marcus Dörr, Tapani Ebeling, Gudny Eiriksdottir, Tõnu Esko, Jessica D Faul, Mao Fu, Kristine Færch, Christian Gieger, Sven Gläser, Jian Gong, Penny Gordon-Larsen, Harald Grallert, Tanja B Grammer, Niels Grarup, Gerard van Grootheest, Kennet Harald, Nicholas D Hastie, Aki S Havulinna, Dena Hernandez, Lucia Hindorff, Lynne J Hocking, Oddgeir L Holmens, Christina Holzapfel, Jouke Jan Hottenga, Jie Huang, Tao Huang, Jennie Hui, Cornelia Huth, Nina Hutri-Kähönen, Alan L James, John-Olov Jansson, Min A Jhun, Markus Juonala, Leena Kinnunen, Heikki A Koistinen, Ivana Kolcic, Pirjo Komulainen, Johanna Kuusisto, Kirsti Kvaløy, Mika Kähönen, Timo A Lakka, Lenore J Launer, Benjamin Lehne, Cecilia M Lindgren, Mattias Lorentzon, Robert Luben, Michel Marre, Yuri Milaneschi, Keri L Monda, Grant W Montgomery, Marleen H M De Moor, Antonella Mulas, Martina Müller-Nurasyid, A W Musk, Reija Männikkö, Satu Männistö, Narisu Narisu, Matthias Nauck, Jennifer A Nettleton, Ilja M Nolte, Albertine J Oldehinkel, Matthias Olden, Ken K Ong, Sandosh Padmanabhan, Lavinia Paternoster, Jeremiah Perez, Markus Perola, Annette Peters, Ulrike Peters, Patricia A Peyser, Inga Prokopenko, Hannu Puolijoki, Olli T Raitakari, Tuomo Rankinen, Laura J Rasmussen-Torvik, Rajesh Rawal, Paul M Ridker, Lynda M Rose, Igor Rudan, Cinzia Sarti, Mark A Sarzynski, Kai Savonen, William R Scott, Serena Sanna, Alan R Shuldiner, Steve Sidney, Günther Silbernagel, Blair H Smith, Jennifer A Smith, Harold Snieder, Alena Stančáková, Barbara Sternfeld, Amy J Swift, Tuija Tammelin, Sian-Tsung Tan, Barbara Thorand, Dorothée Thuillier, Liesbeth Vandenput, Henrik Vestergaard, Jana V van Vliet-Ostaptchouk, Marie-Claude Vohl, Uwe Völker, Gérard Waeber, Mark Walker, Sarah Wild, Andrew Wong, Alan F Wright, M Carola Zillikens, Niha Zubair, Christopher A Haiman, Loic Lemarchand, Ulf Gyllensten, Claes Ohlsson, Albert Hofman, Fernando Rivadeneira, André G Uitterlinden, Louis Pérusse, James F Wilson, Caroline Hayward, Ozren Polasek, Francesco Cucca, Kristian Hveem, Catharina A Hartman, Anke Tönjes, Stefania Bandinelli, Lyle J Palmer, Sharon L R Kardia, Rainer Rauramaa, Thorkild I A Sørensen, Jaakko Tuomilehto, Veikko Salomaa, Brenda W J H Penninx, Eco J C de Geus, Dorret I Boomsma, Terho Lehtimäki, Massimo Mangino, Markku Laakso, Claude Bouchard, Nicholas G Martin, Diana Kuh, Yongmei Liu, Allan Linneberg, Winfried März, Konstantin Strauch, Mika Kivimäki, Tamara B Harris, Vilmundur Gudnason, Henry Völzke, Lu Qi, Marjo-Riitta Järvelin, John C Chambers, Jaspal S Kooner, Philippe Froguel, Charles Kooperberg, Peter Vollenweider, Göran Hallmans, Torben Hansen, Oluf Pedersen, Andres Metspalu, Nicholas J Wareham, Claudia Langenberg, David R Weir, David J Porteous, Eric Boerwinkle, Daniel I Chasman, CHARGE Consortium, EPIC-InterAct Consortium, PAGE Consortium, Gonçalo R Abecasis, Inês Barroso, Mark I McCarthy, Timothy M Frayling, Jeffrey R O'Connell, Cornelia M van Duijn, Michael Boehnke, Iris M Heid, Karen L Mohlke, David P Strachan, Caroline S Fox, Ching-Ti Liu, Joel N Hirschhorn, Robert J Klein, Andrew D Johnson, Ingrid B Borecki, Paul W Franks, Kari E North, L Adrienne Cupples, Ruth J F Loos, and Tuomas O Kilpeläinen
Subjects: Genetics, QH426-470
Abstract: [This corrects the article DOI: 10.1371/journal.pgen.1006528.].
Published: 2017
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9. Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

Author: Mariaelisa Graff, Robert A Scott, Anne E Justice, Kristin L Young, Mary F Feitosa, Llilda Barata, Thomas W Winkler, Audrey Y Chu, Anubha Mahajan, David Hadley, Luting Xue, Tsegaselassie Workalemahu, Nancy L Heard-Costa, Marcel den Hoed, Tarunveer S Ahluwalia, Qibin Qi, Julius S Ngwa, Frida Renström, Lydia Quaye, John D Eicher, James E Hayes, Marilyn Cornelis, Zoltan Kutalik, Elise Lim, Jian'an Luan, Jennifer E Huffman, Weihua Zhang, Wei Zhao, Paula J Griffin, Toomas Haller, Shafqat Ahmad, Pedro M Marques-Vidal, Stephanie Bien, Loic Yengo, Alexander Teumer, Albert Vernon Smith, Meena Kumari, Marie Neergaard Harder, Johanne Marie Justesen, Marcus E Kleber, Mette Hollensted, Kurt Lohman, Natalia V Rivera, John B Whitfield, Jing Hua Zhao, Heather M Stringham, Leo-Pekka Lyytikäinen, Charlotte Huppertz, Gonneke Willemsen, Wouter J Peyrot, Ying Wu, Kati Kristiansson, Ayse Demirkan, Myriam Fornage, Maija Hassinen, Lawrence F Bielak, Gemma Cadby, Toshiko Tanaka, Reedik Mägi, Peter J van der Most, Anne U Jackson, Jennifer L Bragg-Gresham, Veronique Vitart, Jonathan Marten, Pau Navarro, Claire Bellis, Dorota Pasko, Åsa Johansson, Søren Snitker, Yu-Ching Cheng, Joel Eriksson, Unhee Lim, Mette Aadahl, Linda S Adair, Najaf Amin, Beverley Balkau, Juha Auvinen, John Beilby, Richard N Bergman, Sven Bergmann, Alain G Bertoni, John Blangero, Amélie Bonnefond, Lori L Bonnycastle, Judith B Borja, Søren Brage, Fabio Busonero, Steve Buyske, Harry Campbell, Peter S Chines, Francis S Collins, Tanguy Corre, George Davey Smith, Graciela E Delgado, Nicole Dueker, Marcus Dörr, Tapani Ebeling, Gudny Eiriksdottir, Tõnu Esko, Jessica D Faul, Mao Fu, Kristine Færch, Christian Gieger, Sven Gläser, Jian Gong, Penny Gordon-Larsen, Harald Grallert, Tanja B Grammer, Niels Grarup, Gerard van Grootheest, Kennet Harald, Nicholas D Hastie, Aki S Havulinna, Dena Hernandez, Lucia Hindorff, Lynne J Hocking, Oddgeir L Holmens, Christina Holzapfel, Jouke Jan Hottenga, Jie Huang, Tao Huang, Jennie Hui, Cornelia Huth, Nina Hutri-Kähönen, Alan L James, John-Olov Jansson, Min A Jhun, Markus Juonala, Leena Kinnunen, Heikki A Koistinen, Ivana Kolcic, Pirjo Komulainen, Johanna Kuusisto, Kirsti Kvaløy, Mika Kähönen, Timo A Lakka, Lenore J Launer, Benjamin Lehne, Cecilia M Lindgren, Mattias Lorentzon, Robert Luben, Michel Marre, Yuri Milaneschi, Keri L Monda, Grant W Montgomery, Marleen H M De Moor, Antonella Mulas, Martina Müller-Nurasyid, A W Musk, Reija Männikkö, Satu Männistö, Narisu Narisu, Matthias Nauck, Jennifer A Nettleton, Ilja M Nolte, Albertine J Oldehinkel, Matthias Olden, Ken K Ong, Sandosh Padmanabhan, Lavinia Paternoster, Jeremiah Perez, Markus Perola, Annette Peters, Ulrike Peters, Patricia A Peyser, Inga Prokopenko, Hannu Puolijoki, Olli T Raitakari, Tuomo Rankinen, Laura J Rasmussen-Torvik, Rajesh Rawal, Paul M Ridker, Lynda M Rose, Igor Rudan, Cinzia Sarti, Mark A Sarzynski, Kai Savonen, William R Scott, Serena Sanna, Alan R Shuldiner, Steve Sidney, Günther Silbernagel, Blair H Smith, Jennifer A Smith, Harold Snieder, Alena Stančáková, Barbara Sternfeld, Amy J Swift, Tuija Tammelin, Sian-Tsung Tan, Barbara Thorand, Dorothée Thuillier, Liesbeth Vandenput, Henrik Vestergaard, Jana V van Vliet-Ostaptchouk, Marie-Claude Vohl, Uwe Völker, Gérard Waeber, Mark Walker, Sarah Wild, Andrew Wong, Alan F Wright, M Carola Zillikens, Niha Zubair, Christopher A Haiman, Loic Lemarchand, Ulf Gyllensten, Claes Ohlsson, Albert Hofman, Fernando Rivadeneira, André G Uitterlinden, Louis Pérusse, James F Wilson, Caroline Hayward, Ozren Polasek, Francesco Cucca, Kristian Hveem, Catharina A Hartman, Anke Tönjes, Stefania Bandinelli, Lyle J Palmer, Sharon L R Kardia, Rainer Rauramaa, Thorkild I A Sørensen, Jaakko Tuomilehto, Veikko Salomaa, Brenda W J H Penninx, Eco J C de Geus, Dorret I Boomsma, Terho Lehtimäki, Massimo Mangino, Markku Laakso, Claude Bouchard, Nicholas G Martin, Diana Kuh, Yongmei Liu, Allan Linneberg, Winfried März, Konstantin Strauch, Mika Kivimäki, Tamara B Harris, Vilmundur Gudnason, Henry Völzke, Lu Qi, Marjo-Riitta Järvelin, John C Chambers, Jaspal S Kooner, Philippe Froguel, Charles Kooperberg, Peter Vollenweider, Göran Hallmans, Torben Hansen, Oluf Pedersen, Andres Metspalu, Nicholas J Wareham, Claudia Langenberg, David R Weir, David J Porteous, Eric Boerwinkle, Daniel I Chasman, CHARGE Consortium, EPIC-InterAct Consortium, PAGE Consortium, Gonçalo R Abecasis, Inês Barroso, Mark I McCarthy, Timothy M Frayling, Jeffrey R O'Connell, Cornelia M van Duijn, Michael Boehnke, Iris M Heid, Karen L Mohlke, David P Strachan, Caroline S Fox, Ching-Ti Liu, Joel N Hirschhorn, Robert J Klein, Andrew D Johnson, Ingrid B Borecki, Paul W Franks, Kari E North, L Adrienne Cupples, Ruth J F Loos, and Tuomas O Kilpeläinen
Subjects: Genetics, QH426-470
Abstract: Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
Published: 2017
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10. Linkage of health insurance data to the Netherlands Twin Register

Author: Gerard van Grootheest, Adelaide Ariel, Tina Glasner, Bep Verkerk, Toos van Beijsterveldt, Jan van der Laan, Mark de Groot, Sipke Visser, Bart Bakker, and Dorret Boomsma
Subjects: Demography. Population. Vital events, HB848-3697
Abstract: ABSTRACT Objectives We compared four different approaches to record linkage, demonstrating its potential in enriching the Netherlands Twin Register (NTR) with healthcare data from a large health insurance provider (AHD), which covers approximately 26% of the population. Challenges included the fact that young twins share most of their linkage variables and overlapping identification numbers were absent. We extensively validated the linkage results and complemented them with an indicator of representativeness. Approach Subjects born since 1986 were selected in the NTR (N=30,383) and AHD (N=1,532,675). Linkage variables were cleaned and harmonised and linkage keys were chosen that were strong enough to uniquely identify most subjects in either dataset. The four linkages were deterministic, probabilistic, probabilistic with Jaro-Winkler distance, and probabilistic using encrypted identifiers. Validation took place by reviewing linkage variables and information like family relations; linked record pairs were categorised into correct, possible or false links. Furthermore, the consistency of linked data was reviewed focusing on Attention Deficit Hyperactivity Disorder (ADHD), a prevalent condition among children. Finally, we quantified the impact of the linkage on representativeness of the target population. Results Probabilistic linkage with distance calculation linked 7944 NTR subjects to the AHD with 82% correct, 17% possible, and 1% false links. It encompassed nearly all links identified by any of the other methods, which were more conservative. Information about medication was available in the NTR dataset for 40% of the linked subjects. Validation of the information about ADHD inside linked records revealed few discrepancies between the two datasets. Linkage had a modest effect on the representativeness of the population. The current linkage has confirmed a number of known ADHD cases and identified 146 new subjects using methylphenidate and 101 receiving psychiatric care for ADHD, who were not previously recognized as ADHD cases within the NTR. Conclusion Record linkage with sources of data such as a health insurance database can be an efficient way of data collection in cohort research. Our study shows that record linkage is also possible for twin pairs. Although a minority of all NTR subjects were covered by the AHD, the linkage resulted in an enrichment of the NTR dataset. Exact information about the dosage and frequency of drugs was obtained without contacting subjects with detailed questionnaires. With a total of almost eight thousand retrieved records, the size of the linked dataset is sufficiently large for epidemiological research of non-rare conditions.
Published: 2017
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11. Associations of carotid intima media thickness with gene expression in whole blood and genetically predicted gene expression across 48 tissues

Author: Joshua C. Bis, Holger Kirsten, Wolfgang Rathmann, Albert Hofman, Shih-Jen Hwang, Stefan Weiss, Annette Peters, Oscar H. Franco, Klodian Dhana, Brenda W J H Penninx, Katharina Schramm, Christian Herder, Joseph F. Polak, Adrie Seldenrijk, Wolfgang Koenig, Markus Loeffler, Marcus Dörr, Andy B Castaneda, Petra Wolf, Frank Beutner, Christopher J. O’Donnell, Xiaoling Zhang, Jochen Seissler, Christa Meisinger, Joachim Thiery, Holger Prokisch, Rick Jansen, Joyce B. J. van Meurs, André G. Uitterlinden, Nora Franceshini, Jennifer E. Below, Georg Homuth, Paul S. de Vries, Daniel Levy, Marjolein J. Peters, Cohorts for Heart, Gerard van Grootheest, Abbas Dehghan, Markus Scholz, Ulf Schminke, Carola Marzi, Melanie Waldenberger, Knut Krohn, Claudia Giambartolomei, Lauren E. Petty, Maryam Kavousi, Henry Völzke, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Department of Marketing Management, Urology, Internal Medicine, and Epidemiology
Subjects: Oncology, Candidate gene, medicine.medical_specialty, Gene Expression, Biology, Carotid Intima-Media Thickness, Risk Factors, Internal medicine, Gene expression, Genetics, medicine, Humans, cardiovascular diseases, Association Studies Article, 610 Medicine & health, Molecular Biology, Gene, Genetics (clinical), Confounding, General Medicine, Atherosclerosis, Phenotype, Intima-media thickness, cardiovascular system, Biomarker (medicine), DNA microarray, 360 Social problems & social services, Genome-Wide Association Study
Abstract: Carotid intima media thickness (cIMT) is a biomarker of subclinical atherosclerosis and a predictor of future cardiovascular events. Identifying associations between gene expression levels and cIMT may provide insight to atherosclerosis etiology. Here, we use two approaches to identify associations between mRNA levels and cIMT: differential gene expression analysis in whole blood and S-PrediXcan. We used microarrays to measure genome-wide whole blood mRNA levels of 5647 European individuals from four studies. We examined the association of mRNA levels with cIMT adjusted for various potential confounders. Significant associations were tested for replication in three studies totaling 3943 participants. Next, we applied S-PrediXcan to summary statistics from a cIMT genome-wide association study (GWAS) of 71 128 individuals to estimate the association between genetically determined mRNA levels and cIMT and replicated these analyses using S-PrediXcan on an independent GWAS on cIMT that included 22 179 individuals from the UK Biobank. mRNA levels of TNFAIP3, CEBPD and METRNL were inversely associated with cIMT, but these associations were not significant in the replication analysis. S-PrediXcan identified associations between cIMT and genetically determined mRNA levels for 36 genes, of which six were significant in the replication analysis, including TLN2, which had not been previously reported for cIMT. There was weak correlation between our results using differential gene expression analysis and S-PrediXcan. Differential expression analysis and S-PrediXcan represent complementary approaches for the discovery of associations between phenotypes and gene expression. Using these approaches, we prioritize TNFAIP3, CEBPD, METRNL and TLN2 as new candidate genes whose differential expression might modulate cIMT.
Published: 2022
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12. The Relation between Depressive Symptoms and Unsafe Sex among MSM Living with HIV

Author: Gerard Van Grootheest, Annemiek Schade, Johannes H Smit, Psychiatry, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: Health, Toxicology and Mutagenesis, Public Health, Environmental and Occupational Health, HIV, depression, depressive symptoms, sex, unsafe sex, MSM
Abstract: In people living with HIV (PLWH), a positive association is often found between depressive symptoms and unsafe sex, which means sex without a condom. However, the results of such studies are inconclusive. The present study compared the numbers of safe and unsafe sexual contacts from men who have sex with men (MSM) (N = 159), living with HIV and attending a mental health clinic, with those of HIV-negative MSM in the general population (N = 198). We determined whether the presence of depressive symptoms was associated with unsafe sex in either of the two study populations. The depressive symptoms were measured with the Inventory of Depressive Symptoms (IDS), (MSM living with HIV) and with the 2012 Sexual Health Monitor (HIV-negative MSM). Finally, we determined whether MSM living with HIV with depressive symptoms, who received psychiatric treatment as usual, engaged in fewer unsafe sexual contacts one year after baseline. The mental-health-treatment-seeking MSM living with HIV engaged in more unsafe sexual contact than the MSM comparison group without HIV. Neither the treatment-seeking MSM living with HIV nor the MSM without HIV in the general population exhibited a relationship between depressive symptoms and unsafe sex. Moreover, the successful treatment of depressive symptoms in the treatment group did not lead to any reduction in the number of unsafe sexual contacts. Further research is needed to develop interventions that might be effective for MSM living with HIV with mental health symptoms to reduce the number of unsafe sexual contacts.
Published: 2023
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13. Habitual Behavior as a Mediator Between Food-Related Behavioral Activation and Change in Symptoms of Depression in the MooDFOOD Trial

