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1. A polygenic resilience score moderates the genetic risk for schizophrenia

Author

Hess, Jonathan L, Tylee, Daniel S, Mors, Ole, Duan, Jubao, Dudbridge, Frank, Duncanson, Audrey, Durmishi, Naser, Edkins, Sarah, Ehrenreich, Hannelore, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Esko, Tõnu, Nordentoft, Merete, Essioux, Laurent, Fanous, Ayman H, Farh, Kai-How, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freeman, Colin, Freimer, Nelson B, Friedl, Marion, Hougaard, David M, Friedman, Joseph I, Fromer, Menachem, Gejman, Pablo V, Genovese, Giulio, Georgieva, Lyudmila, Giannoulatou, Eleni, Giegling, Ina, Gill, Michael, Gillman, Matthew, Giusti-Rodríguez, Paola, Byberg-Grauholm, Jonas, Godard, Stephanie, Goldstein, Jacqueline I, Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, Gray, Emma, Gurling, Hugh, Gwilliam, Rhian, de Haan, Lieuwe, Hall, Jeremy, Bækvad-Hansen, Marie, Hammer, Christian, Hammond, Naomi, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Hellenthal, Garrett, Henskens, Frans A, Herms, Stefan, Greenwood, Tiffany A, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V, Huang, Hailiang, Hultman, Christina M, Hunt, Sarah E, Ikeda, Masashi, Iwata, Nakao, Iyegbe, Conrad, Tsuang, Ming T, Jablensky, Assen V, Jankowski, Janusz, Jayakumar, Alagurevathi, Joa, Inge, Jönsson, Erik G, Julià, Antonio, Kähler, Anna K, Kahn, René S, Kalaydjieva, Luba, Karachanak-Yankova, Sena, Curtis, David, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C, Kendler, Kenneth S, Kennedy, James L, Khrunin, Andrey, Kim, Yunjung, Kirov, George, Klovins, Janis, Knight, Jo, Steinberg, Stacy, Knowles, James A, Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Langford, Cordelia, Laurent, Claudine, Lawrie, Stephen, Lee, S Hong, Lee, Phil, Sigurdsson, Engilbert, Lee, Jimmy, Legge, Sophie E, Lencz, Todd, Lerer, Bernard, Levinson, Douglas F, Lewis, Cathryn M, Li, Tao, Li, Qingqin S, Li, Miaoxin, Liang, Kung-Yee, Mattheisen, Manuel, Stefánsson, Hreinn, Liddle, Jennifer, Lieberman, Jeffrey, Limborska, Svetlana, Lin, Kuang, Linszen, Don H, Liu, Jianjun, Lönnqvist, Jouko, Loughland, Carmel M, Lubinski, Jan, Macek, Milan, Stefánsson, Kári, Magnusson, Patrik K E, Maher, Brion S, Maier, Wolfgang, Malhotra, Anil K, Mallet, Jacques, Markus, Hugh S, Marsal, Sara, Mata, Ignacio, Mathew, Christopher G, Mattingsdal, Morten, Edenberg, Howard J, McCann, Owen T, McCarley, Robert W, McCarroll, Steven A, McCarthy, Mark I, McDonald, Colm, McIntosh, Andrew M, McQuillin, Andrew, Meier, Sandra, Meijer, Carin J, Melegh, Bela, Holmans, Peter, Melle, Ingrid, Mesholam-Gately, Raquelle I, Metspalu, Andres, Michie, Patricia T, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Moran, Jennifer L, Morris, Derek W, Mowry, Bryan J, Faraone, Stephen V, Müller-Myhsok, Bertram, Murphy, Kieran C, Murray, Robin M, Myin-Germeys, Inez, Neale, Benjamin M, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A, Nestadt, Gerald, Nicodemus, Kristin K, Glatt, Stephen J, Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, Nöthen, Markus M, O'Callaghan, Eadbhard, O'Donovan, Michael C, O'Dushlaine, Colm, O'Neill, F Anthony, Oh, Sang-Yun, Olincy, Ann, Adolfsson, Rolf, Olsen, Line, Ophoff, Roel A, Van Os, Jim, Owen, Michael J, Palmer, Colin N A, Palotie, Aarno, Pantelis, Christos, Papadimitriou, George N, Papiol, Sergi, Parkhomenko, Elena, Agartz, Ingrid, Pato, Michele T, Pato, Carlos N, Paunio, Tiina, Pearson, Richard, Cairns, Murray J, DeLisi, Lynn E, Gershon, Elliot S, Kelly, Brian J, Lam, Max, Norgren, Nina, Agerbo, Esben, Paciga, Sara A, Tooney, Paul A, Wu, Jing Qin, Pejovic-Milovancevic, Milica, Perkins, Diana O, Pers, Tune H, Petryshen, Tracey L, Pietiläinen, Olli, Pimm, Jonathan, Pirinen, Matti, Albus, Margot, Plomin, Robert, Pocklington, Andrew J, Posthuma, Danielle, Potter, Simon C, Powell, John, Price, Alkes, Pulver, Ann E, Purcell, Shaun M, Quested, Digby, Rasmussen, Henrik B, Consortium, Schizophrenia Working Group of the Psychiatric Genomics, Alexander, Madeline, Rautanen, Anna, Ravindrarajah, Radhi, Reichenberg, Abraham, Reimers, Mark A, Richards, Alexander L, Ricketts, Michelle, Rietschel, Marcella, Riley, Brien P, Ripke, Stephan, Roffman, Joshua L, Amin, Farooq, Roussos, Panos, Ruderfer, Douglas M, Rujescu, Dan, Salomaa, Veikko, Sanders, Alan R, Sawcer, Stephen J, Schall, Ulrich, Schubert, Christian R, Schulze, Thomas G, Schwab, Sibylle G, Andreassen, Ole A, Scolnick, Edward M, Scott, Rodney J, Seidman, Larry J, Sham, Pak C, Shi, Jianxin, Silagadze, Teimuraz, Silverman, Jeremy M, Sim, Kang, Sklar, Pamela, Arranz, Maria J, Slominsky, Petr, Smoller, Jordan W, So, Hon-Cheong, Söderman, Erik, Spencer, Chris C A, Clair, David St, Stahl, Eli A, Stogmann, Elisabeth, Strange, Amy, Straub, Richard E, Bacanu, Silviu A, Strengman, Eric, Strohmaier, Jana, Stroup, T Scott, Su, Zhan, Subramaniam, Mythily, Sullivan, Patrick F, Suvisaari, Jaana, Svrakic, Dragan M, Szatkiewicz, Jin P, Tashakkori-Ghanbaria, Avazeh, Bakker, Steven, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Trembath, Richard C, Veijola, Juha, Visscher, Peter M, Viswanathan, Ananth C, Vukcevic, Damjan, Waddington, John, Waller, Matthew, Band, Gavin, Walsh, Dermot, Walshe, Muriel, Walters, James T R, Wang, Qiang, Wang, Dai, Webb, Bradley T, Weinberger, Daniel R, Weisbrod, Matthias, Weiser, Mark, Wendland, Jens R, Barroso, Ines, Weston, Paul, Whittaker, Pamela, Widaa, Sara, Wiersma, Durk, Wildenauer, Dieter B, Williams, Stephanie, Williams, Nigel M, Witt, Stephanie H, Wolen, Aaron R, Wong, Emily H M, Begemann, Martin, Wood, Nicholas W, Wormley, Brandon K, Wray, Naomi R, Xi, Hualin Simon, Zai, Clement C, Zheng, Xuebin, Zimprich, Fritz, Bellenguez, Céline, Research, Lundbeck Foundation Initiative for Integrative Psychiatric, Belliveau, Richard A, Bender, Stephan, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Blackburn, Hannah, Blackwell, Jenefer M, Blackwood, Douglas H R, Børglum, Anders D, Bramon, Elvira, Brown, Matthew A, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Bulik-Sullivan, Brendan, Bumpstead, Suzannah J, Buxbaum, Joseph D, Byerley, William, Cahn, Wiepke, Als, Thomas D, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Casas, Juan P, Catts, Stanley V, Chambert, Kimberley D, Chan, Ronald Y L, Chan, Raymond C K, Grove, Jakob, Chen, Eric Y H, Cheng, Wei, Cheung, Eric F C, Chong, Siow Ann, Cichon, Sven, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Collier, David A, Cormican, Paul, Werge, Thomas, Corvin, Aiden, Craddock, Nick, Crespo-Facorro, Benedicto, Crowley, James J, Daly, Mark J, Darvasi, Ariel, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, Mortensen, Preben Bo, Deloukas, Panos, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Domenici, Enrico, Donnelly, Peter, Donohoe, Gary, Drapeau, Elodie, Dronov, Serge, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Adult Psychiatry, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, Hess, Jonathan L, Tylee, Daniel S, Mattheisen, Manuel, Borglum, Anders D, Glatt, Stephen J, Lee, Sand Hong, Schizophrenia Working Group of thePsychiatric Genomics Consortium, Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, and Myin-Germeys, Inez