Author: Marjolein Visser, Matthew Owens, Mariska Bot, Brenda W.J.H. Penninx, Ingeborg A. Brouwer, Ulrich Hegerl, Elisabeth Kohls, Edward R. Watkins, Miquel Roca, Margalida Gili, Gerard van Grootheest, Health Sciences, APH - Health Behaviors & Chronic Diseases, Nutrition and Health, APH - Aging & Later Life, APH - Societal Participation & Health, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Complex Trait Genetics, AGEM - Endocrinology, metabolism and nutrition, and APH - Digital Health
Subjects: Clinical Psychology, Mediator, ddc:150, Intervention (counseling), Behavioral activation, depression, prevention, behavioral activation, habits, eating styles, Psychology, Depression (differential diagnoses), Depressive symptoms, Clinical psychology
Abstract: In this study, we tested potential mediators that may explain change in depressive symptoms following exposure to a food-related behavioral activation intervention (F-BA). These included behavioral activation, avoidance and rumination, eating styles, body mass index, and dietary behavior at baseline and 3-month and 12-month follow-up. The trial used a community sample of 1,025 overweight adults with elevated depressive symptoms without current major depression. Participants were randomly assigned to one of four trial arms: either daily nutritional supplements (vs. placebo) alone or in combination with F-BA (vs. no F-BA) over 12 months. Although F-BA did not significantly reduce depressive symptoms (standardized regression coefficient [ b] = −0.223, SE = 0.129; p = .084), significant mediators included emotional eating ( b = −0.028, SE = 0.014; p = .042) and uncontrolled eating ( b = −0.039, SE = 0.016; p = .013), suggesting that learning adaptive responses to emotional and food cues may underlie effects of F-BA on depressive symptoms.
Published: 2021
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14. Working memory moderates the relation between the brain-derived neurotropic factor (BDNF) and psychotherapy outcome for depression

Author: Pim Cuijpers, Christiaan H. Vinkers, Sanne J. E. Bruijniks, Hilde de Kluiver, Brenda W.J.H. Penninx, Charlotte E. Teunissen, Frenk Peeters, Gerard van Grootheest, Marcus J.H. Huibers, Clinical Psychology, World Health Organization (WHO) Collaborating Center, APH - Global Health, APH - Mental Health, APH - Personalized Medicine, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Anatomy and neurosciences, Amsterdam Reproduction & Development (AR&D), Clinical chemistry, APH - Digital Health, RS: FPN CPS III, and Section Clinical Psychology
Subjects: DISORDER, Adult, Psychotherapist, medicine.medical_treatment, COGNITIVE THERAPY SKILLS, LIFE STRESS, RELAPSE, BEHAVIORAL ACTIVATION, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Medicine, Humans, METAANALYSIS, Biological Psychiatry, Depression (differential diagnoses), Brain-derived neurotropic factor (BDNF), Major depressive disorder (MDD), Depressive Disorder, Major, business.industry, Working memory, Mechanism (biology), Depression, Brain-Derived Neurotrophic Factor, Brain, Cognition, MAJOR DEPRESSION, PERFORMANCE, medicine.disease, 030227 psychiatry, Cognitive behavioral therapy, Psychotherapy, Working memory capacity, Psychiatry and Mental health, Memory, Short-Term, GENE VAL66MET POLYMORPHISM, Interpersonal psychotherapy, Major depressive disorder, business, rs6265, 030217 neurology & neurosurgery
Abstract: Background: Insight into patient characteristics that predict response to treatment for major depressive disorder (MDD) may help to personalize treatment and improve outcomes. One mechanism that has been linked to the success of treatment for MDD is brain-derived neurotropic factor (BDNF). BDNF is implicated in learning and memory and may play a role in the effects of psychotherapy that involves changing cognitions and behaviors. In addition, only in individuals with low BDNF, low working memory capacity has been associated with increased symptoms of depression. However, the role of BDNF and working memory capacity in psychotherapy outcome is unclear. The aim of this study was to investigate the role of BDNF and its interaction with working memory capacity in psychotherapy outcomes for MDD.Method: Adult patients with MDD were randomized to weekly or twice weekly sessions of cognitive behavioral therapy or interpersonal psychotherapy. BDNF Val66Met polymorphism (rs6265) (n = 138) was defined and serum BDNF was quantified before (n = 138) and after psychotherapy (n = 82).Results: Baseline serum BDNF and the Val66Met polymorphism were not associated with outcome and associations did not differ between treatment conditions. Working memory capacity significantly moderated the relation between baseline serum BDNF and outcome: high serum BDNF at baseline was related to less depressive symptoms following psychotherapy in the presence of high working memory capacity, but not low working memory capacity.Discussion: These findings, if replicated, might indicate that while BDNF may not be related to psychotherapy outcomes in general, they may play a role in the presence of specific learning processes such as working memory capacity.
Published: 2020
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15. A methylation study of long-term depression risk

Author: Karolina A. Aberg, Min Zhao, Andrey A. Shabalin, Johannes H. Smit, Gerard van Grootheest, Lin Ying Xie, Rick Jansen, Yuri Milaneschi, Robin F. Chan, Brenda W.J.H. Penninx, Shaunna L. Clark, Laura K.M. Han, Mohammad W. Hattab, Edwin J. C. G. van den Oord, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, and APH - Digital Health
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Genome-wide association study, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Molecular Biology, Disease burden, Autoimmune disease, Depressive Disorder, Major, Framingham Risk Score, business.industry, Depression, Brain, Methylation, DNA Methylation, medicine.disease, Psychiatry and Mental health, 030104 developmental biology, DNA methylation, Multiple comparisons problem, Chronic Disease, Major depressive disorder, CpG Islands, Disease Susceptibility, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Recurrent and chronic major depressive disorder (MDD) accounts for a substantial part of the disease burden because this course is most prevalent and typically requires long-term treatment. We associated blood DNA methylation profiles from 581 MDD patients at baseline with MDD status 6 years later. A resampling approach showed a highly significant association between methylation profiles in blood at baseline and future disease status (P = 2.0 × 10−16). Top MWAS results were enriched specific pathways, overlapped with genes found in GWAS of MDD disease status, autoimmune disease and inflammation, and co-localized with eQTLS and (genic enhancers of) of transcription sites in brain and blood. Many of these findings remained significant after correction for multiple testing. The major themes emerging were cellular responses to stress and signaling mechanisms linked to immune cell migration and inflammation. This suggests that an immune signature of treatment-resistant depression is already present at baseline. We also created a methylation risk score (MRS) to predict MDD status 6 years later. The AUC of our MRS was 0.724 and higher than risk scores created using a set of five putative MDD biomarkers, genome-wide SNP data, and 27 clinical, demographic and lifestyle variables. Although further studies are needed to examine the generalizability to different patient populations, these results suggest that methylation profiles in blood may present a promising avenue to support clinical decision making by providing empirical information about the likelihood MDD is chronic or will recur in the future.
Published: 2020
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16. Methylome-wide association findings for major depressive disorder overlap in blood and brain and replicate in independent brain samples

Author: Gustavo Turecki, Robin F. Chan, Brenda W.J.H. Penninx, Laura K.M. Han, Gerard van Grootheest, Karolina A. Aberg, Brian Dean, Andrey A. Shabalin, Min Zhao, Yuri Milaneschi, Lin Y. Xie, Shaunna L. Clark, Edwin J. C. G. van den Oord, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, and APH - Digital Health
Subjects: Male, 0301 basic medicine, Receptor expression, Brodmann area 10, Genome-wide association study, Biology, Article, Epigenome, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, Humans, GABBR2, Molecular Biology, Genetic association, Genetics, Depressive Disorder, Major, Brain, DNA Methylation, Middle Aged, medicine.disease, Cytoskeletal Proteins, Psychiatry and Mental health, 030104 developmental biology, Receptors, GABA-B, CpG site, Chromosomes, Human, Pair 2, DNA methylation, Major depressive disorder, CpG Islands, DNA, Intergenic, Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: We present the first large-scale methylome-wide association studies (MWAS) for major depressive disorder (MDD) to identify sites of potential importance for MDD etiology. Using a sequencing-based approach that provides near-complete coverage of all 28 million common CpGs in the human genome, we assay methylation in MDD cases and controls from both blood (N = 1132) and postmortem brain tissues (N = 61 samples from Brodmann Area 10, BA10). The MWAS for blood identified several loci with P ranging from 1.91 × 10−8 to 4.39 × 10−8 and a resampling approach showed that the cumulative association was significant (P = 4.03 × 10−10) with the signal coming from the top 25,000 MWAS markers. Furthermore, a permutation-based analysis showed significant overlap (P = 5.4 × 10−3) between the MWAS findings in blood and brain (BA10). This overlap was significantly enriched for a number of features including being in eQTLs in blood and the frontal cortex, CpG islands and shores, and exons. The overlapping sites were also enriched for active chromatin states in brain including genic enhancers and active transcription start sites. Furthermore, three loci located in GABBR2, RUFY3, and in an intergenic region on chromosome 2 replicated with the same direction of effect in the second brain tissue (BA25, N = 60) from the same individuals and in two independent brain collections (BA10, N = 81 and 64). GABBR2 inhibits neuronal activity through G protein-coupled second-messenger systems and RUFY3 is implicated in the establishment of neuronal polarity and axon elongation. In conclusion, we identified and replicated methylated loci associated with MDD that are involved in biological functions of likely importance to MDD etiology.
Published: 2018
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17. Cell Type–Specific Methylome-wide Association Studies Implicate Neurotrophin and Innate Immune Signaling in Major Depressive Disorder

Author: Gustavo Turecki, Andrey A. Shabalin, Min Zhao, Lin Y. Xie, Robin F. Chan, Brenda W.J.H. Penninx, Brian Dean, Gerard van Grootheest, Karolina A. Aberg, Zachary Kaminsky, Jerry Guintivano, Edwin J. C. G. van den Oord, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, and APH - Digital Health
Subjects: 0301 basic medicine, Genome-wide association study, Article, 03 medical and health sciences, Epigenome, 0302 clinical medicine, Immune system, medicine, Humans, Nerve Growth Factors, Biological Psychiatry, Epigenomics, Depressive Disorder, Major, Innate immune system, biology, Human brain, DNA Methylation, Immunity, Innate, 030104 developmental biology, medicine.anatomical_structure, Nerve growth factor, DNA methylation, Immunology, biology.protein, 030217 neurology & neurosurgery, Neurotrophin, Genome-Wide Association Study
Abstract: Background We sought to characterize methylation changes in brain and blood associated with major depressive disorder (MDD). As analyses of bulk tissue may obscure association signals and hamper the biological interpretation of findings, these changes were studied on a cell type–specific level. Methods In 3 collections of human postmortem brain (n = 206) and 1 collection of blood samples (N = 1132) of MDD cases and controls, we used epigenomic deconvolution to perform cell type–specific methylome-wide association studies within subpopulations of neurons/glia for the brain data and granulocytes/T cells/B cells/monocytes for the blood data. Sorted neurons/glia from a fourth postmortem brain collection (n = 58) were used for validation purposes. Results Cell type–specific methylome-wide association studies identified multiple findings in neurons/glia that were detected across brain collections and were reproducible in physically sorted nuclei. Cell type–specific analyses in blood samples identified methylome-wide significant associations in T cells, monocytes, and whole blood that replicated findings from a past methylation study of MDD. Pathway analyses implicated p75 neurotrophin receptor/nerve growth factor signaling and innate immune toll-like receptor signaling in MDD. Top results in neurons, glia, bulk brain, T cells, monocytes, and whole blood were enriched for genes supported by genome-wide association studies for MDD and other psychiatric disorders. Conclusions We both replicated and identified novel MDD–methylation associations in human brain and blood samples at a cell type–specific level. Our results provide mechanistic insights into how the immune system may interact with the brain to affect MDD susceptibility. Importantly, our findings involved associations with MDD in human samples that implicated many closely related biological pathways. These disease-linked sites and pathways represent promising new therapeutic targets for MDD.
Published: 2019
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18. Effect of Multinutrient Supplementation and Food-Related Behavioral Activation Therapy on Prevention of Major Depressive Disorder among Overweight or Obese Adults with Subsyndromal Depressive Symptoms:The MooDFOOD Randomized Clinical Trial

Author: Edward R. Watkins, Brenda W.J.H. Penninx, Mieke Cabout, Marjolein Visser, Elisabeth Kohls, Miquel Roca, Matthew Owens, Ingeborg A. Brouwer, Margalida Gili, Ulrich Hegerl, Gerard van Grootheest, Mariska Bot, APH - Mental Health, Psychiatry, AGEM - Endocrinology, metabolism and nutrition, APH - Health Behaviors & Chronic Diseases, APH - Digital Health, and Nutrition and Health
Subjects: medicine.medical_specialty, medicine.medical_treatment, Overweight, Placebo, 01 natural sciences, law.invention, Group psychotherapy, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, medicine, 030212 general & internal medicine, 0101 mathematics, SDG 2 - Zero Hunger, Mini-international neuropsychiatric interview, Original Investigation, business.industry, 010102 general mathematics, General Medicine, Odds ratio, medicine.disease, Major depressive disorder, medicine.symptom, business, Body mass index
Abstract: Importance: Effects of nutritional interventions on the prevention of major depressive disorder (MDD) in overweight adults are unknown. Objective: To examine the effect of 2 nutritional strategies (multinutrient supplementation, food-related behavioral activation therapy) and their combination for prevention of a new MDD episode in overweight adults with subsyndromal depressive symptoms. Design, Setting, and Participants: This multicenter 2 × 2 factorial randomized clinical trial included overweight adults (body mass index, 25-40) with elevated depressive symptoms (Patient Health Questionnaire-9 [PHQ-9] scores ≥5) and no MDD episode in the past 6 months from 4 European countries. A total of 1025 adults were randomized (July 30, 2015-October 12, 2016) and followed up for 1 year (October 13, 2017). Interventions: Daily multinutrient supplements (1412-mg omega-3 fatty acids, 30-μg selenium, 400-μg folic acid, and 20-μg vitamin D3 plus 100-mg calcium) vs placebo and 21 individual or group therapy sessions vs none (blinded to researchers) for 1 year. Participants were allocated to placebo without therapy (n = 257), placebo with therapy (n = 256), supplements without therapy (n = 256), and supplements with therapy (n = 256). Main Outcome and Measures: Cumulative 1-year onset of MDD via the Mini International Neuropsychiatric Interview at 3, 6, and 12 months. Logistic regression using effect-coded variables (-1 indicating control, 1 indicating intervention) evaluated intervention effects both individually and in combination (interaction) on MDD onset. Results: Among 1025 participants (mean age, 46.5 years; 772 women [75%]; mean BMI, 31.4), 779 (76%) completed the trial. During the 12-month follow-up, 105 (10%) developed MDD: 25 (9.7%) patients in the placebo without therapy, 26 (10.2%) in the placebo with therapy, 32 (12.5%) in the supplement without therapy, and 22 (8.6%) in the supplement with therapy group. None of the treatment strategies affected MDD onset. The odds ratio (OR) for supplements was 1.06 (95% CI, 0.87-1.29); for therapy, 0.93 (95% CI, 0.76-1.13); and for their combination, 0.93 (95% CI, 0.76-1.14; P for interaction,48). One person in the supplementation with therapy group, died. Twenty-four patients in each of the placebo groups and 24 patients in the supplementation with therapy group were hospitalized, and 26 patients in the supplementation-only group were hospitalized. Conclusions and Relevance: Among overweight or obese adults with subsyndromal depressive symptoms, multinutrient supplementation compared with placebo and food-related behavioral activation therapy compared with no therapy did not reduce episodes of major depressive disorder during 1 year. These findings do not support the use of these interventions for prevention of major depressive disorder. Trial registration: ClinicalTrials.gov Identifier: NCT02529423.
Published: 2019
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19. Convergence of evidence from a methylome-wide CpG-SNP association study and GWAS of major depressive disorder

Author: Andrey A. Shabalin, Karolina A. Aberg, Yuri Milaneschi, Gaurav Kumar, Shaunna L. Clark, Lin Y. Xie, Robin F. Chan, Brenda W.J.H. Penninx, Gerard van Grootheest, Min Zhao, Edwin J. C. G. van den Oord, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, and APH - Digital Health
Subjects: 0301 basic medicine, Adult, Male, Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, lcsh:RC321-571, Epigenesis, Genetic, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, SNP, Humans, Epigenetics, Allele, Allele frequency, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Alleles, Genetic association, Genetics, Depressive Disorder, Major, DNA Methylation, Middle Aged, Psychiatry and Mental health, 030104 developmental biology, Phenotype, Genetic Loci, Case-Control Studies, DNA methylation, CpG Islands, Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: DNA methylation is an epigenetic modification that provides stability and diversity to the cellular phenotype. It is influenced by both genetic sequence variation and environmental factors, and can therefore potentially account for variation of heritable phenotypes and disorders. Therefore, methylome-wide association studies (MWAS) are promising complements to genome-wide association studies (GWAS) of genetic variants. Of particular interest are methylation sites (CpGs) that are created or destroyed by the alleles of single-nucleotide polymorphisms (SNPs), as these so-called CpG-SNPs may show variation in methylation levels on top of what can be explained by the sequence variation. Using sequencing-based data from 1132 major depressive disorder (MDD) cases and controls, we performed a MWAS of 970,414 common CpG-SNPs. The analysis identified 27 suggestively significant (P −5) CpG-SNPs associations. Furthermore, the MWAS results were over-represented (odds ratios ranging 1.36–5.00; P ranging 4.9 × 10−3–8.1 × 10−2) among findings from three recent GWAS for MDD-related phenotypes. Overlapping loci included, e.g., ROBO2, ASIC2, and DCC. As the CpG-SNP analysis accounts for the number of alleles that creates CpGs, the methylation differences could not be explained by differences in allele frequencies. Thus, the results show that the MWAS and GWASs provide independent lines of evidence for the involvement of these loci in MDD. In conclusion, our methylation study of MDD contributes novel information about loci of relevance that complements previous findings and generates new hypothesis about MDD etiology, such as that the functional effects of genetic association may be partly mediated and/or enhanced by the methylation status in these loci.
Published: 2018
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20. Cell-type-specific methylome-wide association studies implicate neurodegenerative processes and neuroimmune communication in major depressive disorder

Author: Robin F. Chan, Brenda W.J.H. Penninx, Andrey A. Shabalin, Gerard van Grootheest, Gustavo Turecki, Jerry Guintivano, Karolina A. Aberg, Min Zhao, Lin Y. Xie, Zachary Kaminsky, Brian Dean, and Edwin J. C. G. van den Oord
Subjects: 0303 health sciences, Cell type, CD14, Neurodegeneration, Genome-wide association study, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, DNA methylation, medicine, Major depressive disorder, Neuroscience, 030217 neurology & neurosurgery, 030304 developmental biology, Epigenomics, Genetic association
Abstract: We studied the methylome in three collections of human postmortem brain (N=206) and blood samples (N=1,132) of subjects with major depressive disorder (MDD) and controls. Using an epigenomic deconvolution approach we performed cell-type-specific methylome-wide association studies (MWAS) within sub-populations of neurons/glia and granulocytes/T-cells/B-cells/monocytes for bulk brain and blood data, respectively. Multiple MWAS findings in neurons/glia replicated across brain collections (ORs=509-538, P-values−5) and were reproducible in an array-based MWAS of sorted neurons/glia from a fourth brain collection (N=58). Pathway analyses implicated p75NTR/VEGF signaling, neurodegeneration, and blood-brain barrier perturbation. Cell-type-specific analysis in blood identified associations in CD14+ monocytes -- a cell type strongly linked to neuroimmune processes and stress. Top results in neurons/glia/bulk and monocytes were enriched for genes supported by GWAS for MDD (ORs=2.02-2.87, P-values=0.003 to −5), neurodegeneration and other psychiatric disorders. In summary, we identified novel MDD-methylation associations by using epigenomic deconvolution that provided important mechanistic insights for the disease.
Published: 2018
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21. Biomarker-based subtyping of depression and anxiety disorders using Latent Class Analysis. A NESDA study

Author: Lian Beijers, Marrit K. de Boer, Klaas J. Wardenaar, Brenda W.J.H. Penninx, Femke Lamers, Robert A. Schoevers, Gerard van Grootheest, Fokko J. Bosker, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), and Clinical Cognitive Neuropsychiatry Research Program (CCNP)
Subjects: Adult, Male, subtyping, Overweight, Anxiety, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Heart Rate, Medicine, Humans, Saliva, Applied Psychology, Depression (differential diagnoses), Netherlands, Psychiatric Status Rating Scales, business.industry, Depression, biomarkers, Original Articles, medicine.disease, Anxiety Disorders, Latent class model, 030227 psychiatry, Psychiatry and Mental health, Latent Class Analysis, Biomarker (medicine), Female, medicine.symptom, business, 030217 neurology & neurosurgery, Anxiety disorder, Clinical psychology, Psychopathology, Cohort study
Abstract: BackgroundEtiological research of depression and anxiety disorders has been hampered by diagnostic heterogeneity. In order to address this, researchers have tried to identify more homogeneous patient subgroups. This work has predominantly focused on explaining interpersonal heterogeneity based on clinical features (i.e. symptom profiles). However, to explain interpersonal variations in underlying pathophysiological mechanisms, it might be more effective to take biological heterogeneity as the point of departure when trying to identify subgroups. Therefore, this study aimed to identify data-driven subgroups of patients based on biomarker profiles.MethodsData of patients with a current depressive and/or anxiety disorder came from the Netherlands Study of Depression and Anxiety, a large, multi-site naturalistic cohort study (n = 1460). Thirty-six biomarkers (e.g. leptin, brain-derived neurotrophic factor, tryptophan) were measured, as well as sociodemographic and clinical characteristics. Latent class analysis of the discretized (lower 10%, middle, upper 10%) biomarkers were used to identify different patient clusters.ResultsThe analyses resulted in three classes, which were primarily characterized by different levels of metabolic health: ‘lean’ (21.6%), ‘average’ (62.2%) and ‘overweight’ (16.2%). Inspection of the classes’ clinical features showed the highest levels of psychopathology, severity and medication use in the overweight class.ConclusionsThe identified classes were strongly tied to general (metabolic) health, and did not reflect any natural cutoffs along the lines of the traditional diagnostic classifications. Our analyses suggested that especially poor metabolic health could be seen as a distal marker for depression and anxiety, suggesting a relationship between the ‘overweight’ subtype and internalizing psychopathology.
Published: 2018
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22. Differential gene expression patterns between smokers and non-smokers: cause or consequence?