Subjects
Multifactorial Inheritance, Schizophrenia/genetics, Genome-wide association study, Disease, Medical and Health Sciences, 0302 clinical medicine, Risk Factors, schizophrenia, genetics, risk, 2.1 Biological and endogenous factors, genetics, polygenic score, Aetiology, genome wide association study, risk, Genetics, Psychiatry, 0303 health sciences, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Genetic Predisposition to Disease/genetics, Single Nucleotide, Genomics, Biological Sciences, Serious Mental Illness, Polymorphism, Single Nucleotide/genetics, Penetrance, 3. Good health, Psychiatry and Mental health, Mental Health, Mendelian disease, Erfðarannsóknir, Life Sciences & Biomedicine, Single Nucleotide/genetics, Biochemistry & Molecular Biology, Schizophrenia (object-oriented programming), high risk, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Geðklofi, Humans, Genetic Predisposition to Disease, ddc:610, Allele, Polymorphism, Resilience (network), Molecular Biology, resilience, Multifactorial Inheritance/genetics, Alleles, 030304 developmental biology, Science & Technology, Prevention, Human Genome, Psychology and Cognitive Sciences, Neurosciences, Brain Disorders, Lundbeck Foundation Initiative for Integrative Psychiatric Research, schizophrenia, Good Health and Well Being, Schizophrenia, Neurosciences & Neurology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein), Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531–538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected individuals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known “polygenic resilience score” that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent samples. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder., SJG is supported by grants from the U.S. National Institutes of Health (5R01MH101519, 5R01AG054002), the Sidney R. Baer, Jr. Foundation, and NARSAD: The Brain & Behavior Research Foundation. SVF is supported by the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement number 602805, the European Union’s Horizon 2020 research and innovation programme under grant agreement number 667302 and NIMH grants 5R01MH101519 and U01 MH109536-01. HJE is supported by grants from the U.S. National Institutes of Health (U10 AA008401; U01 MH109532). Statistical analyses were conducted on the Genetic Cluster Computer, which is financially supported by the Netherlands Scientific Organization (NOW; 480-05-003) along with a supplement from the Dutch Brain Foundation and VU University. The Danish iPSYCH (The Lundbeck Foundation Initiative for Integrative Psychiatric Research) and GEMS2 teams acknowledge funding from The Lundbeck Foundation (grant no R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, an Advanced Grant from the European Research Council (project no: 294838), the Danish Strategic Research Council and grants from Aarhus University to the iSEQ and CIRRAU centers. The Danish National Biobank resource at Statens Serum Institut was supported by the Novo Nordisk Foundation. Computational resources for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility were provided by the iSEQ center, Aarhus University, Denmark (grant to ADB).

Published
2021

2. Complement genes contribute sex-biased vulnerability in diverse disorders

Author

Kamitaki, Nolan, Sekar, Aswin, Consortium, Schizophrenia Working Group of the Psychiatric Genomics, Friedman, Joseph I, Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Gershon, Elliot S, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Golimbet, Vera, Boehnke, Michael, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Mitjans, Marina, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Henskens, Frans A, Kimberly, Robert P, Herms, Stefan, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V, Hougaard, David M, Ikeda, Masashi, Joa, Inge, Julià, Antonio, Kahn, René S, Kaufman, Kenneth M, Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C, Kelly, Brian J, Kennedy, James L, Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Harley, John B, Knowles, James A, Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Kähler, Anna K, Laurent, Claudine, Keong, Jimmy Lee Chee, Lee, S Hong, Legge, Sophie E, Langefeld, Carl D, Lerer, Bernard, Li, Miaoxin, Li, Tao, Liang, Kung-Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M, Lubinski, Jan, Lönnqvist, Jouko, Macek, Milan, Seidman, Christine E, Magnusson, Patrik K E, Maher, Brion S, Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattheisen, Manuel, Mattingsdal, Morten, McCarley, Robert W, McDonald, Colm, McIntosh, Andrew M, Pato, Michele T, Meier, Sandra, Meijer, Carin J, Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I, Metspalu, Andres, Michie, Patricia T, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Pato, Carlos N, Morris, Derek W, Mors, Ole, Murphy, Kieran C, Murray, Robin M, Myin-Germeys, Inez, Müller-Myhsok, Bertram, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A, Nestadt, Gerald, Ophoff, Roel A, Nicodemus, Kristin K, Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, O'Neill, F Anthony, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, Handsaker, Robert E, Graham, Robert R, Van Os, Jim, Pantelis, Christos, Papadimitriou, George N, Steixner, Agnes A, Parkhomenko, Elena, Paunio, Tiina, Pejovic-Milovancevic, Milica, Perkins, Diana O, Pietiläinen, Olli, Criswell, Lindsey A, Pimm, Jonathan, Pocklington, Andrew J, Powell, John, Price, Alkes, Pulver, Ann E, Purcell, Shaun M, Quested, Digby, Rasmussen, Henrik B, Reichenberg, Abraham, Reimers, Mark A, Vyse, Timothy J, Richards, Alexander L, Roffman, Joshua L, Roussos, Panos, Ruderfer, Douglas M, Salomaa, Veikko, Sanders, Alan R, Schall, Ulrich, Schubert, Christian R, Schulze, Thomas G, Schwab, Sibylle G, McCarroll, Steven A, Scolnick, Edward M, Scott, Rodney J, Seidman, Larry J, Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M, Sim, Kang, Slominsky, Petr, Smoller, Jordan W, Ripke, Stephan, So, Hon-Cheong, Spencer, Chris C A, Stahl, Eli A, Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E, Strengman, Eric, Strohmaier, Jana, Stroup, T Scott, Neale, Benjamin M, Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M, Szatkiewicz, Jin P, Söderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tooney, Paul A, Tosato, Sarah, Veijola, Juha, Corvin, Aiden, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T, Weiser, Mark, Wildenauer, Dieter B, Williams, Nigel M, Williams, Stephanie, Witt, Stephanie H, Walters, James T R, Wolen, Aaron R, Wong, Emily H M, Wormley, Brandon K, Wu, Jing Qin, Xi, Hualin Simon, Zai, Clement C, Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R, Stefansson, Kari, Farh, Kai-How, Visscher, Peter M, Adolfsson, Rolf, Andreassen, Ole A, Blackwood, Douglas H R, Bramon, Elvira, Buxbaum, Joseph D, Børglum, Anders D, Cichon, Sven, Darvasi, Ariel, Domenici, Enrico, Holmans, Peter A, Ehrenreich, Hannelore, Esko, Tõnu, Gejman, Pablo V, Gill, Michael, Gurling, Hugh, Hultman, Christina M, Iwata, Nakao, Jablensky, Assen V, Jönsson, Erik G, Kendler, Kenneth S, de Rivera, Heather, Lee, Phil, Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F, Li, Qingqin S, Liu, Jianjun, Malhotra, Anil K, McQuillin, Andrew, Moran, Jennifer L, Bulik-Sullivan, Brendan, Mortensen, Preben B, Mowry, Bryan J, Nöthen, Markus M, Owen, Michael J, Palotie, Aarno, Petryshen, Tracey L, Posthuma, Danielle, Rietschel, Marcella, Collier, David A, Riley, Brien P, Rujescu, Dan, Sham, Pak C, Sklar, Pamela, Clair, David St, Weinberger, Daniel R, Wendland, Jens R, Werge, Thomas, Daly, Mark J, Sullivan, Patrick F, Huang, Hailiang, O'Donovan, Michael C, Pers, Tune H, Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Tooley, Katherine, Bacanu, Silviu A, Begemann, Martin, Belliveau, Richard A, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Morris, David L, Buckner, Randy L, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Cairns, Murray J, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Taylor, Kimberly E, Chambert, Kimberly D, Chan, Raymond C K, Chen, Ronald Y L, Chen, Eric Y H, Cheng, Wei, Cheung, Eric F C, Chong, Siow Ann, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Whelan, Christopher W, Cormican, Paul, Craddock, Nick, Crespo-Facorro, Benedicto, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, DeLisi, Lynn E, Tombleson, Philip, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Loohuis, Loes M Olde, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Friedl, Marion, Adult Psychiatry, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Kamitaki, Nolan, Sekar, Aswin, Handsaker, Robert E, de Rivera, Heather, Lee, S Hong, McCarroll, Steven A, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Helsinki University Hospital Area, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, HUS Psychiatry, Department of Psychiatry, Center for Population, Health and Society, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Human genetics, and Amsterdam Reproduction & Development (AR&D)