Author: Rick Jansen, Gerard van Grootheest, Gonneke Willemsen, Andrew Brooks, Eco J. C. de Geus, Dorret I. Boomsma, Jan Smit, Brenda W.J.H. Penninx, and Jacqueline M. Vink
Subjects: 0301 basic medicine, Pharmacology, education.field_of_study, medicine.medical_treatment, Population, Case-control study, Medicine (miscellaneous), Physiology, Monozygotic twin, Quantitative trait locus, Biology, Bioinformatics, 3. Good health, Transcriptome, 03 medical and health sciences, Psychiatry and Mental health, 030104 developmental biology, Gene expression, medicine, Smoking cessation, education, Gene
Abstract: The molecular mechanisms causing smoking-induced health decline are largely unknown. To elucidate the molecular pathways involved in cause and consequences of smoking behavior, we conducted a genome-wide gene expression study in peripheral blood samples targeting 18 238 genes. Data of 743 smokers, 1686 never smokers and 890 ex-smokers were available from two population-based cohorts from the Netherlands. In addition, data of 56 monozygotic twin pairs discordant for ever smoking were used. One hundred thirty-two genes were differentially expressed between current smokers and never smokers (P < 1.2 x 10-6, Bonferroni correction). The most significant genes were G protein-coupled receptor 15 (P < 1 x 10-150) and leucine-rich repeat neuronal 3 (P
Published: 2015
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23. Huntingtin gene repeat size variations affect risk of lifetime depression

Author: Willeke M. C. van Roon-Mom, Brenda W.J.H. Penninx, Johannes H. Smit, Gerard van Grootheest, Martine J. van Belzen, Richard C. Oude Voshaar, Albert M. van Hemert, Robert A. Schoevers, Roos C. van der Mast, Maarten Pieter Rozing, Hannie C. Comijs, Aartjan T.F. Beekman, N. Ahmad Aziz, Sarah L. Gardiner, Raymund A.C. Roos, and Merel W. Boogaard
Subjects: 0301 basic medicine, Oncology, Male, DISORDER, SYMPTOMS, Review, Logistic regression, DISEASE, Cohort Studies, 0302 clinical medicine, Trinucleotide Repeats, Risk Factors, Depression (differential diagnoses), Aged, 80 and over, education.field_of_study, Huntingtin Protein, MOUSE MODEL, Middle Aged, OLDER PERSONS, Psychiatry and Mental health, Cohort, Female, BEHAVIOR, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Population, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, Internal medicine, mental disorders, medicine, Humans, Genetic Predisposition to Disease, Allele, education, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Aged, POLYGLUTAMINE, Depressive Disorder, Polymorphism, Genetic, business.industry, Other Research Radboud Institute for Health Sciences [Radboudumc 0], Odds ratio, Confidence interval, nervous system diseases, 030104 developmental biology, TRINUCLEOTIDE REPEAT, CAG LENGTH, Human medicine, PITUITARY-ADRENAL AXIS, Trinucleotide repeat expansion, business, 030217 neurology & neurosurgery
Abstract: Huntington disease (HD) is a severe neuropsychiatric disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the HTT gene. Although HD is frequently complicated by depression, it is still unknown to what extent common HTT CAG repeat size variations in the normal range could affect depression risk in the general population. Using binary logistic regression, we assessed the association between HTT CAG repeat size and depression risk in two well-characterized Dutch cohorts─the Netherlands Study of Depression and Anxiety and the Netherlands Study of Depression in Older Persons─including 2165 depressed and 1058 non-depressed persons. In both cohorts, separately as well as combined, there was a significant non-linear association between the risk of lifetime depression and HTT CAG repeat size in which both relatively short and relatively large alleles were associated with an increased risk of depression (β = −0.292 and β = 0.006 for the linear and the quadratic term, respectively; both P HTT CAG repeat size of 21 (odds ratio: 0.71, 95% confidence interval: 0.52 to 0.98) compared to the average odds in the total cohort. In conclusion, lifetime depression risk was higher with both relatively short and relatively large HTT CAG repeat sizes in the normal range. Our study provides important proof-of-principle that repeat polymorphisms can act as hitherto unappreciated but complex genetic modifiers of depression.
Published: 2017
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24. An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype

Author: Katri Räikkönen, Myriam Fornage, Jianxin Shi, Najaf Amin, Dale R. Nyholt, Jordan W. Smoller, Tõnu Esko, Wei Zhao, Carsten Horn, Andres Metspalu, Harold Snieder, Enrique Castelao, Luigi Ferrucci, Catharina A. Hartman, Thomas G. Schulze, Stanley I. Shyn, Joanne M. Murabito, James B. Potash, Cathryn M. Lewis, Karestan C. Koenen, Azmeraw T. Amare, Jari Lahti, Stephan Ripke, Michele L. Pergadia, Cornelia M. van Duijn, Michael Conlon O'Donovan, Markus M. Nöthen, Grant C.B. Sinnamon, Rudolf Uher, Roy H. Perlis, Qingqin S. Li, Hans-Jörgen Grabe, Johannes H. Smit, Bernhard T. Baune, Donald J. MacIntyre, Erin C. Dunn, Alexander Teumer, Gonneke Willemsen, Nicholas G. Martin, Udo Dannlowski, Karin Hek, Shaun Purcell, Toni-Kim Clarke, Toshiko Tanaka, Jorge A. Quiroz, Myrna M. Weissman, Andrew M. McIntosh, Kathryn L. Lunetta, Scott D. Gordon, David R. Weir, Daniel Umbricht, Marcella Rietschel, Zoltán Kutalik, Stephanie Williams, Michael Gill, Albert Hofman, Enrico Domenici, Margarita Rivera, Pamela A. F. Madden, Jingyun Yang, John P. Rice, Sandra Van der Auwera, Steven P. Hamilton, Georg Homuth, David A. Bennett, Stefan Kloiber, Sharon L.R. Kardia, Anders D. Børglum, Sven Cichon, Nese Direk, Jessica D. Faul, Susanne Lucae, Dorret I. Boomsma, Douglas Blackwood, Jouke-Jan Hottenga, Marilyn C. Cornelis, Erin B. Ware, Enda M. Byrne, Andrew C. Heath, Philip L. De Jager, Ole Mors, Karl-Heinz Ladwig, Bertram Müller-Myhsok, Thomas H. Mosley, Jennifer A. Smith, Tracy Air, Yuri Milaneschi, Glyn Lewis, Brenda W.J.H. Penninx, David J. Llewellyn, Gerard van Grootheest, Eco J. C. de Geus, Henning Tiemeier, Grant W. Montgomery, Martin Preisig, Katherine E. Tansey, Patrick F. Sullivan, Douglas F. Levinson, Henriette N. Buttenschøn, Gerome Breen, Johan G. Eriksson, Ayse Demirkan, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, APH - Methodology, APH - Digital Health, Epidemiology, Child and Adolescent Psychiatry / Psychology, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Medicum, Department of Psychology and Logopedics, and Developmental Psychology Research Group
Subjects: DISORDER, Netherlands Twin Register (NTR), Linkage disequilibrium, SYMPTOMS, STRESS, CHARGE consortium, genetics [Depressive Disorder], Genome-wide association study, 3124 Neurology and psychiatry, 0302 clinical medicine, Neoplasm Proteins/genetics, MINOR DEPRESSION, European Continental Ancestry Group/genetics, POPULATION, RISK, Genetics, education.field_of_study, HERITABILITY, Depression, Depressive symptoms, Depression/genetics, Acid Anhydride Hydrolases, Neoplasm Proteins, 3. Good health, genetics [European Continental Ancestry Group], Phenotype, fragile histidine triad protein, Major depressive disorder, genetics [Depression], Psychology, 515 Psychology, Population, genetics [White People], Single-nucleotide polymorphism, Locus (genetics), White People, Psychiatric Genomics Consortium, FHIT gene, 03 medical and health sciences, SDG 3 - Good Health and Well-being, ddc:570, Depressive Disorder/genetics, NATIONAL COMORBIDITY SURVEY, medicine, Journal Article, Humans, SNP, genetics [Acid Anhydride Hydrolases], Genetic Predisposition to Disease, ddc:610, education, Biological Psychiatry, Genetic association, Depressive Disorder, genetics [Neoplasm Proteins], major depressive disorder, 3112 Neurosciences, MAJOR DEPRESSION, medicine.disease, SUBTHRESHOLD DEPRESSION, 030227 psychiatry, Acid Anhydride Hydrolases/genetics, Genetic Loci, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: BACKGROUND: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder.METHODS: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures.RESULTS: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10(-9)) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10(-9)).CONCLUSIONS: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.
Published: 2017
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25. PREDICTING THE FUTURE DISEASE STATUS OF DEPRESSED PATIENTS FROM DNA METHYLATION PATTERNS IN BLOOD

Author: Lin Xie, Andrey A. Shabalin, Robin F. Chan, Brenda W.J.H. Penninx, Min Zhao, Gerard van Grootheest, Edwin J. C. G. van den Oord, Mohammad W. Hattab, Rick Jansen, Shaunna L. Clark, Johannes H. Smit, Karolina A. Aberg, Yuri Milaneschi, and Laura K.M. Han
Subjects: Pharmacology, Oncology, Disease status, medicine.medical_specialty, Framingham Risk Score, business.industry, Area under the curve, medicine.disease, Psychiatry and Mental health, Neurology, Internal medicine, DNA methylation, Medicine, Anxiety, Major depressive disorder, Pharmacology (medical), Neurology (clinical), medicine.symptom, business, Biological Psychiatry, Depression (differential diagnoses), Severe disorder
Abstract: Background Major Depressive Disorder (MDD) is a severe disorder with a lifetime prevalence of 15%. Recurrent or chronic MDD, which typically requires long-term treatment, occurs in the majority of patients. As previous efforts to predict recurrence/chronicity have met with limited success, novel avenues are required. In this study, we aimed to predict the future disease status of MDD patients from DNA methylation patterns in blood. Methods We assayed 28 million methylation sites in 581 MDD patients from the Netherlands Study of Depression and Anxiety (NESDA). A Machine Learning algorithm condensed all information into a single predictor labeled methylation risk score (MRS). The outcome was MDD disease status six years later. To evaluate the predictive power of our MRS, we obtained an unbiased estimate of the area under the curve (AUC) using k-fold cross validation. Results The AUC of the MRS was 0.724. We compared our MRS with predictions based on a set of five putative MDD biomarkers (e.g., assaying neurotrophic factors or inflammation), genome-wide genetic variant data, and 27 clinical, demographic or lifestyle variables (e.g., MDD symptom severity, childhood trauma, alcohol use). The MRS not only outperformed all these predictors but also seemed to capture their predictive power as the inclusion of any of these sets did not significantly increase the AUC of the MRS. Discussion The current study suggests a novel avenue for predicting future MDD status using DNA methylation patterns in blood. The predictive power of the MRS is comparable to the AUC of the Framingham Risk Score, one of the most widely used clinical tools to predict coronary heart disease. This AUC level can potentially support clinical decisions about treatment strategies by providing empirical information about the likelihood MDD is chronic or will recur in the future.
Published: 2019
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26. METHYLOME-WIDE ASSOCIATION STUDIES FOR MAJOR DEPRESSIVE DISORDER IN BLOOD OVERLAP WITH METHYLATION RESULTS FROM BRAIN AND LARGE-SCALE GWAS

Author: Laura K.M. Han, Yuri Milaneschi, Shaunna L. Clark, Min Zhao, Robin F. Chan, Brenda W.J.H. Penninx, Lin Xie, Mohammad W. Hattab, Rick Jansen, Edwin J. C. G. van den Oord, Andrey A. Shabalin, Karolina A. Aberg, Brian Dean, Gerard van Grootheest, Moji Aghajani, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, and APH - Digital Health
Subjects: Pharmacology, Single-nucleotide polymorphism, Genome-wide association study, Computational biology, Biology, medicine.disease, Psychiatry and Mental health, Neurology, CpG site, Genotype, DNA methylation, medicine, Major depressive disorder, Pharmacology (medical), Neurology (clinical), Epigenetics, Biological Psychiatry, Genetic association
Abstract: Background Epigenetic modifications such as DNA methylation provide stability and diversity to the cellular phenotype and aberrant methylation has been implicated in processes underlying psychiatric disorders. Therefore, studies combining DNA methylation and genotype information provide a promising approach to study disorders where genotype information alone has failed to reveal the full etiology. Methods We applied an optimized MBD-seq protocol to assay the complete CpG methylome in cases with Major Depressive Disorder (MDD) and controls using blood samples (N=1,132) from Netherlands Study of Depression and Anxiety and brain samples (N=64) from the Victorian Brain Bank Network. Data were analyzed with RaMWAS, a novel Bioconductor package specifically designed for Methylome-Wide Association Studies (MWAS). To study the overlap between top MWAS findings in blood and brain, we used a permutation based enrichment test (shiftR) that accounted for the dependency between adjacent CpG sites. Furthermore, we utilized the methylation data in combination with existing genotype information from the same individuals in a MWAS of CpGs created or destroyed by SNPs. Next, we tested whether top results from this CpG-SNP MWAS overlapped with recent large-scale GWAS to identify robust associations with genomic loci of importance for MDD etiology. Results The MWAS in blood identified five methylome-wide significant sites (P Discussion This work involves the largest MWAS for MDD performed to date. Our integrated analysis with brain tissue, genotype information and GWAS results highlighted biological functions of potential value for MDD etiology. Part of the associated methylation marks in blood overlapped with MWAS finding in brain. As blood can easily be collected in a clinical setting, these loci may be of direct value as potential diagnostic biomarkers for MDD.
Published: 2019
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27. Applying polygenic risk scores to postpartum depression

Author: Nicholas G. Martin, Brett Chapman, Dorret I. Boomsma, Samantha Meltzer-Brody, David M. Evans, Brenda W.J.H. Penninx, Paul Lichtenstein, Gerard van Grootheest, Debbie A Lawlor, Enda M. Byrne, Lynn Boschloo, Mikael Landén, Naomi R. Wray, George McMahon, Anjali K. Henders, Pamela A. F. Madden, Hannah M Sallis, Michele L. Pergadia, Andrew C. Heath, Tania Carrillo-Roa, Patrick F. Sullivan, Alexander Viktorin, Patrik K. E. Magnusson, Grant W. Montgomery, Psychiatry, NCA - Neurobiology of mental health, EMGO - Mental health, Functional Genomics, Clinical, Neuro- & Developmental Psychology, APH - Mental Health, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, and EMGO+ - Mental Health
Subjects: Postpartum depression, Male, Netherlands Twin Register (NTR), Multifactorial Inheritance, Bipolar Disorder, Logistic regression, 0302 clinical medicine, Risk Factors, Surveys and Questionnaires, Depression (differential diagnoses), Depression, Bipolar Disorder/genetics, Obstetrics and Gynecology, Major/genetics, Single Nucleotide, Psychiatry and Mental health, Cohort, Major depressive disorder, Female, Psychology, Depressive Disorder, Major/genetics, Postpartum/genetics, Adult, medicine.medical_specialty, Genotype, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Article, Depression, Postpartum, 03 medical and health sciences, Young Adult, SDG 3 - Good Health and Well-being, mental disorders, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, Polymorphism, Psychiatry, Retrospective Studies, Depressive Disorder, Major, Depressive Disorder, Genetic Variation, medicine.disease, 030227 psychiatry, Standard error, Depression, Postpartum/genetics, Logistic Models, Etiology, 030217 neurology & neurosurgery, Demography
Abstract: The etiology of major depressive disorder (MDD) is likely to be heterogeneous, but postpartum depression (PPD) is hypothesized to represent a more homogenous subset of MDD. We use genome-wide SNP data to explore this hypothesis. We assembled a total cohort of 1,420 self-report cases of PPD and 9,473 controls with genome-wide genotypes from Australia, The Netherlands, Sweden and the UK. We estimated the total variance attributable to genotyped variants. We used association results from the Psychiatric Genomics Consortia (PGC) of bipolar disorder (BPD) and MDD to create polygenic scores in PPD and related MDD data sets to estimate the genetic overlap between the disorders. We estimated that the percentage of variance on the liability scale explained by common genetic variants to be 0.22 with a standard error of 0.12, p = 0.02. The proportion of variance (R (2)) from a logistic regression of PPD case/control status in all four cohorts on a SNP profile score weighted by PGC-BPD association results was small (0.1 %) but significant (p = 0.004) indicating a genetic overlap between BPD and PPD. The results were highly significant in the Australian and Dutch cohorts (R (2) > 1.1 %, p
Published: 2014
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28. Evolutionary and functional data power search for obsessive-compulsive disorder genes