Subjects
0301 basic medicine, Male, SLE, Sjogren's Syndrome/blood, complement cascade, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, 0302 clinical medicine, MOLECULAR-BASIS, HLA Antigens, Genotype, 2.1 Biological and endogenous factors, Lupus Erythematosus, Systemic, Medicine, Aetiology, SYSTEMIC-LUPUS-ERYTHEMATOSUS, Complement C3/analysis, SUSCEPTIBILITY VARIANTS, RISK, SJOGRENS-SYNDROME, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Complement component 4, Sex Characteristics, Multidisciplinary, Complement C4, Complement C3, HLA Antigens/genetics, Middle Aged, 3. Good health, Complement cascade, Mental Health, Sjogren's Syndrome, genetic association study, Female, ddc:500, Systemic/blood, Biotechnology, Sex characteristics, Adult, General Science & Technology, Lupus, Human leukocyte antigen, Autoimmune Disease, Lupus Erythematosus, Systemic/blood, 03 medical and health sciences, Young Adult, Systemic lupus erythematosus, C4 DEFICIENCY, SDG 3 - Good Health and Well-being, Genetics, Humans, Genetic Predisposition to Disease, Allele, Alleles, Genetic association study, Differential disease vulnerability, Lupus erythematosus, Lupus Erythematosus, business.industry, Inflammatory and immune system, Systemic, Haplotype, C4A, medicine.disease, Brain Disorders, COPY-NUMBER, 030104 developmental biology, Haplotypes, Sjögren’s syndrome, Immunology, Schizophrenia, Complement C4/analysis, AUTOANTIBODIES, 3111 Biomedicine, MHC, business, DEFICIENCY STATES, 030217 neurology & neurosurgery
Abstract

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren’s syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren’s syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3–6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren’s syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren’s syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women’s greater risk of SLE and Sjögren’s syndrome and men’s greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

Published
2020

3. Gene expression imputation across multiple brain regions provides insights into schizophrenia risk

Author

Huckins, Laura M, Dobbyn, Amanda, Ruderfer, Douglas M, Hoffman, Gabriel, Wang, Weiqing, Pardinas, Antonio F, Rajagopal, Veera M, Als, Thomas D, Nguyen, Hoang T, Girdhar, Kiran, Boocock, James, Roussos, Panos, Fromer, Menachem, Kramer, Robin, Domenici, Enrico, Gamazon, Eric R, Purcell, Shaun, Demontis, Ditte, Borglum, Anders D, Walters, James TR, O'Donovan, Michael C, Sullivan, Patrick, Owen, Michael J, Devlin, Bernie, Sieberts, Solveig K, Cox, Nancy J, Im, Hae Kyung, Sklar, Pamela, Stahl, Eli A, Johnson, Jessica S, Shah, Hardik R, Klein, Lambertus L, Dang, Kristen K, Logsdon, Benjamin A, Mahajan, Milind C, Mangravite, Lara M, Toyoshiba, Hiroyoshi, Gur, Raquel E, Hahn, Chang-Gyu, Schadt, Eric, Lewis, David A, Haroutunian, Vahram, Peters, Mette A, Lipska, Barbara K, Buxbaum, Joseph D, Hirai, Keisuke, Perumal, Thanneer M, Essioux, Laurent, Rajagopal, Veera Manikandan, Mattheisen, Manuel, Grove, Jakob, Werge, Thomas, Mortensen, Preben Bo, Pedersen, Carsten Bocker, Agerbo, Esben, Pedersen, Marianne Giortz, Mors, Ole, Nordentoft, Merete, Hougaard, David M, Bybjerg-Grauholm, Jonas, Baekvad-Hansen, Marie, Hansen, Christine Soholm, Ripke, Stephan, Neale, Benjamin M, Corvin, Aiden, Farh, Kai-How, Holmans, Peter A, Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A, Huang, Hailiang, Pers, Tune H, Agartz, Ingrid, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A, Begemann, Martin, Jr, Belliveau Richard A, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberly D, Chan, Raymond CK, Chen, Ronald YL, Chen, Eric YH, Cheng, Wei, Cheung, Eric FC, Chong, Siow Ann, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Fanous, Ayman H, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Friedl, Marion, Friedman, Joseph I, Genovese, Giulio, Georgieva, Lyudmila, Giegling, Ina, Giusti-Rodriguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Hartmann, Annette M, Henskens, Frans A, Herms, Stefan, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V, Ikeda, Masashi, Joa, Inge, Julia, Antonio, Kahn, Rene S, Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C, Kennedy, James L, Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Knowles, James A, Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Kahler, Anna K, Laurent, Claudine, Keong, Jimmy Lee Chee, Lee, S Hong, Legge, Sophie E, Lerer, Bernard, Li, Miaoxin, Li, Tao, Liang, Kung-Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M, Lubinski, Jan, Lonnqvist, Jouko, Jr, Macek Milan, Magnusson, Patrik KE, Maher, Brion S, Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattingsdal, Morten, McCarley, Robert W, McDonald, Colm, McIntosh, Andrew M, Meier, Sandra, Meijer, Carin J, Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I, Metspalu, Andres, Michie, Patricia T, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W, Murphy, Kieran C, Murray, Robin M, Myin-Germeys, Inez, Muller-Myhsok, Bertram, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A, Nestadt, Gerald, Nicodemus, Kristin K, Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, O'Neill, F Anthony, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, Van Os, Jim, Pantelis, Christos, Papadimitriou, George N, Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T, Paunio, Tiina, Pejovic-Milovancevic, Milica, Perkins, Diana O, Pietilainen, Olli, Pimm, Jonathan, Pocklington, Andrew J, Powell, John, Price, Alkes, Pulver, Ann E, Purcell, Shaun M, Quested, Digby, Rasmussen, Henrik B, Reichenberg, Abraham, Reimers, Mark A, Richards, Alexander L, Roffman, Joshua L, Salomaa, Veikko, Sanders, Alan R, Schall, Ulrich, Schubert, Christian R, Schulze, Thomas G, Schwab, Sibylle G, Scolnick, Edward M, Scott, Rodney J, Seidman, Larry J, Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M, Sim, Kang, Slominsky, Petr, Smoller, Jordan W, So, Hon-Cheong, Spencer, Chris CA, Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E, Strengman, Eric, Strohmaier, Jana, Stroup, T Scott, Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M, Szatkiewicz, Jin P, Soderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Veijola, Juha, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T, Weiser, Mark, Wildenauer, Dieter B, Williams, Nigel M, Williams, Stephanie, Witt, Stephanie H, Wolen, Aaron R, Wong, Emily HM, Wormley, Brandon K, Xi, Hualin Simon, Zai, Clement C, Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R, Stefansson, Kari, Visscher, Peter M, Adolfsson, Rolf, Andreassen, Ole A, Blackwood, Douglas HR, Bramon, Elvira, Cichon, Sven, Darvasi, Ariel, Ehrenreich, Hannelore, Esko, Tonu, Gejman, Pablo V, Gill, Michael, Gurling, Hugh, Hultman, Christina M, Iwata, Nakao, Jablensky, Assen V, Jonsson, Erik G, Kendler, Kenneth S, Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F, Li, Qingqin S, Liu, Jianjun, Malhotra, Anil K, McCarroll, Steven A, McQuillin, Andrew, Moran, Jennifer L, Mortensen, Preben B, Mowry, Bryan J, Nothen, Markus M, Ophoff, Roel A, Palotie, Aarno, Pato, Carlos N, Petryshen, Tracey L, Posthuma, Danielle, Rietschel, Marcella, Riley, Brien P, Rujescu, Dan, Sham, Pak C, St Clair, David, Weinberger, Daniel R, Wendland, Jens R, Daly, Mark J, Sullivan, Patrick F, Consortium, CommonMind, Consortium, Psychiat Genomics, Working, iPSYCH-GEMS Schizophrenia, Child and Adolescent Psychiatry / Psychology, ANS - Complex Trait Genetics, APH - Mental Health, Adult Psychiatry, Perceptual and Cognitive Neuroscience (PCN), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Stem Cell Aging Leukemia and Lymphoma (SALL), Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, CommonMind Consortium, Psychiat Genomics Consortium, iPSYCH-GEMS Schizophrenia Working, Huckins, LM, Dobbyn, A, Ruderfer, DM, Hoffman, G, Lee, SH, Im, HK, iPSYCH-GEMS Schizophrenia Working Group, The Schizophrenia Working Group of the PsyUniversity of Copenhagenchiatric Genomics, Amsterdam Reproduction & Development (AR&D), Human genetics, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, and MUMC+: Hersen en Zenuw Centrum (3)