Author: Hyun Ji Noh, Ruqi Tang, Jason Flannick, Colm O’Dushlaine, Ross Swofford, Daniel Howrigan, Diane P. Genereux, Jeremy Johnson, Gerard van Grootheest, Edna Grünblatt, Erik Andersson, Diana R. Djurfeldt, Paresh D. Patel, Michele Koltookian, Christina Hultman, Michele T. Pato, Carlos N. Pato, Steven A. Rasmussen, Michael A. Jenike, Gregory L. Hanna, S. Evelyn Stewart, James A. Knowles, Stephan Ruhrmann, Hans-Jörgen Grabe, Michael Wagner, Christian Rück, Carol A. Mathews, Susanne Walitza, Daniëlle C. Cath, Guoping Feng, Elinor K. Karlsson, and Kerstin Lindblad-Toh
Subjects: Genetics, Neuroblastoma cell, Postsynaptic potential, Obsessive compulsive, Transcription (biology), Genomic data, Glutamate receptor, Genomics, Biology, Gene
Abstract: SUMMARYObsessive-compulsive disorder (OCD) is a severe psychiatric disorder linked to abnormalities in the cortico-striatal circuit and in glutamate signaling. We sequenced coding and regulatory elements for 608 genes implicated in OCD from humans and two animal models (mouse and dog). Using a new method, PolyStrat, which prioritizes variants disrupting evolutionarily conserved, functional regions, we found four strongly associated genes when comparing 592 cases to 560 controls. These results were validated in a second, larger cohort. NRXN1 and HTR2A are enriched for coding variants altering postsynaptic protein-binding domains, while CTTNBP2 (synapse maintenance) and REEP3 (vesicle trafficking) are enriched for regulatory variants. The rare coding variant burden in NRXN1 achieves genomewide significance (p=6.37×10−11) when we include public data for 33,370 controls. Of 17 regulatory variants identified in CTTNBP2 and REEP3, we show that at least six alter transcription factor-DNA binding in human neuroblastoma cells. Our findings suggest synaptic adhesion as a key function in compulsive behaviors across three species, and demonstrate how combining targeted sequencing with functional annotations can identify potentially causative variants in both coding and noncoding regions, even when genomic data is limited.
Published: 2017
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29. Prevention of depression through nutritional strategies in high-risk persons: rationale and design of the MooDFOOD prevention trial

Author: Margalida Gili, Matthew Owens, Edward R. Watkins, Marjolein Visser, Brenda W.J.H. Penninx, Mieke Cabout, Ingeborg A. Brouwer, Miquel Roca, Elisabeth Kohls, Gerard van Grootheest, Ulrich Hegerl, Mariska Bot, Psychiatry, EMGO - Mental health, Internal medicine, Nutrition and Health, and EMGO+ - Lifestyle, Overweight and Diabetes
Subjects: Male, Gerontology, humanos, depresión, adolescente, estudios de viabilidad, Overweight, Anxiety, law.invention, Study Protocol, 0302 clinical medicine, Randomized controlled trial, Clinical Protocols, law, Behavior Therapy, Risk Factors, Clinical endpoint, Medicine, 030212 general & internal medicine, mediana edad, vitaminas, 2. Zero hunger, anciano, sobrepeso, Depression, dieta, Behavior change, Vitamins, Middle Aged, adulto, 3. Good health, Europe, adulto joven, Psychiatry and Mental health, Research Design, Major depressive disorder, Female, terapia conductista, medicine.symptom, Clinical psychology, Adult, Adolescent, Diet therapy, Food behavior, 03 medical and health sciences, Young Adult, Quality of life (healthcare), SDG 3 - Good Health and Well-being, trastorno depresivo, dietoterapia, Humans, factores de riesgo, Obesity, SDG 2 - Zero Hunger, obesidad, Aged, Depressive Disorder, Major, Depressive Disorder, conducta alimentaria, protocolos clínicos, business.industry, Prevention, Feeding Behavior, ansiedad, Food behavioral activation, medicine.disease, 030227 psychiatry, Diet, Multi-nutrient supplements, Dietary Supplements, calidad de vida, Quality of Life, Feasibility Studies, business, diseño de la investigación, Diet Therapy
Abstract: Background: Obesity and depression are two prevalent conditions that are costly to individuals and society. The bidirectional association of obesity with depression, in which unhealthy dietary patterns may play an important role, has been well established. Few experimental studies have been conducted to investigate whether supplementing specific nutrients or improving diet and food-related behaviors can prevent depression in overweight persons. Method/Design: The MooDFOOD prevention trial examines the feasibility and effectiveness of two different nutritional strategies [multi-nutrient supplementation and food-related behavioral change therapy (FBC)] to prevent depression in individuals who are overweight and have elevated depressive symptoms but who are not currently or in the last 6 months meeting criteria for an episode of major depressive disorder (MDD). The randomized controlled prevention trial has a two-by-two factorial design: participants are randomized to daily multi-nutrient supplement (omega-3 fatty acids, calcium, selenium, B-11 vitamin and D-3 vitamin) versus placebo, and/or FBC therapy sessions versus usual care. Interventions last 12 months. In total 1000 participants aged 18-75 years with body mass index between 25-40 kg/m(2) and with a Patient Health Questionnaire-9 score >= 5 will be recruited at four study sites in four European countries. Baseline and follow-up assessments take place at 0, 3, 6, and 12 months. Primary endpoint is the onset of an episode of MDD, assessed according to DSM-IV based criteria using the MINI 5. 0 interview. Depressive symptoms, anxiety, food and eating behavior, physical activity and health related quality of life are secondary outcomes. During the intervention, compliance, adverse events and potentially mediating variables are carefully monitored. Discussion: The trial aims to provide a better understanding of the causal role of specific nutrients, overall diet, and food-related behavior change with respect to the incidence of MDD episodes. This knowledge will be used to develop and disseminate innovative evidence-based, feasible, and effective nutritional public health strategies for the prevention of clinical depression., Funding for this paper was provided by the European Union FP7 MooDFOOD Project 'Multi-country cOllaborative project on the rOle of Diet, FOod-related behaviour, and Obesity in the prevention of Depression' (grant agreement no. 613598). This work is supported in the UK by the National Institute for Health Research (NIHR), through the Primary Care Research Network, and the NIHR Exeter Clinical Research Facility. Funding sponsors did not participate in the study design; collection, management, analysis, and interpretation of data; or writing of the report. They did not participated in the decision to submit the report for publication, nor had ultimate authority over any of these activities.
Published: 2016
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30. Mindfulness Based Cognitive Therapy (MBCT) as An Addition to Psychiatric Care as Usual Useful for HIV-infected Patients with Mental Health Symptoms

Author: Johannes H. Smit, Gerard van Grootheest, and Annemiek Schadé
Subjects: medicine.medical_specialty, business.industry, medicine.medical_treatment, Immunology, Dermatology, Omics, Mental health, 030227 psychiatry, law.invention, Group psychotherapy, 03 medical and health sciences, 0302 clinical medicine, Infectious Diseases, Randomized controlled trial, law, Virology, Health care, medicine, Anxiety, Outpatient clinic, 030212 general & internal medicine, medicine.symptom, business, Psychiatry, Mindfulness-based cognitive therapy
Abstract: Objectives: HIV-infected patients suffer from both physical and mental health symptoms and treatment of both symptoms is important. The 8-week Mindfulness Based Cognitive Therapy (henceforth MBCT) was originally developed for both mental and physical symptoms and is easy to implement. It is unknown, however, whether the addition of MBCT to psychiatric care as usual is effective in the long term and feasible for this group of patients. We measured depressive and anxiety symptoms, suicidal thoughts and fatigue in HIV-infected patients receiving psychiatric care as usual with or without MBCT, at intake and after one year. Methods: The study was conducted at the outpatient clinic for HIV and Mental Health at GGZ inGeest in Amsterdam, the Netherlands, between March 2006 and September 2009. MBCT was offered as a group therapy in addition to individual care as usual to all (N=208) patients in their first year of psychiatric treatment. Results: In the research period, 58 patients opted for the MBCT and 150 did not. Twenty patients did not complete the MBCT and questionnaires of both time points were available from 22 patients with and from 60 patients without MBCT. During their first year of psychiatric care, patients in both treatment groups showed significant improvement on depressive and anxiety symptoms, suicidal thoughts and fatigue. Conclusion: Measured after one year, the addition of MBCT to psychiatric care as usual for HIV-infected patients had no measurable added effect on the treatment of depressive and anxiety symptoms, suicidal thoughts and fatigue. The present study was an explorative study to investigate the role of additional MBCT to psychiatric care as usual. It seems that general addition of MBCT is not feasible in this group of patients. However, further research, for example in a randomized controlled trial (RCT) is necessary to confirm the resu
Published: 2016
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31. Behavior Genetics Association 45th Annual Meeting Abstracts

Author: Dorret I. Boomsma, Michel G. Nivard, Stéphanie Martine van den Berg, Jacqueline M. Vink, Christel M. Middeldorp, Meike Bartels, Gerard van Grootheest, Yuri Milaneschi, Gonneke Willemsen, Marleen H.M. de Moor, Eco J. C. de Geus, Jouke-Jan Hottenga, Brenda W.J.H. Penninx, and Abdel Abdellaoui
Subjects: medicine.medical_specialty, Genetic variants, 02 engineering and technology, 010402 general chemistry, 021001 nanoscience & nanotechnology, medicine.disease, 01 natural sciences, Neuroticism, 0104 chemical sciences, 3. Good health, mental disorders, Cohort, Genetics, medicine, Anxiety, Big Five personality traits, medicine.symptom, 0210 nano-technology, Psychology, Psychiatry, Borderline personality disorder, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Imputation (genetics)
Abstract: The first genetic variants associated with neuroticism were identified in a meta-analysis of genome-wide association (GWA) results based on 1000Genomes imputation in 63,661 participants from 29 discovery cohorts and 9786 participants from a replication cohort. Participants came from Europe, the United States or Australia (Van den Berg et al. Behav Genet 2014; de Moor et al. in press). Polygenic scores based on the meta-analysis of neuroticism in 27 cohorts (removing data from NTR and NESDA) significantly predicted neuroticism and MDD in NTR and NESDA. Here we extend the polygenic score prediction to other traits hypothesized to show genetic overlap with a higher neuroticism (anxiety, borderline personality disorder, migraine, smoking), with lower neuroticism (e.g. exercise) or to be independent of neuroticism (other NEO personality traits, alcohol use).
Published: 2015

32. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

Author: Anita Thapar, Lena Backlund, Lindsey Kent, Walter J. Muir, A. Jeremy Willsey, Sandra K. Loo, Michael Boehnke, Christa Lese Martin, Ania Korszun, Guiomar Oliveira, Veronica J. Vieland, Stephen W. Scherer, René S. Kahn, Darina Czamara, Jeremy R. Parr, Michael E. Goddard, Willem A. Nolen, Josep Antoni Ramos-Quiroga, Stephen Sanders, Karola Rehnstroem, Nelson B. Freimer, Erin N. Smith, Ann Olincy, Ingrid Melle, Myrna M. Weissman, James A. Knowles, William Byerley, Aravinda Chakravarti, Shaun Purcell, Jens Treutlein, Sebastian Zoellner, Hakon Hakonarson, Susanne Lucae, Markus M. Noethen, Ian B. Hickie, Marion Friedl, Srinivasa Thirumalai, Stephen Newhouse, Joseph Piven, Andrew M. McIntosh, Cathryn M. Lewis, Srdjan Djurovic, Francis J. McMahon, Ayman H. Fanous, Bernie Devlin, Steven A. McCarroll, Alan F. Schatzberg, Peter Szatmari, Marta Ribasés, C. Robert Cloninger, Brenda W.J.H. Penninx, Gerard van Grootheest, Phil Lee, Richard Anney, Elaine K. Green, Geraldine Dawson, Joseph A. Sergeant, Digby Quested, Magdalena Gross, Jack D. Barchas, Nicholas G. Martin, Timothy W. Yu, Jouke-Jan Hottenga, Mark Lathrop, Federica Tozzi, Martin Hautzinger, Alysa E. Doyle, Cinnamon S. Bloss, Sandra Meier, Louise Gailagher, David A. Collier, Farooq Amin, Michael C. Neale, Martin Schalling, Lieuwe de Haan, Bru Cormand, Falk W. Lohoff, Jennifer Crosbie, Howard J. Edenberg, Aarno Palotie, Johannes H. Smit, Robert Freedman, Katherine Gordon-Smith, Michele L. Pergadia, Enda M. Byrne, Hans-Christoph Steinhausen, Benjamin M. Neale, Anjali K. Henders, Michele T. Pato, Manuel Mattheisen, Urban Ösby, Edward M. Scolnick, Evaristus A. Nwulia, Fritz Poustka, Gonneke Willemsen, Andrew C. Heath, David St. Cair, Emma M. Quinn, I. Nicol Ferrier, John R. Kelsoe, Vanessa Hus, Andrew McQuillin, John P. Rice, William M. McMahon, Joseph Biederman, Danyu Lin, Wolfgang Maier, Frans G. Zitman, Josephine Elia, Nicholas J. Schork, Stéphane Jamain, Lizzy Rossin, Jubao Duan, Ingrid Agartz, Devin Absher, Jordan W. Smoller, Matthew W. State, Richard M. Myers, Shrikant Mane, Carlos N. Pato, William E. Bunney, Marian L. Hamshere, Manfred Uhr, Nicholas John Craddock, Astrid M. Vicente, Tobias Banaschewski, David Curtis, Anne Farmer, Scott D. Gordon, Anna K. Kaehler, Eric M. Morrow, Marcella Rietschel, Patrik K. E. Magnusson, Klaus-Peter Lesch, Rebecca McKinney, Jana Strohmaier, Thomas F. Wienker, Pablo V. Gejman, Douglas Blackwood, Maria Helena Pinto de Azevedo, Tiffany A. Greenwood, Don H. Linszen, Daniel L. Koller, Richard Bruggeman, Vinay Puri, Naomi R. Wray, Stanley J. Watson, Elena Maestrini, Valentina Moskvina, Frank Dudbridge, Danielle Posthuma, Edward G. Jones, Lambertus Klei, Sarah E. Bergen, Fan Meng, Steven P. Hamilton, Guy A. Rouleau, Pierandrea Muglia, Mikael Landén, Stephanie H. Witt, Laramie E. Duncan, Stanley Zammit, Judith A. Badner, Florian Holsboer, Eco J. C. de Geus, Daniel Moreno-De-Luca, Benjamin S. Pickard, Gunnar Morken, Michael Conlon O'Donovan, Michael Steffens, Kathryn Roeder, Dorret I. Boomsma, Paul D. Shilling, Stephan Ripke, Nigel Williams, Jeremy M. Silverman, David Craig, Mark J. Daly, Michael Bauer, Detelina Grozeva, Markus J. Schwarz, Peter Holmans, Hugh Gurling, T. Scott Stroup, Aribert Rothenberger, Gary Donohoe, Eric Fombonne, Joseph D. Buxbaum, Matthew Flicldnger, Bryan J. Mowry, Thomas Hansen, Ina Giegling, Grant W. Montgomery, Caroline M. Nievergelt, Susan L. Smalley, Jung-Ying Tzeng, David H. Ledbetter, Christopher A. Walsh, Gerard D. Schellenberg, Sarah E. Medland, Robert D. Oades, James B. Potash, Dan E. Arking, Johannes Schumacher, Michael Gill, James J. McGough, Jennifer L. Moran, Donald W. Black, Sian Caesar, Neelroop N. Parikshak, Ian W. Craig, Sabine M. Klauck, Wade H. Berrettini, T. Foroud, Peter P. Zandi, Inez Myin-Germeys, Marcus Ising, Sven Cichon, Alexandre A. Todorov, Mònica Bayés, Thomas Werge, Susan L. Slager, Stanley I. Shyn, Jim van Os, Derek W. Morris, Douglas M. Ruderfer, Thomas W. Muehleisen, Matthew C. Keller, Susmita Datta, Ian Jones, John B. Vincent, James L. Kennedy, Anthony P. Monaco, Jianxin Shi, Dale R. Nyholt, Bruno Etain, Christine Fraser, Paul Cormican, Miguel Casas, Radhika Kandaswamy, Gerome Breen, Stephen V. Faraone, Jonna Kuntsi, Thomas Bettecken, Witte J.G. Hoogendijk, Nancy G. Buccola, Franziska Degenhardt, Lyudmila Georgieva, Marion Leboyer, Alan R. Sanders, John Strauss, Dan Rujescu, Russell Schachar, Helena Medeiros, Lisa Jones, Peter M. Visscher, Lauren A. Weiss, René Breuer, John I. Nurnberger, Andreas Reif, Phoenix Kwan, Vihra Milanova, Chunyu Liu, Martin A. Kohli, Donald J. MacIntyre, Nicholas Bass, Khalid Choudhury, Edwin H. Cook, Catherine Lord, Andrew D. Paterson, Jobst Meyer, Richard P. Ebstein, Zhaoming Zhao, Niklas Laengstroem, Thomas G. Schulze, Peter Propping, Wei Xu, Robert C. Thompson, Kimberly Chambert, Jonathan Pimm, Ivan Nikolov, Pamela A. F. Madden, Kevin A. McGhee, Jacob Lawrence, Jan K. Buitelaar, Andres Ingason, Christine M. Freitag, Robert Krasucki, Wiepke Cahn, Rita M. Cantor, Christina M. Hultman, Melvin G. McInnis, Catalina Betancur, Eftichia Duketis, Michael T. Murtha, Thomas H. Wassink, Philip Asherson, John S. Witte, Elaine Kenny, Edmund J.S. Sonuga-Barke, Lydia Krabbendam, Line Olsen, Agatino Battaglia, Laura J. Scott, Annette M. Hartmann, Yunjung Kim, Richard O. Day, Edwin J. C. G. van den Oord, Ole A. Andreassen, Herbert Roeyers, Michael John Owen, Colm O'Dushlaine, Peng Zhang, Morten Mattingsdal, Michael L. Cuccaro, Margaret A. Pericak-Vance, Joachim Hallmayer, Jun Li, Pamela B. Mahon, Elisabeth B. Binder, William A. Scheftner, Daniel H. Geschwind, Christel M. Middeldorp, Josef Frank, Keith Matthews, Jennifer K. Lowe, Paul Lichtenstein, Verneri Anttila, Pamela Sklar, Szabocls Szelinger, Roel A. Ophoff, Peter McGuffin, Stefan Herms, Bettina Konte, George Kirov, Hilary Coon, Maria Hipolito, Louise Frisén, Kenneth S. Kendler, Frank Bellivier, James S. Sutdiffe, Jeffrey A. Lieberman, Todd Lencz, Susanne Hoefels, Alan W. McLean, Barbara Franke, Huda Akil, Soumya Raychaudhuri, Ellen M. Wijsman, Vishwajit L. Nimgaonkar, Roy H. Perlis, Patrick J. McGrath, Susan L. Santangelo, William Coryell, Henrik B. Rasmussen, Weihua Guan, William Lawson, Elliot S. Gershon, Sean Ennis, Aiden Corvin, Allan H. Young, Thomas B. Barrett, Jonathan L. Haines, Douglas F. Levinson, Ana Miranda, Anil K. Malhotra, S. Hong Lee, Stan F. Nelson, Anthony J. Bailey, Patrick F. Sullivan, Dorothy E. Grice, Lefkos T. Middleton, Bertram Mueller-Myhsok, Michael R. Barnes, Adebayo Anjorin, O'Dushlaine, C, Rossin, L, Lee, Ph, Duncan, L, Parikshak, Nn, Newhouse, S, Ripke, S, Neale, Bm, Purcell, Sm, Posthuma, D, Nurnberger, Ji, Lee, Sh, Faraone, Sv, Perlis, Rh, Mowry, Bj, Thapar, A, Goddard, Me, Witte, J, Absher, D, Agartz, I, Akil, H, Amin, F, Andreassen, Oa, Anjorin, A, Anney, R, Anttila, V, Arking, De, Asherson, P, Azevedo, Mh, Backlund, L, Badner, Ja, Bailey, Aj, Banaschewski, T, Barchas, Jd, Barnes, Mr, Barrett, Tb, Bass, N, Battaglia, A, Bauer, M, Bayés, M, Bellivier, F, Bergen, Se, Berrettini, W, Betancur, C, Bettecken, T, Biederman, J, Binder, Eb, Black, Dw, Blackwood, Dh, Bloss, C, Boehnke, M, Boomsma, Di, Breuer, R, Bruggeman, R, Cormican, P, Buccola, Ng, Buitelaar, Jk, Bunney, We, Buxbaum, Jd, Byerley, Wf, Byrne, Em, Caesar, S, Cahn, W, Cantor, Rm, Casas, M, Chakravarti, A, Chambert, K, Choudhury, K, Cichon, S, Mattheisen, M, Cloninger, Cr, Collier, Da, Cook, Eh, Coon, H, Cormand, B, Corvin, A, Coryell, Wh, Craig, Dw, Craig, Iw, Crosbie, J, Cuccaro, Ml, Curtis, D, Czamara, D, Datta, S, Dawson, G, Day, R, De Geus, Ej, Degenhardt, F, Djurovic, S, Donohoe, Gj, Doyle, Ae, Duan, J, Dudbridge, F, Duketis, E, Ebstein, Rp, Edenberg, Hj, Elia, J, Ennis, S, Etain, B, Fanous, A, Farmer, Ae, Ferrier, In, Flickinger, M, Fombonne, E, Foroud, T, Frank, J, Franke, B, Fraser, C, Freedman, R, Freimer, Nb, Freitag, Cm, Friedl, M, Frisén, L, Gallagher, L, Gejman, Pv, Georgieva, L, Gershon, E, Giegling, I, Gill, M, Gordon, Sd, Gordon-Smith, K, Green, Ek, Greenwood, Ta, Grice, De, Gross, M, Grozeva, D, Guan, W, Gurling, H, De Haan, L, Haines, Jl, Hakonarson, H, Hallmayer, J, Hamilton, Sp, Hamshere, Ml, Hansen, Tf, Hartmann, Am, Hautzinger, M, Heath, Ac, Henders, Ak, Herms, S, Hickie, Ib, Hipolito, M, Hoefels, S, Holsboer, F, Hoogendijk, Wj, Hottenga, Jj, Hultman, Cm, Hus, V, Ingason, A, Ising, M, Jamain, S, Jones, Eg, Jones, I, Jones, L, Tzeng, Jy, Kähler, Ak, Kahn, R, Kandaswamy, R, Keller, Mc, Kennedy, Jl, Kenny, E, Kent, L, Kim, Y, Kirov, Gk, Klauck, Sm, Klei, L, Knowles, Ja, Kohli, Ma, Koller, Dl, Konte, B, Korszun, A, Krabbendam, L, Krasucki, R, Kuntsi, J, Kwan, P, Landén, M, Längström, N, Lathrop, M, Lawrence, J, Lawson, Wb, Leboyer, M, Ledbetter, Dh, Lencz, T, Lesch, Kp, Levinson, Df, Lewis, Cm, Li, J, Lichtenstein, P, Lieberman, Ja, Lin, Dy, Linszen, Dh, Liu, C, Lohoff, Fw, Loo, Sk, Lord, C, Lowe, Jk, Lucae, S, Macintyre, Dj, Madden, Pa, Maestrini, E, Magnusson, Pk, Mahon, Pb, Maier, W, Malhotra, Ak, Mane, Sm, Martin, Cl, Martin, Ng, Matthews, K, Mattingsdal, M, Mccarroll, Sa, Mcghee, Ka, Mcgough, Jj, Mcgrath, Pj, Mcguffin, P, Mcinnis, Mg, Mcintosh, A, Mckinney, R, Mclean, Aw, Mcmahon, Fj, Mcmahon, Wm, Mcquillin, A, Medeiros, H, Medland, Se, Meier, S, Melle, I, Meyer, J, Middeldorp, Cm, Middleton, L, Milanova, V, Miranda, A, Monaco, A, Montgomery, Gw, Moran, Jl, Moreno-De-Luca, D, Morken, G, Morris, Dw, Morrow, Em, Moskvina, V, Muglia, P, Mühleisen, Tw, Muir, Wj, Müller-Myhsok, B, Murtha, M, Myers, Rm, Myin-Germeys, I, Neale, Mc, Nelson, Sf, Nievergelt, Cm, Nikolov, I, Nimgaonkar, V, Nolen, Wa, Nöthen, Mm, Nwulia, Ea, Nyholt, Dr, Oades, Rd, Olincy, A, Oliveira, G, Olsen, L, Ophoff, Ra, Osby, U, Owen, Mj, Palotie, A, Parr, Jr, Paterson, Ad, Pato, Cn, Pato, Mt, Penninx, Bw, Pergadia, Ml, Pericak-Vance, Ma, Pickard, B, Pimm, J, Piven, J, Potash, Jb, Poustka, F, Propping, P, Puri, V, Quested, Dj, Quinn, Em, Ramos-Quiroga, Ja, Rasmussen, Hb, Raychaudhuri, S, Rehnström, K, Reif, A, Ribasés, M, Rice, Jp, Rietschel, M, Roeder, K, Roeyers, H, Rothenberger, A, Rouleau, G, Ruderfer, D, Rujescu, D, Sanders, Ar, Sanders, Sj, Santangelo, Sl, Sergeant, Ja, Schachar, R, Schalling, M, Schatzberg, Af, Scheftner, Wa, Schellenberg, Gd, Scherer, Sw, Schork, Nj, Schulze, Tg, Schumacher, J, Schwarz, M, Scolnick, E, Scott, Lj, Shi, J, Shilling, Pd, Shyn, Si, Silverman, Jm, Slager, Sl, Smalley, Sl, Smit, Jh, Smith, En, Sonuga-Barke, Ej, St Clair, D, State, M, Steffens, M, Steinhausen, Hc, Strauss, J, Strohmaier, J, Stroup, T, Sutcliffe, J, Szatmari, P, Szelinger, S, Thirumalai, S, Thompson, Rc, Todorov, Aa, Tozzi, F, Treutlein, J, Uhr, M, van den Oord, Jc, Van Grootheest, G, Van Os, J, Vicente, A, Vieland, Vj, Vincent, Jb, Visscher, Pm, Walsh, Ca, Wassink, Th, Watson, Sj, Weissman, Mm, Werge, T, Wienker, Tf, Wijsman, Em, Willemsen, G, Williams, N, Willsey, Aj, Witt, Sh, Xu, W, Young, Ah, Yu, Tw, Zammit, S, Zandi, Pp, Zhang, P, Zitman, Fg, Zöllner, S, Devlin, B, Kelsoe, Jr, Sklar, P, Daly, Mj, O'Donovan, Mc, Craddock, N, Kendler, K, Weiss, La, Wray, Nr, Zhao, Z, Geschwind, Dh, Sullivan, Pf, Smoller, Jw, Holmans, Pa, Breen, G., Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Human genetics, Psychiatry, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, Child and Adolescent Psychiatry / Psychology, Epidemiology, Gastroenterology & Hepatology, Hematology, University of St Andrews. School of Medicine, University of St Andrews. Institute of Behavioural and Neural Sciences, Psychiatrie & Neuropsychologie, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), RS: MHeNs - R2 - Mental Health, ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Universitat de Barcelona, Perceptual and Cognitive Neuroscience (PCN), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Complex Trait Genetics, Biological Psychology, Educational Neuroscience, Clinical Neuropsychology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, LEARN! - Brain, learning and development, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), O'Dushlaine, Colm, Rossin, Lizzy, Lee, Phil H, Duncan, Laramie, Lee, S Hong, Breen, Gerome, International Inflammatory Bowel Disease Genetics Consortium (IIBDGC), Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium, and Myin-Germeys, Inez
Subjects: Netherlands Twin Register (NTR), Statistical methods, Autism, Medizin, LOCI, Genome-wide association study, heritability, Genome-wide association studies, Histones, Genètica mèdica, 0302 clinical medicine, Histone methylation, Databases, Genetic, 2.1 Biological and endogenous factors, Psychology, GWAS, Aetiology, Psychiatric genetics, R2C, bipolar disorder, Psychiatry, 0303 health sciences, Disorders, Loci, Depression, General Neuroscience, Mental Disorders, Medical genetics, METHYLATION, Brain, 3rd-DAS, Serious Mental Illness, Psychiatric Disorders, 3. Good health, Histone, Mental Health, Schizophrenia, Mental Disorder, Cognitive Sciences, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Promoters, BDC, BURDEN, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, Human, Signal Transduction, medicine.medical_specialty, DISORDERS, Genomics, Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium, Burden, Biology, Methylation, Article, Biological pathway, PROMOTERS, 03 medical and health sciences, Databases, Genetic, medicine, Genetics, Humans, Genetic Predisposition to Disease, histone methylation, Bipolar disorder, Psiquiatria, AUTISM, 030304 developmental biology, Genetic association, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Neurology & Neurosurgery, Neuroscience (all), Human Genome, Neurosciences, medicine.disease, Brain Disorders, Good Health and Well Being, DE-NOVO MUTATIONS, Perturbações do Desenvolvimento Infantil e Saúde Mental, RC0321, Genome-wide Association Studies, De-novo mutations, major depression, Neuroscience, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: G.B. and S.N. acknowledge funding support for this work from the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. P.H.L. is supported by US National Institute of Mental Health (NIMH) grant K99MH101367. Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders. Postprint
Published: 2015
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33. Joint Analysis of Psychiatric Disorders Increases Accuracy of Risk Prediction for Schizophrenia, Bipolar Disorder, and Major Depressive Disorder

Author: Robert Maier, Gerhard Moser, Guo-Bo Chen, Stephan Ripke, William Coryell, James B. Potash, William A. Scheftner, Jianxin Shi, Myrna M. Weissman, Christina M. Hultman, Mikael Landén, Douglas F. Levinson, Kenneth S. Kendler, Jordan W. Smoller, Naomi R. Wray, S. Hong Lee, Devin Absher, Ingrid Agartz, Huda Akil, Farooq Amin, Ole A. Andreassen, Adebayo Anjorin, Richard Anney, Dan E. Arking, Philip Asherson, Maria H. Azevedo, Lena Backlund, Judith A. Badner, Anthony J. Bailey, Tobias Banaschewski, Jack D. Barchas, Michael R. Barnes, Thomas B. Barrett, Nicholas Bass, Agatino Battaglia, Michael Bauer, Mònica Bayés, Frank Bellivier, Sarah E. Bergen, Wade Berrettini, Catalina Betancur, Thomas Bettecken, Joseph Biederman, Elisabeth B. Binder, Donald W. Black, Douglas H.R. Blackwood, Cinnamon S. Bloss, Michael Boehnke, Dorret I. Boomsma, Gerome Breen, René Breuer, Richard Bruggeman, Nancy G. Buccola, Jan K. Buitelaar, William E. Bunney, Joseph D. Buxbaum, William F. Byerley, Sian Caesar, Wiepke Cahn, Rita M. Cantor, Miguel Casas, Aravinda Chakravarti, Kimberly Chambert, Khalid Choudhury, Sven Cichon, C. Robert Cloninger, David A. Collier, Edwin H. Cook, Hilary Coon, Bru Cormand, Paul Cormican, Aiden Corvin, William H. Coryell, Nicholas Craddock, David W. Craig, Ian W. Craig, Jennifer Crosbie, Michael L. Cuccaro, David Curtis, Darina Czamara, Mark J. Daly, Susmita Datta, Geraldine Dawson, Richard Day, Eco J. De Geus, Franziska Degenhardt, Bernie Devlin, Srdjan Djurovic, Gary J. Donohoe, Alysa E. Doyle, Jubao Duan, Frank Dudbridge, Eftichia Duketis, Richard P. Ebstein, Howard J. Edenberg, Josephine Elia, Sean Ennis, Bruno Etain, Ayman Fanous, Stephen V. Faraone, Anne E. Farmer, I. Nicol Ferrier, Matthew Flickinger, Eric Fombonne, Tatiana Foroud, Josef Frank, Barbara Franke, Christine Fraser, Robert Freedman, Nelson B. Freimer, Christine M. Freitag, Marion Friedl, Louise Frisén, Louise Gallagher, Pablo V. Gejman, Lyudmila Georgieva, Elliot S. Gershon, Daniel H. Geschwind, Ina Giegling, Michael Gill, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Tiffany A. Greenwood, Dorothy E. Grice, Magdalena Gross, Detelina Grozeva, Weihua Guan, Hugh Gurling, Lieuwe De Haan, Jonathan L. Haines, Hakon Hakonarson, Joachim Hallmayer, Steven P. Hamilton, Marian L. Hamshere, Thomas F. Hansen, Annette M. Hartmann, Martin Hautzinger, Andrew C. Heath, Anjali K. Henders, Stefan Herms, Ian B. Hickie, Maria Hipolito, Susanne Hoefels, Peter A. Holmans, Florian Holsboer, Witte J. Hoogendijk, Jouke-Jan Hottenga, Vanessa Hus, Andrés Ingason, Marcus Ising, Stéphane Jamain, Ian Jones, Lisa Jones, Anna K. Kähler, René S. Kahn, Radhika Kandaswamy, Matthew C. Keller, John R. Kelsoe, James L. Kennedy, Elaine Kenny, Lindsey Kent, Yunjung Kim, George K. Kirov, Sabine M. Klauck, Lambertus Klei, James A. Knowles, Martin A. Kohli, Daniel L. Koller, Bettina Konte, Ania Korszun, Lydia Krabbendam, Robert Krasucki, Jonna Kuntsi, Phoenix Kwan, Niklas Långström, Mark Lathrop, Jacob Lawrence, William B. Lawson, Marion Leboyer, David H. Ledbetter, Phil H. Lee, Todd Lencz, Klaus-Peter Lesch, Cathryn M. Lewis, Jun Li, Paul Lichtenstein, Jeffrey A. Lieberman, Dan-Yu Lin, Don H. Linszen, Chunyu Liu, Falk W. Lohoff, Sandra K. Loo, Catherine Lord, Jennifer K. Lowe, Susanne Lucae, Donald J. MacIntyre, Pamela A.F. Madden, Elena Maestrini, Patrik K.E. Magnusson, Pamela B. Mahon, Wolfgang Maier, Anil K. Malhotra, Shrikant M. Mane, Christa L. Martin, Nicholas G. Martin, Manuel Mattheisen, Keith Matthews, Morten Mattingsdal, Steven A. McCarroll, Kevin A. McGhee, James J. McGough, Patrick J. McGrath, Peter McGuffin, Melvin G. McInnis, Andrew McIntosh, Rebecca McKinney, Alan W. McLean, Francis J. McMahon, William M. McMahon, Andrew McQuillin, Helena Medeiros, Sarah E. Medland, Sandra Meier, Ingrid Melle, Fan Meng, Jobst Meyer, Christel M. Middeldorp, Lefkos Middleton, Vihra Milanova, Ana Miranda, Anthony P. Monaco, Grant W. Montgomery, Jennifer L. Moran, Daniel Moreno-De-Luca, Gunnar Morken, Derek W. Morris, Eric M. Morrow, Valentina Moskvina, Bryan J. Mowry, Pierandrea Muglia, Thomas W. Mühleisen, Bertram Müller-Myhsok, Michael Murtha, Richard M. Myers, Inez Myin-Germeys, Benjamin M. Neale, Stan F. Nelson, Caroline M. Nievergelt, Ivan Nikolov, Vishwajit Nimgaonkar, Willem A. Nolen, Markus M. Nöthen, John I. Nurnberger, Evaristus A. Nwulia, Dale R. Nyholt, Michael C. O’Donovan, Colm O’Dushlaine, Robert D. Oades, Ann Olincy, Guiomar Oliveira, Line Olsen, Roel A. Ophoff, Urban Osby, Michael J. Owen, Aarno Palotie, Jeremy R. Parr, Andrew D. Paterson, Carlos N. Pato, Michele T. Pato, Brenda W. Penninx, Michele L. Pergadia, Margaret A. Pericak-Vance, Roy H. Perlis, Benjamin S. Pickard, Jonathan Pimm, Joseph Piven, Danielle Posthuma, Fritz Poustka, Peter Propping, Shaun M. Purcell, Vinay Puri, Digby J. Quested, Emma M. Quinn, Josep Antoni Ramos-Quiroga, Henrik B. Rasmussen, Soumya Raychaudhuri, Karola Rehnström, Andreas Reif, Marta Ribasés, John P. Rice, Marcella Rietschel, Kathryn Roeder, Herbert Roeyers, Lizzy Rossin, Aribert Rothenberger, Guy Rouleau, Douglas Ruderfer, Dan Rujescu, Alan R. Sanders, Stephan J. Sanders, Susan L. Santangelo, Russell Schachar, Martin Schalling, Alan F. Schatzberg, Gerard D. Schellenberg, Stephen W. Scherer, Nicholas J. Schork, Thomas G. Schulze, Johannes Schumacher, Markus Schwarz, Edward Scolnick, Laura J. Scott, Joseph A. Sergeant, Paul D. Shilling, Stanley I. Shyn, Jeremy M. Silverman, Pamela Sklar, Susan L. Slager, Susan L. Smalley, Johannes H. Smit, Erin N. Smith, Edmund J.S. Sonuga-Barke, David St Clair, Matthew State, Michael Steffens, Hans-Christoph Steinhausen, John S. Strauss, Jana Strohmaier, T. Scott Stroup, Patrick F. Sullivan, James Sutcliffe, Peter Szatmari, Szabocls Szelinger, Anita Thapar, Srinivasa Thirumalai, Robert C. Thompson, Alexandre A. Todorov, Federica Tozzi, Jens Treutlein, Jung-Ying Tzeng, Manfred Uhr, Edwin J.C.G. van den Oord, Gerard Van Grootheest, Jim Van Os, Astrid M. Vicente, Veronica J. Vieland, John B. Vincent, Peter M. Visscher, Christopher A. Walsh, Thomas H. Wassink, Stanley J. Watson, Lauren A. Weiss, Thomas Werge, Thomas F. Wienker, Durk Wiersma, Ellen M. Wijsman, Gonneke Willemsen, Nigel Williams, A. Jeremy Willsey, Stephanie H. Witt, Wei Xu, Allan H. Young, Timothy W. Yu, Stanley Zammit, Peter P. Zandi, Peng Zhang, Frans G. Zitman, Sebastian Zöllner, University of Zurich, Lee, S Hong, Epidemiology and Data Science, Psychiatry, EMGO - Mental health, NCA - Neurobiology of mental health, Human genetics, NCA - Brain mechanisms in health and disease, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Maier, Robert, Moser, Gerhard, Chen, Guo-Bo, Ripke, Stephan, Coryell, William, Potash, James B, Scheftner, William A, Shi, Jianxin, Weissman, Myrna M, Hultman, Christina M, Landen, Mikael, Levinson, Douglas F, Kendler, Kenneth S, Smoller, Jordan, Wray, Naomi R, Cross-Disorder Working Group of the Psychiatric Genomics Consortium, Oades, Robert D. (Beitragende*r), Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of St Andrews. School of Medicine, University of St Andrews. Institute of Behavioural and Neural Sciences, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Maier R., Moser G., Chen G.-B., Ripke S., Coryell W., Potash J.B., Scheftner W.A., Shi J., Weissman M.M., Hultman C.M., Landen M., Levinson D.F., Kendler K.S., Smoller J.W., Wray N.R., Lee S.H., Absher D., Agartz I., Akil H., Amin F., Andreassen O.A., Anjorin A., Anney R., Arking D.E., Asherson P., Azevedo M.H., Backlund L., Badner J.A., Bailey A.J., Banaschewski T., Barchas J.D., Barnes M.R., Barrett T.B., Bass N., Battaglia A., Bauer M., Bayes M., Bellivier F., Bergen S.E., Berrettini W., Betancur C., Bettecken T., Biederman J., Binder E.B., Black D.W., Blackwood D.H.R., Bloss C.S., Boehnke M., Boomsma D.I., Breen G., Breuer R., Bruggeman R., Buccola N.G., Buitelaar J.K., Bunney W.E., Buxbaum J.D., Byerley W.F., Caesar S., Cahn W., Cantor R.M., Casas M., Chakravarti A., Chambert K., Choudhury K., Cichon S., Robert Cloninger C., Collier D.A., Cook E.H., Coon H., Cormand B., Cormican P., Corvin A., Coryell W.H., Craddock N., Craig D.W., Craig I.W., Crosbie J., Cuccaro M.L., Curtis D., Czamara D., Daly M.J., Datta S., Dawson G., Day R., De Geus E.J., Degenhardt F., Devlin B., Djurovic S., Donohoe G.J., Doyle A.E., Duan J., Dudbridge F., Duketis E., Ebstein R.P., Edenberg H.J., Elia J., Ennis S., Etain B., Fanous A., Faraone S.V., Farmer A.E., Nicol Ferrier I., Flickinger M., Fombonne E., Foroud T., Frank J., Franke B., Fraser C., Freedman R., Freimer N.B., Freitag C.M., Friedl M., Frisen L., Gallagher L., Gejman P.V., Georgieva L., Gershon E.S., Geschwind D.H., Giegling I., Gill M., Gordon S.D., Gordon-Smith K., Green E.K., Greenwood T.A., Grice D.E., Gross M., Grozeva D., Guan W., Gurling H., De Haan L., Haines J.L., Hakonarson H., Hallmayer J., Hamilton S.P., Hamshere M.L., Hansen T.F., Hartmann A.M., Hautzinger M., Heath A.C., Henders A.K., Herms S., Hickie I.B., Hipolito M., Hoefels S., Holmans P.A., Holsboer F., Hoogendijk W.J., Hottenga J.-J., Hus V., Ingason A., Ising M., Jamain S., Jones I., Jones L., Kahler A.K., Kahn R.S., Kandaswamy R., Keller M.C., Kelsoe J.R., Kennedy J.L., Kenny E., Kent L., Kim Y., Kirov G.K., Klauck S.M., Klei L., Knowles J.A., Kohli M.A., Koller D.L., Konte B., Korszun A., Krabbendam L., Krasucki R., Kuntsi J., Kwan P., Langstrom N., Lathrop M., Lawrence J., Lawson W.B., Leboyer M., Ledbetter D.H., Lee P.H., Lencz T., Lesch K.-P., Lewis C.M., Li J., Lichtenstein P., Lieberman J.A., Lin D.-Y., Linszen D.H., Liu C., Lohoff F.W., Loo S.K., Lord C., Lowe J.K., Lucae S., MacIntyre D.J., Madden P.A.F., Maestrini E., Magnusson P.K.E., Mahon P.B., Maier W., Malhotra A.K., Mane S.M., Martin C.L., Martin N.G., Mattheisen M., Matthews K., Mattingsdal M., McCarroll S.A., McGhee K.A., McGough J.J., McGrath P.J., McGuffin P., McInnis M.G., McIntosh A., McKinney R., McLean A.W., McMahon F.J., McMahon W.M., McQuillin A., Medeiros H., Medland S.E., Meier S., Melle I., Meng F., Meyer J., Middeldorp C.M., Middleton L., Milanova V., Miranda A., Monaco A.P., Montgomery G.W., Moran J.L., Moreno-De-Luca D., Morken G., Morris D.W., Morrow E.M., Moskvina V., Mowry B.J., Muglia P., Muhleisen T.W., Muller-Myhsok B., Murtha M., Myers R.M., Myin-Germeys I., Neale B.M., Nelson S.F., Nievergelt C.M., Nikolov I., Nimgaonkar V., Nolen W.A., Nothen M.M., Nurnberger J.I., Nwulia E.A., Nyholt D.R., O'Donovan M.C., O'Dushlaine C., Oades R.D., Olincy A., Oliveira G., Olsen L., Ophoff R.A., Osby U., Owen M.J., Palotie A., Parr J.R., Paterson A.D., Pato C.N., Pato M.T., Penninx B.W., Pergadia M.L., Pericak-Vance M.A., Perlis R.H., Pickard B.S., Pimm J., Piven J., Posthuma D., Poustka F., Propping P., Purcell S.M., Puri V., Quested D.J., Quinn E.M., Ramos-Quiroga J.A., Rasmussen H.B., Raychaudhuri S., Rehnstrom K., Reif A., Ribases M., Rice J.P., Rietschel M., Roeder K., Roeyers H., Rossin L., Rothenberger A., Rouleau G., Ruderfer D., Rujescu D., Sanders A.R., Sanders S.J., Santangelo S.L., Schachar R., Schalling M., Schatzberg A.F., Schellenberg G.D., Scherer S.W., Schork N.J., Schulze T.G., Schumacher J., Schwarz M., Scolnick E., Scott L.J., Sergeant J.A., Shilling P.D., Shyn S.I., Silverman J.M., Sklar P., Slager S.L., Smalley S.L., Smit J.H., Smith E.N., Sonuga-Barke E.J.S., St Clair D., State M., Steffens M., Steinhausen H.-C., Strauss J.S., Strohmaier J., Scott Stroup T., Sullivan P.F., Sutcliffe J., Szatmari P., Szelinger S., Thapar A., Thirumalai S., Thompson R.C., Todorov A.A., Tozzi F., Treutlein J., Tzeng J.-Y., Uhr M., van den Oord E.J.C.G., Van Grootheest G., Van Os J., Vicente A.M., Vieland V.J., Vincent J.B., Visscher P.M., Walsh C.A., Wassink T.H., Watson S.J., Weiss L.A., Werge T., Wienker T.F., Wiersma D., Wijsman E.M., Willemsen G., Williams N., Jeremy Willsey A., Witt S.H., Xu W., Young A.H., Yu T.W., Zammit S., Zandi P.P., Zhang P., Zitman F.G., and Zollner S.
Subjects: Netherlands Twin Register (NTR), Multifactorial Inheritance, Multivariate analysis, Bipolar Disorder, genome annotation, Medizin, R Medicine (General), Medical and Health Sciences, Genome-wide association studies, 0302 clinical medicine, 2.5 Research design and methodologies (aetiology), GWAS, Genetics(clinical), Aetiology, Multivariate Analysi, Genetics (clinical), Genetics & Heredity, bipolar disorder, 0303 health sciences, education.field_of_study, Depression, Mental Disorders, Single Nucleotide, 3rd-DAS, Biological Sciences, 10058 Department of Child and Adolescent Psychiatry, Serious Mental Illness, Psychiatric Disorders, 3. Good health, Mental Health, Schizophrenia, Mental Disorder, Linear Model, Major depressive disorder, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Risk assessment, Human, medicine.medical_specialty, 2716 Genetics (clinical), Genetics, Medical, Population, SNP, 610 Medicine & health, QH426 Genetics, Best linear unbiased prediction, Polymorphism, Single Nucleotide, Risk Assessment, 03 medical and health sciences, 1311 Genetics, Medical, Report, medicine, Genetics, Humans, Bipolar disorder, Genetic Testing, Polymorphism, education, Psychiatry, QH426, 030304 developmental biology, Depressive Disorder, Depressive Disorder, Major, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Cross-Disorder Working Group of the Psychiatric Genomics Consortium, Prevention, Human Genome, Major, medicine.disease, genetic risk prediction, R1, Brain Disorders, schizophrenia, Sample size determination, Perturbações do Desenvolvimento Infantil e Saúde Mental, Multivariate Analysis, Linear Models, business, depressive disorders, 030217 neurology & neurosurgery
Abstract: Cross-Disorder Working Group of the Psychiatric Genomics Consortium - Vicente A.M. Acessível em: http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25640677/ Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate linear mixed model and apply multi-trait genomic best linear unbiased prediction for genetic risk prediction. This method exploits correlations between disorders and simultaneously evaluates individual risk for each disorder. We show that the multivariate approach significantly increases the prediction accuracy for schizophrenia, bipolar disorder, and major depressive disorder in the discovery as well as in independent validation datasets. By grouping SNPs based on genome annotation and fitting multiple random effects, we show that the prediction accuracy could be further improved. The gain in prediction accuracy of the multivariate approach is equivalent to an increase in sample size of 34% for schizophrenia, 68% for bipolar disorder, and 76% for major depressive disorders using single trait models. Because our approach can be readily applied to any number of GWAS datasets of correlated traits, it is a flexible and powerful tool to maximize prediction accuracy. With current sample size, risk predictors are not useful in a clinical setting but already are a valuable research tool, for example in experimental designs comparing cases with high and low polygenic risk
Published: 2015
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34. Heritability and genomics of gene expression in peripheral blood