Subjects
DISORDER, Schizophrenia/genetics, iPSYCH-GEMS Schizophrenia Working Group, CHILDHOOD, Gene Expression, Genome-wide association study, VARIANTS, MOUSE, Medical and Health Sciences, ACUTE INTERMITTENT PORPHYRIA, Genome-wide association studies, 0302 clinical medicine, CommonMind Consortium, 2.1 Biological and endogenous factors, Aetiology, Prefrontal cortex, 0303 health sciences, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Schizophrenia Working Group of the PsyUniversity of Copenhagenchiatric Genomics Consortium, Brain, Case-Control Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, Schizophrenia, Transcriptome, Single Nucleotide, ASSOCIATION, Transcriptome/genetics, Biological Sciences, Polymorphism, Single Nucleotide/genetics, Mental Health, Genome-Wide Association Study/methods, Medical genetics, TRAITS, Psychosis, medicine.medical_specialty, Computational biology, Quantitative trait locus, Biology, Article, 03 medical and health sciences, PSYCHOSIS, SDG 3 - Good Health and Well-being, medicine, Genetics, Polymorphism, Transcriptomics, Gene, 030304 developmental biology, Brain/physiopathology, Human Genome, medicine.disease, Brain Disorders, Gene Expression/genetics, COGNITIVE DEFICITS, Expression quantitative trait loci, Human medicine, Gene expression, Quantitative Trait Loci/genetics, 030217 neurology & neurosurgery, Imputation (genetics), Developmental Biology
Abstract