Author: Andrew Brooks, Sandra Batista, Vered Madar, Patrick F. Sullivan, David D'Ambrosio, Johannes H. Smit, Gonneke Willemsen, Brenda W.J.H. Penninx, Jung-Ying Tzeng, Gerard van Grootheest, Jouke-Jan Hottenga, Jacqueline M. Vink, Andrey A. Shabalin, Rick Jansen, Laura Todd, Yi-Hui Zhou, Wei Wang, Paul J. Gallins, Shunping Huang, Mathijs Kattenberg, Eco J. C. de Geus, Guanhua Chen, Min Jin Ha, Wei Sun, Fei Zou, Abdel Abdellaoui, Wonil Chung, Ting Huei Chen, Kai Xia, Fred A. Wright, Casey Butler, Dorret I. Boomsma, Ani Qu, Qi Wang, Weibo Wang, Jay A. Tischfield, Zhaoyu Yin, Christel M. Middeldorp, Jaspreet Kochar, Psychiatry, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Functional Genomics, Biological Psychology, Animal Ecology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, and Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease
Subjects: Netherlands Twin Register (NTR), Genotype, Quantitative Trait Loci, Inheritance Patterns, Genome-wide association study, Genomics, heritability, Biology, Quantitative trait locus, eQTL, Polymorphism, Single Nucleotide, Medical and Health Sciences, Article, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, twin study, Polymorphism, Gene, 030304 developmental biology, Netherlands, 0303 health sciences, Likelihood Functions, expression quantitative trait loci, Gene Expression Profiling, Human Genome, Single Nucleotide, Heritability, Biological Sciences, peripheral blood, Twin study, Gene expression profiling, Blood, Gene Expression Regulation, Expression quantitative trait loci, SDG 1 - No Poverty, gene expression, 030217 neurology & neurosurgery, Biotechnology, Developmental Biology
Abstract: We assessed gene expression profiles in 2,752 twins, using a classic twin design to quantify expression heritability and quantitative trait loci (eQTLs) in peripheral blood. The most highly heritable genes (â ̂1/4777) were grouped into distinct expression clusters, enriched in gene-poor regions, associated with specific gene function or ontology classes, and strongly associated with disease designation. The design enabled a comparison of twin-based heritability to estimates based on dizygotic identity-by-descent sharing and distant genetic relatedness. Consideration of sampling variation suggests that previous heritability estimates have been upwardly biased. Genotyping of 2,494 twins enabled powerful identification of eQTLs, which we further examined in a replication set of 1,895 unrelated subjects. A large number of non-redundant local eQTLs (6,756) met replication criteria, whereas a relatively small number of distant eQTLs (165) met quality control and replication standards. Our results provide a new resource toward understanding the genetic control of transcription. © 2014 Nature America, Inc. All rights reserved.
Published: 2014
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35. Harmonization of Neuroticism and Extraversion phenotypes across inventories and cohorts in the Genetics of Personality Consortium: an application of Item Response Theory

Author: Stéphanie M. van den Berg, Marleen H. M. de Moor, Matt McGue, Erik Pettersson, Antonio Terracciano, Karin J. H. Verweij, Najaf Amin, Jaime Derringer, Tõnu Esko, Gerard van Grootheest, Narelle K. Hansell, Jennifer Huffman, Bettina Konte, Jari Lahti, Michelle Luciano, Lindsay K. Matteson, Alexander Viktorin, Jasper Wouda, Arpana Agrawal, Jüri Allik, Laura Bierut, Ulla Broms, Harry Campbell, and Georg
Published: 2014
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36. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

Author: Laura J. Scott, Bernie Devlin, Steven A. McCarroll, James S. Sutcliffe, Stefan Herms, Yunjung Kim, Richard O. Day, Thomas F. Wienker, Frank Dudbridge, I. Nicol Ferrier, Bettina Konte, Marta Ribasés, C. Robert Cloninger, Brenda W.J.H. Penninx, Detelina Grozeva, Herbert Roeyers, Peter Holmans, Colm O'Dushlaine, Scott D. Gordon, Sarah E. Bergen, Fan Meng, Morten Mattingsdal, Hugh Gurling, Ina Giegling, Gerard van Grootheest, Ania Korszun, Markus J. Schwarz, George Kirov, Sebastian Zöllner, Kenneth S. Kendler, Nicholas G. Martin, Michael Conlon O'Donovan, Michael C. Neale, Jim van Os, Aravinda Chakravarti, Timothy W. Yu, Mikael Landén, Inez Myin-Germeys, Markus M. Nöthen, Kathryn Roeder, James B. Potash, Alan W. McLean, Louise Gallagher, Anna K. Kähler, Thomas Bettecken, Nigel Williams, Frank Bellivier, Joseph D. Buxbaum, Derek W. Morris, Susan L. Smalley, Jung-Ying Tzeng, Martin Schalling, Douglas M. Ruderfer, Caroline M. Nievergelt, T. Scott Stroup, David H. Ledbetter, Jennifer Crosbie, Anita Thapar, Barbara Franke, Jeffrey A. Lieberman, Huda Akil, Miguel Casas, Daniel H. Geschwind, Paul Cormican, Bertram Müller-Myhsok, Lyudmila Georgieva, Robert Krasucki, Martin Hautzinger, Alysa E. Doyle, Cinnamon S. Bloss, Gerard D. Schellenberg, Todd Lencz, Melvin G. McInnis, Catalina Betancur, Josep Antoni Ramos-Quiroga, Stephen Sanders, Eftichia Duketis, Don H. Linszen, Matthew W. State, Richard M. Myers, Soumya Raychaudhuri, Lizzy Rossin, Howard J. Edenberg, Michael E. Goddard, S. Hong Lee, Elisabeth B. Binder, Pablo V. Gejman, William A. Scheftner, Wolfgang Maier, Judith A. Badner, Christel M. Middeldorp, Maria Helena Pinto de Azevedo, Johannes H. Smit, Willem A. Nolen, Lieuwe de Haan, Gonneke Willemsen, Keith Matthews, Ellen M. Wijsman, Jennifer K. Lowe, Rebecca McKinney, Magdalena Gross, Dorothy E. Grice, James A. Knowles, Andrew C. Heath, Jana Strohmaier, Vishwajit L. Nimgaonkar, William Byerley, William E. Bunney, Dan E. Arking, Andrew McQuillin, William M. McMahon, Manuel Mattheisen, Hans-Christoph Steinhausen, Joseph Biederman, Guy A. Rouleau, James J. McGough, Sian Caesar, Edward M. Scolnick, Lefkos T. Middleton, Jack D. Barchas, Ian B. Hickie, Danyu Lin, Patrik K. E. Magnusson, Douglas Blackwood, Francis J. McMahon, Ingrid Agartz, Elena Maestrini, Marian L. Hamshere, Lindsey Kent, Walter J. Muir, Stephan Ripke, Lydia Krabbendam, Christine Fraser, Maria Hipolito, Louise Frisén, Eric Fombonne, Emma M. Quinn, Michael Bauer, Richard P. Ebstein, Michael Steffens, Jordan W. Smoller, Stanley J. Watson, Michael Boehnke, Philip Asherson, Agatino Battaglia, Elliot S. Gershon, Russell Schachar, Marcus Ising, Peng Zhang, Margaret A. Pericak-Vance, Joachim Hallmayer, Sean Ennis, Radhika Kandaswamy, René S. Kahn, Susanne Hoefels, Thomas W. Mühleisen, Pamela Sklar, Paul Lichtenstein, Verneri Anttila, Michael L. Cuccaro, Florian Holsboer, René Breuer, Eric M. Morrow, Vinay Puri, Naomi R. Wray, Szabocls Szelinger, Sabine M. Klauck, John B. Vincent, Shrikant Mane, Aribert Rothenberger, Marion Friedl, Ian Jones, Khalid Choudhury, Michael R. Barnes, Adebayo Anjorin, Edwin H. Cook, William Lawson, Allan H. Young, Lambertus Klei, Bryan J. Mowry, Johannes Schumacher, Michael Gill, James L. Kennedy, Marcella Rietschel, Aiden Corvin, Henrik B. Rasmussen, Susmita Datta, Kimberly Chambert, Daniel Moreno-De-Luca, Benjamin S. Pickard, Stan F. Nelson, Veronica J. Vieland, Stephen W. Scherer, Peter M. Visscher, John Strauss, Andreas Reif, Andrew D. Paterson, Ann Olincy, Phoenix Kwan, Anthony J. Bailey, Patrick F. Sullivan, Pierandrea Muglia, Gunnar Morken, Susanne Lucae, Ayman H. Fanous, Jacob Lawrence, Donald J. MacIntyre, Nancy G. Buccola, Rita M. Cantor, Christina M. Hultman, Weihua Guan, Anthony P. Monaco, Jouke-Jan Hottenga, Elaine Kenny, Jianxin Shi, Dale R. Nyholt, Kevin A. McGhee, Falk W. Lohoff, Jonna Kuntsi, Niklas Långström, John I. Nurnberger, Nelson B. Freimer, Erin N. Smith, John P. Rice, Michael T. Murtha, Thomas H. Wassink, Alexandre A. Todorov, Edmund J.S. Sonuga-Barke, Dan Rujescu, Roy H. Perlis, John S. Witte, Christopher A. Walsh, Matthew C. Keller, Pamela B. Mahon, Patrick J. McGrath, Susan L. Santangelo, Annette M. Hartmann, Ole A. Andreassen, Tatiana Foroud, Shaun Purcell, Josef Frank, Douglas F. Levinson, William Coryell, Ana Miranda, Alan F. Schatzberg, Peter Szatmari, Jun Li, Gerome Breen, Stephen V. Faraone, Anil K. Malhotra, Helena Medeiros, Martin A. Kohli, Nicholas Bass, Catherine Lord, Peter Propping, Wei Xu, Federica Tozzi, Ivan Nikolov, Jan K. Buitelaar, Thomas G. Schulze, Katherine Gordon-Smith, Michele L. Pergadia, Fritz Poustka, Valentina Moskvina, David Curtis, Tobias Banaschewski, Devin Absher, Danielle Posthuma, Stanley Zammit, Gary Donohoe, Ingrid Melle, Karola Rehnström, Thomas Hansen, Myrna M. Weissman, Stanley I. Shyn, Hakon Hakonarson, Christa Lese Martin, Digby Quested, Darina Czamara, Jeremy R. Parr, Pamela A. F. Madden, Jens Treutlein, Aarno Palotie, Robert Freedman, Sandra Meier, Bru Cormand, Nicholas J. Schork, Michele T. Pato, John R. Kelsoe, Vanessa Hus, Frans G. Zitman, Josephine Elia, David St Clair, Roel A. Ophoff, Peter McGuffin, Jonathan Pimm, Jonathan L. Haines, Wiepke Cahn, Matthew Flickinger, Steven P. Hamilton, Michael John Owen, Paul D. Shilling, Jeremy M. Silverman, David Craig, Mark J. Daly, Sarah E. Medland, Robert D. Oades, Marion Leboyer, Alan R. Sanders, Vihra Milanova, Chunyu Liu, Jobst Meyer, Dorret I. Boomsma, Evaristus A. Nwulia, Thomas B. Barrett, Jennifer L. Moran, Donald W. Black, Mònica Bayés, Witte J.G. Hoogendijk, Franziska Degenhardt, Benjamin M. Neale, Daniel L. Koller, Carlos N. Pato, Nicholas John Craddock, Richard Bruggeman, Enda M. Byrne, Edward G. Jones, Eco J. C. de Geus, Stéphane Jamain, Jubao Duan, Anne Farmer, Astrid M. Vicente, Grant W. Montgomery, Thomas Werge, Cathryn M. Lewis, Srdjan Djurovic, Phil Lee, Richard Anney, Elaine K. Green, Wade H. Berrettini, Peter P. Zandi, Susan L. Slager, Stephanie H. Witt, Ian W. Craig, Lisa Jones, Sven Cichon, Bruno Etain, Mark Lathrop, Hilary Coon, Robert C. Thompson, Lena Backlund, A. Jeremy Willsey, Andres Ingason, Christine M. Freitag, Sandra K. Loo, Guiomar Oliveira, Line Olsen, Edwin J. C. G. van den Oord, Geraldine Dawson, Joseph A. Sergeant, David A. Collier, Farooq Amin, Srinivasa Thirumalai, Manfred Uhr, Joseph Piven, Andrew M. McIntosh, Anjali K. Henders, Urban Ösby, Klaus-Peter Lesch, Tiffany A. Greenwood, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Lee, S Hong, Ripke, Stephan, Neale, Benjamin M, Faraone, Stephen V, Wray, Naomi R, Cross-Disorder Group of the Psychiatric Genomics Consortium, International Inflammatory Bowel Disease Genetics Consortium (IIBDGC), Queensland Brain Institute, University of Queensland [Brisbane], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], SUNY Upstate Medical University, State University of New York (SUNY), Mount Sinai School of Medicine, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), Psychiatric and Neurodevelopmental Genetics Unit, Queensland Centre for Mental Health Research, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council (MRC)-School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], New South Wales Department of Primary Industries (NSW DPI), Faculty of Land and Food Resources, University of Melbourne, HudsonAlpha Institute for Biotechnology [Huntsville, AL], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Diakonhjemmet Hospital, University of Michigan [Ann Arbor], University of Michigan System, Molecular and Behavioral Neuroscience Institute (MBNI), University of Michigan System-University of Michigan System, Emory University [Atlanta, GA], Oslo University Hospital [Oslo], University College of London [London] (UCL), Trinity College Dublin, Johns Hopkins University School of Medicine [Baltimore], MRC Social Genetic Developmental and Psychiatry Centre, Institute of Psychiatry, King's College London, University of Coimbra [Portugal] (UC), Karolinska Institutet [Stockholm], University of Chicago, University of British Columbia (UBC), Department of Child and Adolescent Psychiatry and Psychotherapy [Mannheim], Universität Heidelberg [Heidelberg] = Heidelberg University, Weill Medical College of Cornell University [New York], GlaxoSmithKline, Glaxo Smith Kline, Portland Veterans Administration Medical Center, Windeyer Institute for Medical Sciences, IRCCS Fondazione Stella Maris [Pisa], University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), European Network of Bipolar Research Expert Centres (ENBREC), ENBREC, Department of Psychiatry [Philadelphia], University of Pennsylvania, Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche Phytopharmacie et Médiateurs Chimiques (UPMC), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Massachusetts General Hospital [Boston, MA, USA], University of Iowa [Iowa City], University of Edinburgh, Royal Hospital for Sick Children [Edinburgh], The Scripps Research Institute [La Jolla, San Diego], MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London-The Institute of Psychiatry, Institute of Medical Sciences, University of Aberdeen, Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London, Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg] = Heidelberg University-Central Institute of Mental Health Mannheim, Department of Psychiatry, University of Groningen [Groningen]-University Medical Center Groningen [Groningen] (UMCG), Trinity College Dublin-St. James's Hospital, School of Nursing, Louisiana State University (LSU), Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud University [Nijmegen]-Radboud University [Nijmegen], Department of Psychiatry and Human Behavior, University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Friedman Brain Institute, Mount Sinai, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Seaver Autism Center for Research and Treatment, Department of Neuroscience, Departments of Psychiatry, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Seaver Autism Center-, The Mindich Child Health & Development Institute, Friedman Brain Institute, The Mindich Child Health and Development Institute, University of California [San Francisco] (UC San Francisco), Department of Psychiatry, School of Clinical and Experimental Medicine, University of Alabama at Birmingham [ Birmingham] (UAB), Department of Human Genetics, Los Angeles, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Stanley Center for Psychiatric Research, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Mental Health Sciences Unit, Department of Genomics, Life and Brain Center, Universität Bonn = University of Bonn, Institute of Human Genetics, Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Academic Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Department of Disability and Human Development, University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Department of Developmental Neuroscience, Neuropsychiatric Genetics Research Group, University of California [San Diego] (UC San Diego), John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], East London NHS Foundation Trust, Queen Mary University of London (QMUL), Max-Planck-Institut für Psychiatrie, Genetics Institute, Autism Speaks and the Department of Psychiatry, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), School of Neurology, Neurobiology and Psychiatry, Royal Victoria Infirmary, Medstar Research Institute, KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Deparment of Medical Genetics, Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Psychiatry and Behavioral Sciences, University of Chicago-NorthShore University Health System, Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine (LSHTM), Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Psychology Department, National University of Singapore (NUS), Department of Biochemistry and Molecular Biology, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indiana University System-Indiana University System, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University (VCU), University of Dundee School of Medicine, University of Dundee, Department of Biostatistics and Center for Statistical Genetics, University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Department of Child Psychiatry, McGill University = Université McGill [Montréal, Canada]-Montreal Children's Hospital, McGill University Health Center [Montreal] (MUHC)-McGill University Health Center [Montreal] (MUHC), Howard University College of Medicine, University of Colorado [Denver], Center for Neurobehavioral Genetics, Department of Genomics, Department of Molecular Medicine, Department of Neurology, University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Medical Research Council-Cardiff University, Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Fisico-Quimica Biologica, Universidade Federal do Rio de Janeiro (UFRJ), Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania-Children’s Hospital of Philadelphia (CHOP ), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Institute for Human Genetics, Neurosciences Centre of Excellence in Drug Discovery, GlaxoSmithKline Research and Development, Center for Genomic Medicine, Copenhagen University Hospital-Rigshospitalet [Copenhagen], Copenhagen University Hospital, Department of Clinical and Developmental Psychology, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Clinical Research Unit, Brain & Mind Research Institute-The University of Sydney, Functional Genomics, Neuronal Plasticity / Mouse Behaviour, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Medical Epidemiology and Biostatistics (MEB), Autism and Communicative Disorders Centre, Center for Human Genetic Research, Center for neuroscience-University of California [Davis] (UC Davis), Bioinformatics Research Center, North Carolina State University [Raleigh] (NC State), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU)-Norwegian University of Science and Technology (NTNU), Emory University [Atlanta, GA]-Atlanta Veterans Affairs Medical Center, Psychiatric Neurogenetics Section, Centre for Addiction and Mental Health, School of Medicine, University of St Andrews [Scotland], Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Ecology and Evolutionary Biology, Insitute of Neuroscience and Physiology, University of Gothenburg (GU), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Developmental Brain and Behaviour Unit, University of Southampton, Division of Psychiatric Genomics, Rheinische Friedrich-Wilhelms-Universität Bonn, Statistical Genetics Group, Department of Human Genetics, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Department of Psychiatry and Psychotherapy, Department of Mental Health, Johns Hopkins University and Hospital, W.M. Keck Biotechnology Resource Laboratory, Yale University [New Haven], Institutes of Neuroscience and Health and Society, Newcastle University [Newcastle], Genetic Epidemiology Unit, Queensland Institute of Medical Research, Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], Sorlandet Hospital HF, Division of Psychiatry, University of Edinburgh-Royal Edinburgh Hospital, Medical Genetics Section, University of Edinburgh-Western General Hospital, Unit on the Genetic Basis of Mood and Anxiety Disorders, National Institutes of Health [Bethesda] (NIH), Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Division of Mental Health and Addiction, Molecular Psychiatry Laboratory, University of Michigan System-University of Michigan System-Molecular and Behavioral Neuroscience Institute, Research and Development, First Psychiatric Clinic-Alexander University Hospital, Registo Oncológico Regional-Sul, Instituto Português de Oncologia de Francisco Gentil, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, St. Olav's Hospital, Brown University, Department of Molecular Biology, Cell Biology and Biochemistry, Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig-Universität Leipzig, Human Genetics Department, University of Pittsburgh (PITT), Institute for Biomedical Imaging and Life Science, University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Head of Medical Sequencing, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Carolina Institute for Developmental Disabilities, Analytic and Translational Genetics Unit, Rush University Medical Center [Chicago], Julius-Maximilians-Universität Würzburg (JMU), Washington University in Saint Louis (WUSTL), Department of Statistics, Carnegie Mellon University [Pittsburgh] (CMU), Department of Experimental Clinical and Health Psychology, Universiteit Gent = Ghent University (UGENT), Department of Child and Adolescent Psychiatry, Georg-August-University = Georg-August-Universität Göttingen, Department of Medicine, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM)-Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Departments of Psychiatry and Genetics, Yale School of Medicine [New Haven, Connecticut] (YSM), Maine Medical Center, Free University of Amsterdam, Department of Psychiatry and Behavioral Sciences [Stanford], Pathology and Laboratory Medicine, The Scripps Translational Science Institute and The Scripps Research Institute, Psychiatric Center Nordbaden, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), The Scripps Translational Science Institute and Scripps Health, Child and Adolescent Psychiatry, Aarhus University Hospital, Molecular Neuropsychiatry and Development Laboratory, Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, The Translational Genomics Research Institute (TGen), Oxford Health NHS Foundation Trust, Marlborough House Secure Unit, Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, University of Toronto, Diamantina Institute, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Departments of Biostatistics and Medicine, University of Washington [Seattle], ArcelorMittal Maizières Research SA, ArcelorMittal, Institute of Mental Health, Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU)-Johns Hopkins University (JHU), Psychiatrie & Neuropsychologie, Farmacologie en Toxicologie, RS: CARIM School for Cardiovascular Diseases, RS: MHeNs School for Mental Health and Neuroscience, Biological Psychology, Educational Neuroscience, Clinical Neuropsychology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, Biophotonics and Medical Imaging, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, LEARN! - Brain, learning and development, EMGO+ - Mental Health, LEARN!, Neuroscience Campus Amsterdam - Brain Imaging Technology, LaserLaB - Biophotonics and Microscopy, State University of New York (SUNY)-State University of New York (SUNY), Department of Neuroscience and Physiology, Faculty of Land and Environment, Biosciences Research Division, Department of Environment and Primary Industries Victoria, Department of Epidemiology and Biostatistics, University of California [San Francisco] (UCSF), University of California-University of California, Universität Heidelberg [Heidelberg], Cornell University [New York]-Weill Medical College of Cornell University [New York], Bioinformatics, Internal Medicine, Portland Va Medical Center : Ganzini Linda MD, Technische Universität Dresden = Dresden University of Technology (TU Dresden)-University Hospital Carl Gustav Carus, Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona (PCB), University of Pennsylvania [Philadelphia], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Division Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, Radboud university [Nijmegen]-Radboud university [Nijmegen], University of California [Irvine] (UCI), University of California-University of California-University of California [Los Angeles] (UCLA), University of Bonn, University of California-University of California-David Geffen School of Medicine [Los Angeles], Cardiff University-Medical Research Council, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Bureau d'Économie Théorique et Appliquée (BETA), Institut National de la Recherche Agronomique (INRA)-Université de Strasbourg (UNISTRA)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Oxford [Oxford], Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Universiteit Gent = Ghent University [Belgium] (UGENT), University of Göttingen - Georg-August-Universität Göttingen, Yale University School of Medicine, Georg-August-University [Göttingen], ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Psychiatry, Human genetics, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH, Mowry BJ, Thapar A, Goddard ME, Witte JS, Absher D, Agartz I, Akil H, Amin F, Andreassen OA, Anjorin A, Anney R, Anttila V, Arking DE, Asherson P, Azevedo MH, Backlund L, Badner JA, Bailey AJ, Banaschewski T, Barchas JD, Barnes MR, Barrett TB, Bass N, Battaglia A, Bauer M, Bayés M, Bellivier F, Bergen SE, Berrettini W, Betancur C, Bettecken T, Biederman J, Binder EB, Black DW, Blackwood DH, Bloss CS, Boehnke M, Boomsma DI, Breen G, Breuer R, Bruggeman R, Cormican P, Buccola NG, Buitelaar JK, Bunney WE, Buxbaum JD, Byerley WF, Byrne EM, Caesar S, Cahn W, Cantor RM, Casas M, Chakravarti A, Chambert K, Choudhury K, Cichon S, Cloninger CR, Collier DA, Cook EH, Coon H, Cormand B, Corvin A, Coryell WH, Craig DW, Craig IW, Crosbie J, Cuccaro ML, Curtis D, Czamara D, Datta S, Dawson G, Day R, De Geus EJ, Degenhardt F, Djurovic S, Donohoe GJ, Doyle AE, Duan J, Dudbridge F, Duketis E, Ebstein RP, Edenberg HJ, Elia J, Ennis S, Etain B, Fanous A, Farmer AE, Ferrier IN, Flickinger M, Fombonne E, Foroud T, Frank J, Franke B, Fraser C, Freedman R, Freimer NB, Freitag CM, Friedl M, Frisén L, Gallagher L, Gejman PV, Georgieva L, Gershon ES, Geschwind DH, Giegling I, Gill M, Gordon SD, Gordon-Smith K, Green EK, Greenwood TA, Grice DE, Gross M, Grozeva D, Guan W, Gurling H, De Haan L, Haines JL, Hakonarson H, Hallmayer J, Hamilton SP, Hamshere ML, Hansen TF, Hartmann AM, Hautzinger M, Heath AC, Henders AK, Herms S, Hickie IB, Hipolito M, Hoefels S, Holmans PA, Holsboer F, Hoogendijk WJ, Hottenga JJ, Hultman CM, Hus V, Ingason A, Ising M, Jamain S, Jones EG, Jones I, Jones L, Tzeng JY, Kähler AK, Kahn RS, Kandaswamy R, Keller MC, Kennedy JL, Kenny E, Kent L, Kim Y, Kirov GK, Klauck SM, Klei L, Knowles JA, Kohli MA, Koller DL, Konte B, Korszun A, Krabbendam L, Krasucki R, Kuntsi J, Kwan P, Landén M, Långström N, Lathrop M, Lawrence J, Lawson WB, Leboyer M, Ledbetter DH, Lee PH, Lencz T, Lesch KP, Levinson DF, Lewis CM, Li J, Lichtenstein P, Lieberman JA, Lin DY, Linszen DH, Liu C, Lohoff FW, Loo SK, Lord C, Lowe JK, Lucae S, MacIntyre DJ, Madden PA, Maestrini E, Magnusson PK, Mahon PB, Maier W, Malhotra AK, Mane SM, Martin CL, Martin NG, Mattheisen M, Matthews K, Mattingsdal M, McCarroll SA, McGhee KA, McGough JJ, McGrath PJ, McGuffin P, McInnis MG, McIntosh A, McKinney R, McLean AW, McMahon FJ, McMahon WM, McQuillin A, Medeiros H, Medland SE, Meier S, Melle I, Meng F, Meyer J, Middeldorp CM, Middleton L, Milanova V, Miranda A, Monaco AP, Montgomery GW, Moran JL, Moreno-De-Luca D, Morken G, Morris DW, Morrow EM, Moskvina V, Muglia P, Mühleisen TW, Muir WJ, Müller-Myhsok B, Murtha M, Myers RM, Myin-Germeys I, Neale MC, Nelson SF, Nievergelt CM, Nikolov I, Nimgaonkar V, Nolen WA, Nöthen MM, Nurnberger JI, Nwulia EA, Nyholt DR, O'Dushlaine C, Oades RD, Olincy A, Oliveira G, Olsen L, Ophoff RA, Osby U, Owen MJ, Palotie A, Parr JR, Paterson AD, Pato CN, Pato MT, Penninx BW, Pergadia ML, Pericak-Vance MA, Pickard BS, Pimm J, Piven J, Posthuma D, Potash JB, Poustka F, Propping P, Puri V, Quested DJ, Quinn EM, Ramos-Quiroga JA, Rasmussen HB, Raychaudhuri S, Rehnström K, Reif A, Ribasés M, Rice JP, Rietschel M, Roeder K, Roeyers H, Rossin L, Rothenberger A, Rouleau G, Ruderfer D, Rujescu D, Sanders AR, Sanders SJ, Santangelo SL, Sergeant JA, Schachar R, Schalling M, Schatzberg AF, Scheftner WA, Schellenberg GD, Scherer SW, Schork NJ, Schulze TG, Schumacher J, Schwarz M, Scolnick E, Scott LJ, Shi J, Shilling PD, Shyn SI, Silverman JM, Slager SL, Smalley SL, Smit JH, Smith EN, Sonuga-Barke EJ, St Clair D, State M, Steffens M, Steinhausen HC, Strauss JS, Strohmaier J, Stroup TS, Sutcliffe JS, Szatmari P, Szelinger S, Thirumalai S, Thompson RC, Todorov AA, Tozzi F, Treutlein J, Uhr M, van den Oord EJ, Van Grootheest G, Van Os J, Vicente AM, Vieland VJ, Vincent JB, Visscher PM, Walsh CA, Wassink TH, Watson SJ, Weissman MM, Werge T, Wienker TF, Wijsman EM, Willemsen G, Williams N, Willsey AJ, Witt SH, Xu W, Young AH, Yu TW, Zammit S, Zandi PP, Zhang P, Zitman FG, Zöllner S, Devlin B, Kelsoe JR, Sklar P, Daly MJ, O'Donovan MC, Craddock N, Sullivan PF, Smoller JW, Kendler KS, Wray NR, Cardiff University-Medical Research Council (MRC), HudsonAlpha Institute for Biotechnology, The Institute of Psychiatry-King‘s College London, Cornell University-Weill Medical College of Cornell University [New York], Stanford University Medical School, Technische Universität Dresden (TUD)-University Hospital Carl Gustav Carus, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, McGill University-Montreal Children's Hospital, Universidade Federal do Rio de Janeiro [Rio de Janeiro] (UFRJ), Stanford University School of Medicine [Stanford], Stanford University [Stanford], Eberhard Karls Universität Tübingen, Friedrich Alexander University [Erlangen-Nürnberg], Università di Bologna [Bologna] (UNIBO), University of Toronto-The Hospital for Sick Children-Department of Molecular Genetics-McLaughlin Centre, Washington University School of Medicine, Ghent University [Belgium] (UGENT), University of Goettingen, CHUM Research Center, Psychiatry and Behavioral Science, Stanford University School of Medicine [CA, USA], Aalborg Psychiatric Hospital, Aarhus University Hospital, Washington University in St Louis, Instituto Nacional de Saude Dr Ricardo Jorge, Oades, Robert D., Guellaen, Georges, Medical Oncology, Epidemiology, Child and Adolescent Psychiatry / Psychology, and Hematology
Subjects: Netherlands Twin Register (NTR), Medizin, Inheritance Patterns, Social Sciences, AUTISM SPECTRUM DISORDERS, nosology, heritability, COMMON SNPS, 0302 clinical medicine, Crohn Disease, SCHIZOPHRENIA, Child, Psychiatric genetics, Genetics & Heredity, MAJOR DEPRESSIVE DISORDER, RISK, 0303 health sciences, ATTENTION-DEFICIT/HYPERACTIVITY DISORDER, 120 000 Neuronal Coherence, Mental Disorders, Variants, BIPOLAR DISORDER, ASSOCIATION, Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], Psychiatric Disorders, CROHNS-DISEASE, 3. Good health, Schizophrenia, genetic association study, Medical genetics, Major depressive disorder, SNPs, Adult, medicine.medical_specialty, genetic etiology, medical genetics, DEFICIT HYPERACTIVITY DISORDER, Biology, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], Heritability, Genetic Heterogeneity, 03 medical and health sciences, Prevalence of mental disorders, mental disorders, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, medicine, ddc:61, Humans, Attention deficit hyperactivity disorder, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, DCN PAC - Perception action and control NCEBP 9 - Mental health, ddc:610, Medizinische Fakultät » Universitätsklinikum Essen » LVR-Klinikum Essen » Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Bipolar disorder, Psychiatry, 030304 developmental biology, Depressive Disorder, Major, Genome, Human, Genetic heterogeneity, medicine.disease, schizophrenia, Attention Deficit Disorder with Hyperactivity, Child Development Disorders, Pervasive, Perturbações do Desenvolvimento Infantil e Saúde Mental, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: AM Vicente - Cross-Disorder Group of the Psychiatric Genomics Consortium Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
Published: 2013
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37. A mega-analysis of genome-wide association studies for major depressive disorder

Author: Thomas Bettecken, Hogni Oskarsson, William Lawson, Isaac S. Kohane, Elisabeth B. Binder, William A. Scheftner, Christel M. Middeldorp, Jeffrey B. Weilburg, Cathryn M. Lewis, Donald J. MacIntyre, Stanley I. Shyn, Manfred Uhr, Hreinn Stefansson, Federica Tozzi, Anjali K. Henders, Nicholas G. Martin, Magdalena Gross, Roy H. Perlis, Paul Lichtenstein, Glyn Lewis, Stefan Herms, Brenda P Penninx, Patrick J. McGrath, Andrea Schulz, Shawn N. Murphy, Vivian S. Gainer, Gerard van Grootheest, Nancy L. Pedersen, G. M. Montgomery, William Coryell, Scott D. Gordon, Susan L. Slager, Dan V. Iosifescu, Lefkos T. Middleton, Susanne Churchill, James B. Potash, Lisa Jones, Ian W. Craig, Mikael Landén, Peter McGuffin, Sven Cichon, Marcella Rietschel, Bertram Müller-Myhsok, Benjamin M. Neale, Zoltán Kutalik, Michael Steffens, Dorret I. Boomsma, Johannes H. Smit, Gonneke Willemsen, Andrew C. Heath, Michael R. Barnes, René Breuer, Engilbert Sigurdsson, Patrick F. Sullivan, Josef Frank, Witte J.G. Hoogendijk, Franziska Degenhardt, Susanne Hoefels, Jordan W. Smoller, Susanne Lucae, Sergey Goryachev, Patrik K. E. Magnusson, Florian Holsboer, Michael Conlon O'Donovan, Willem A. Nolen, Douglas Blackwood, Enda M. Byrne, James A. Knowles, Edwin J. C. G. van den Oord, Victor M. Castro, Alan W. McLean, Andrew M. McIntosh, Jouke-Jan Hottenga, Anne Farmer, Kari Stefansson, Nicholas John Craddock, Pamela A. F. Madden, Marcus Ising, Ian B. Hickie, Patience J. Gallagher, Thomas G Schulze, Douglas F. Levinson, Alexander Viktorin, Danyu Lin, Maurizio Fava, Matthias Nauck, Henry Völzke, Manuel Mattheisen, Naomi R. Wray, Jianxin Shi, Dale R. Nyholt, Tzeng Jung-Ying, Eco J. C. de Geus, Myrna M. Weissman, Thorgeir E. Thorgeirsson, Rudolf Uher, Michel Guipponi, Alexander Teumer, Stephan Ripke, Ian Jones, Frans G. Zitman, Stacy Steinberg, Jens Treutlein, Markus M. Noethen, Steven P. Hamilton, Mark J. Daly, Hans J. Grabe, Michele L. Pergadia, Darina Czamara, Ania Korszun, Martin Preisig, Katherine E. Tansey, Wolfgang Maier, Pierandrea Muglia, Gerome Breen, Martin A. Kohli, Psychiatry, Epidemiology and Data Science, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Faculteit Medische Wetenschappen/UMCG, and Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE)
Subjects: Oncology, Male, Netherlands Twin Register (NTR), mega-analysis, Bipolar Disorder, Genome-wide association study, 0302 clinical medicine, CARDIOVASCULAR RISK-FACTORS, genetics, Genetics, 0303 health sciences, PSYCHIATRIC-DISORDERS, BIPOLAR DISORDER, 3. Good health, Psychiatry and Mental health, Meta-analysis, Major depressive disorder, Female, Psychology, medicine.medical_specialty, MOOD DISORDERS, SUSCEPTIBILITY LOCI, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Article, White People, TWIN REGISTRY, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Internal medicine, mental disorders, MENTAL-DISORDERS, medicine, NATIONAL COMORBIDITY SURVEY, SNP, Humans, Genetic Predisposition to Disease, Bipolar disorder, Molecular Biology, 030304 developmental biology, Genetic association, Depressive Disorder, Major, SEROTONIN TRANSPORTER GENE, genome-wide association study, major depressive disorder, medicine.disease, meta-analysis, Case-Control Studies, Age of onset, HUMAN HEIGHT, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-Analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-Analysis using 819 autosomal SNPs with P
Published: 2013
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38. HIV-infected mental health patients: characteristics and comparison with HIV-infected patients from the general population and non-infected mental health patients

Author: Gerard van Grootheest, Johannes H. Smit, Annemiek Schadé, Epidemiology and Data Science, Psychiatry, EMGO - Mental health, and EMGO+ - Mental Health
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Personality Inventory, lcsh:RC435-571, Substance-Related Disorders, Population, Psychological intervention, HIV Infections, Young Adult, SDG 3 - Good Health and Well-being, lcsh:Psychiatry, Surveys and Questionnaires, medicine, Outpatient clinic, Humans, Homosexual men, Homosexuality, Male, education, Psychiatry, Suicidal ideation, Aged, Netherlands, Psychiatric Status Rating Scales, education.field_of_study, Depressive Disorder, Depression, Public health, Prevention, Mental Disorders, virus diseases, HIV, Drugs, Middle Aged, medicine.disease, Mental health, Substance abuse, Psychiatry and Mental health, Female, medicine.symptom, Psychology, Clinical psychology, Psychopathology, Research Article
Abstract: Objectives HIV-infected patients are at increased risk of developing mental health symptoms, which negatively influence the treatment of the HIV-infection. Mental health problems in HIV-infected patients may affect public health. Psychopathology, including depression and substance abuse, can increase hazardous sexual behaviour and, with it, the chance of spreading HIV. Therefore, it is important to develop an optimal treatment plan for HIV-infected patients with mental health problems. The majority of HIV-infected patients in the Netherlands (almost 60%) are homosexual men. The main objectives of this study were to describe the clinical and demographic characteristics of patients with HIV who seek treatment for their mental health symptoms in the Netherlands. Secondly, we tested whether HIV infected and non-infected homosexual patients with a lifetime depressive disorder differed on several mental health symptoms. Methods We compared a cohort of 196 patients who visited the outpatient clinic for HIV and Mental Health with HIV-infected patients in the general population in Amsterdam (ATHENA-study) and with non-HIV infected mental health patients (NESDA-study). DSM-IV diagnoses were determined, and several self-report questionnaires were used to assess mental health symptoms. Results Depressive disorders were the most commonly occurring diagnoses in the cohort and frequent drug use was common. HIV-infected homosexual men with a depressive disorder showed no difference in depressive symptoms or sleep disturbance, compared with non-infected depressive men. However, HIV-positive patients did express more symptoms like fear, anger and guilt. Although they showed significantly more suicidal ideation, suicide attempts were not more prevalent among HIV-infected patients. Finally, the HIV-infected depressive patients displayed a considerably higher level of drug use than the HIV-negative group. Conclusion Habitual drug use is a risk factor for spreading HIV. It is also more often diagnosed in HIV-infected homosexual men with a lifetime depression or dysthymic disorder than in the non-infected population. Untreated mental health problems, such as depressive symptoms and use of drugs can have serious repercussions. Therefore, general practitioners and internists should be trained to recognize mental health problems in HIV-infected patients.
Published: 2013
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39. I8 Huntingtin gene repeat polymorphisms affect risk of lifetime depression in the general population

Author: Maarten Pieter Rozing, Albert M. van Hemert, Willeke M. C. van Roon-Mom, Hannie C. Comijs, Brenda W.J.H. Penninx, Aartjan T.F. Beekman, Sarah L. Gardiner, Roos C. van der Mast, Gerard van Grootheest, N. Ahmad Aziz, Johannes H. Smit, Robert A. Schoevers, Raymund A.C. Roos, Merel W. Boogaard, and Martine J. van Belzen
Subjects: Oncology, Genetics, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, education.field_of_study, Population, Odds ratio, Disease, Logistic regression, nervous system diseases, Psychiatry and Mental health, Internal medicine, mental disorders, medicine, Anxiety, Surgery, Neurology (clinical), Allele, medicine.symptom, Psychology, Trinucleotide repeat expansion, education, Depression (differential diagnoses)
Abstract: Background Expanded DNA repeats are associated with many hereditary neurological disorders, among the most common of which is Huntington’s disease (HD), a severe neuropsychiatric disorder caused by a CAG repeat expansion in the HTT gene. Although HD is frequently complicated by depression, it is still unknown to what extent common HTT CAG repeat size variations could affect depression risk in the general population. Therefore, we aimed to assess the contribution of the whole spectrum of HTT CAG repeat length variations to depression susceptibility. Methods We determined HTT CAG repeat size in all participants from two well-characterised Dutch cohorts – the Netherlands Study of Depression and Anxiety and the Netherlands Study of Depression in Old People – in whom DNA samples were available (including 2165 depressed and 1058 non-depressed persons). The association between HTT CAG repeat size and depression risk was assessed through binary logistic regression as well as non-parametrically by calculating odds ratios (OR) for each repeat with respect to the modal size. Results In both cohorts separately as well as combined there was a significant non-linear association between the risk of lifetime depression and HTT CAG repeat size in the longer allele in which both relatively short and relatively large alleles were associated with an increased risk of depression as compared to alleles near the middle of the distribution (β = −0.292 and β = 0.006 for the linear and the quadratic term, respectively; both p ≤ 0.009 after adjustment for the effects of sex, age and education level). The odds of lifetime depression were lowest in persons with a HTT CAG repeat size of 21 (OR = 0.66, 95% CI: 0.48 to 0.91). Conclusion We found a non-linear association between HTT CAG repeat size and risk of lifetime depression in which lifetime depression risk increased with both relatively short and relatively large alleles. Our study provides proof-of-principle that repeat polymorphisms could act as hitherto unappreciated but important complex genetic modifiers of depression.
Published: 2016
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40. Differential involvement of the dorsal hippocampus in passive avoidance in C57bl/6J and DBA/2J mice

Author: Petra J.J. Baarendse, Matthijs Verhage, René F. Jansen, Sven Ove Ögren, Oliver Stiedl, Anton W. Pieneman, Gerard van Grootheest, Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam 2008, and Human genetics
Subjects: Male, SDG 16 - Peace, Cognitive Neuroscience, Hippocampus, Hippocampal formation, Mice, Latent inhibition, Species Specificity, Avoidance Learning, Reaction Time, Animals, Circadian rhythm, Fear conditioning, Analysis of Variance, Behavior, Animal, SDG 16 - Peace, Justice and Strong Institutions, Justice and Strong Institutions, Circadian Rhythm, Mice, Inbred C57BL, Inhibition, Psychological, 2-Amino-5-phosphonovalerate, Mice, Inbred DBA, NMDA receptor, Conditioning, Analysis of variance, Psychology, Neuroscience, Excitatory Amino Acid Antagonists
Abstract: The inferior performance of DBA/2 mice when compared to C57BL/6 mice in hippocampus-dependent behavioral tasks including contextual fear conditioning has been attributed to impaired hippocampal function. However, DBA/2J mice have been reported to perform similarly or even better than C57BL/6J mice in the passive avoidance (PA) task that most likely also depends on hippocampal function. The apparent discrepancy in PA versus fear conditioning performance in these two strains of mice was investigated using an automated PA system. The aim was to determine whether these two mouse strains utilize different strategies involving a different contribution of hippocampal mechanisms to encode PA. C57BL/6J mice exhibited significantly longer retention latencies than DBA/2J mice when tested 24 h after training irrespective of the circadian cycle. Dorsohippocampal NMDA receptor inhibition by local injection of the selective antagonist DL-2-amino-S-phosphonovaleric acid (AP5, 3.2 μg/mouse) before training resulted in impaired PA retention in C57BL/6J but not in DBA/2J mice. Furthermore, nonreinforced pre-exposure to the PA system before training caused a latent inhibition-like reduction of retention latencies in C57BL/6J, whereas it improved PA retention in DBA/2J mice. These pre-exposure experiments facilitated the discrimination of hippocampal involvement without local pharmacological intervention. The results indicate differences in PA learning between these two strains based on a different NMDA receptor involvement in the dorsal hippocampus in this emotional learning task. We hypothesize that mouse strains can differ in their PA learning performance based on their relative ability to form associations on the basis of unisensory versus multisensory contextual/spatial cues that involve hippocampal processing. © 2007 Wiley-Liss, Inc.
Published: 2008
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41. Sex differences in the human peripheral blood transcriptome

Author: Fred A. Wright, Brenda W.J.H. Penninx, Cor L. Verweij, Gerard van Grootheest, Yuri Milaneschi, Dorret I. Boomsma, Jay A. Tischfield, Patrick F. Sullivan, Wouter J. Peyrot, Jacqueline M. Vink, Johannes H. Smit, Gonneke Willemsen, Eco J. C. de Geus, Hamdi Mbarek, Rick Jansen, Sandra Batista, Vered Madar, Jouke-Jan Hottenga, Andrew Brooks, Psychiatry, Pathology, NCA - Neurobiology of mental health, EMGO - Mental health, Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, and EMGO+ - Mental Health
Subjects: Netherlands Twin Register (NTR), Adult, Male, medicine.drug_class, Biology, Genome, Polymorphism, Single Nucleotide, Transcriptome, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, Sex Factors, SDG 3 - Good Health and Well-being, Polymorphism (computer science), Gene expression, Genetics, medicine, Contraceptive Agents, Female, Humans, Gene, 030304 developmental biology, 0303 health sciences, Chromosomes, Human, X, Chromosomes, Human, Y, Age Factors, Cancer, Estrogens, DNA, Middle Aged, medicine.disease, Kidney Neoplasms, 3. Good health, Postmenopause, Estrogen, RNA, Female, DNA microarray, 030217 neurology & neurosurgery, Biotechnology, Research Article
Abstract: Background: Genomes of men and women differ in only a limited number of genes located on the sex chromosomes, whereas the transcriptome is far more sex-specific. Identification of sex-biased gene expression will contribute to understanding the molecular basis of sex-differences in complex traits and common diseases.Results: Sex differences in the human peripheral blood transcriptome were characterized using microarrays in 5,241 subjects, accounting for menopause status and hormonal contraceptive use. Sex-specific expression was observed for 582 autosomal genes, of which 57.7% was upregulated in women (female-biased genes). Female-biased genes were enriched for several immune system GO categories, genes linked to rheumatoid arthritis (16%) and genes regulated by estrogen (18%). Male-biased genes were enriched for genes linked to renal cancer (9%). Sex-differences in gene expression were smaller in postmenopausal women, larger in women using hormonal contraceptives and not caused by sex-specific eQTLs, confirming the role of estrogen in regulating sex-biased genes.Conclusions: This study indicates that sex-bias in gene expression is extensive and may underlie sex-differences in the prevalence of common diseases. © 2014 Jansen et al.; licensee BioMed Central Ltd.
Published: 2014
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42. Linkage of health insurance data to the Netherlands Twin Register

Author: Adelaide Ariel, Tina Glasner, Bep Verkerk, Toos van Beijsterveldt, Gerard van Grootheest, Jan van der Laan, Mark de Groot, Sipke Visser, Bakker, Bart F. M., Boomsma, Dorret I., Van Grootheest, G., De Groot, M., Van der Laan, J., Smit, J., and Bakker, B.
Subjects: Netherlands Twin Register (NTR)

43. Correcting for cell-type effects in DNA methylation studies: reference-based method outperforms latent variable approaches in empirical studies

Author: Robin F. Chan, Brenda W.J.H. Penninx, Patrik K. E. Magnusson, Gerard van Grootheest, Gaurav Kumar, Christina M. Hultman, Min Zhao, Andrey A. Shabalin, Mohammad W. Hattab, Lin Ying Xie, Rick Jansen, Edwin J. C. G. van den Oord, Shaunna L. Clark, Karolina A. Aberg, Laura K.M. Han, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, and APH - Digital Health
Subjects: 0301 basic medicine, Empirical data, Latent variable, Cell Separation, Biology, Sensitivity and Specificity, Monocytes, Arthritis, Rheumatoid, 03 medical and health sciences, Genetic Heterogeneity, 0302 clinical medicine, Empirical research, Correspondence, Econometrics, Humans, Computer Simulation, Confounding, Contrast (statistics), Reproducibility of Results, Replicate, Sequence Analysis, DNA, DNA Methylation, Small set, 030104 developmental biology, Evolutionary biology, Organ Specificity, Case-Control Studies, DNA methylation, Colorectal Neoplasms, 030217 neurology & neurosurgery, Algorithms
Abstract: Many different methods exist to adjust for variability in cell-type mixture proportions when analyzing DNA methylation studies. Here we present the result of an extensive simulation study, built on cell-separated DNA methylation profiles from Illumina Infinium 450K methylation data, to compare the performance of eight methods including the most commonly used approaches.We designed a rich multi-layered simulation containing a set of probes with true associations with either binary or continuous phenotypes, confounding by cell type, variability in means and standard deviations for population parameters, additional variability at the level of an individual cell-type-specific sample, and variability in the mixture proportions across samples. Performance varied quite substantially across methods and simulations. In particular, the number of false positives was sometimes unrealistically high, indicating limited ability to discriminate the true signals from those appearing significant through confounding. Methods that filtered probes had consequently poor power. QQ plots of p values across all tested probes showed that adjustments did not always improve the distribution. The same methods were used to examine associations between smoking and methylation data from a case-control study of colorectal cancer, and we also explored the effect of cell-type adjustments on associations between rheumatoid arthritis cases and controls.We recommend surrogate variable analysis for cell-type mixture adjustment since performance was stable under all our simulated scenarios.
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