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression. Working Group The Schizophrenia Working Group of the Psychiatric Genomics Consortium Stephan Ripke37,38 Benjamin M. Neale37,38,39,40 Aiden Corvin41 James T. R. Walters6 Kai-How Farh37 Peter A. Holmans6,42 Phil Lee37,38,40 Brendan Bulik-Sullivan37,38 David A. Collier43,44 Hailiang Huang37,39 Tune H. Pers39,45,46 Ingrid Agartz47,48,49 Esben Agerbo8,32,33 Margot Albus50 Madeline Alexander51 Farooq Amin52,53 Silviu A. Bacanu54 Martin Begemann55 Richard A. Belliveau Jr38 Judit Bene56,57 Sarah E. Bergen38,58 Elizabeth Bevilacqua38 Tim B. Bigdeli54 Donald W. Black59 Richard Bruggeman60 Nancy G. Buccola61 Randy L. Buckner62,63,64 William Byerley65 Wiepke Cahn66 Guiqing Cai2,3 Dominique Campion67 Rita M. Cantor10 Vaughan J. Carr68,69 Noa Carrera6 Stanley V. Catts68,70 Kimberly D. Chambert38 Raymond C. K. Chan71 Ronald Y. L. Chen72 Eric Y. H. Chen72,73 Wei Cheng15 Eric F. C. Cheung74 Siow Ann Chong75 C. Robert Cloninger76 David Cohen77 Nadine Cohen78 Paul Cormican41 Nick Craddock6,42 James J. Crowley79 David Curtis80,81 Michael Davidson82 Kenneth L. Davis3 Franziska Degenhardt83,84 Jurgen Del Favero85 Ditte Demontis7,8,9 Dimitris Dikeos86 Timothy Dinan87 Srdjan Djurovic49,88 Gary Donohoe41,89 Elodie Drapeau3 Jubao Duan90,91 Frank Dudbridge92 Naser Durmishi93 Peter Eichhammer94 Johan Eriksson95,96,97 Valentina Escott-Price6 Laurent Essioux98 Ayman H. Fanous99,100,101,102 Martilias S. Farrell79 Josef Frank103 Lude Franke104 Robert Freedman105 Nelson B. Freimer106 Marion Friedl107 Joseph I. Friedman3 Menachem Fromer1,37,38,40 Giulio Genovese38 Lyudmila Georgieva6 Ina Giegling107,108 Paola Giusti-Rodríguez79 Stephanie Godard109 Jacqueline I. Goldstein37,39 Vera Golimbet110 Srihari Gopal111 Jacob Gratten112 Lieuwe de Haan113 Christian Hammer55 Marian L. Hamshere6 Mark Hansen114 Thomas Hansen8,30 Vahram Haroutunian3,25,23 Annette M. Hartmann107 Frans A. Henskens68,115,116 Stefan Herms83,84,117 Joel N. Hirschhorn39,46,118 Per Hoffmann83,84,117 Andrea Hofman83,84 Mads V. Hollegaard36 David M. Hougaard36 Masashi Ikeda119 Inge Joa120 Antonio Julia121 Rene S. Kahn66 Luba Kalaydjieva122,123 Sena Karachanak-Yankova124 Juha Karjalainen104 David Kavanagh6 Matthew C. Keller125 James L. Kennedy126,127,128 Andrey Khrunin129 Yunjung Kim79 Janis Klovins130 James A. Knowles131 Bettina Konte107 Vaidutis Kucinskas132 Zita Ausrele Kucinskiene132 Hana Kuzelova-Ptackova133 Anna K. Kahler58 Claudine Laurent51,134 Jimmy Lee Chee Keong75,135 S. Hong Lee112 Sophie E. Legge6 Bernard Lerer136 Miaoxin Li72,73,137 Tao Li138 Kung-Yee Liang139 Jeffrey Lieberman140 Svetlana Limborska129 Carmel M. Loughland68,141 Jan Lubinski142 Jouko Lonnqvist143 Milan Macek Jr133 Patrik K. E. Magnusson58 Brion S. Maher144 Wolfgang Maier145 Jacques Mallet146 Sara Marsal121 Manuel Mattheisen7,8,9,147 Morten Mattingsdal49,148 Robert W. McCarley149,150 Colm McDonald151 Andrew M. McIntosh152,153 Sandra Meier103 Carin J. Meijer113 Bela Melegh56,57 Ingrid Melle49,154 Raquelle I. Mesholam-Gately149,155 Andres Metspalu156 Patricia T. Michie68,157 Lili Milani156 Vihra Milanova158 Younes Mokrab43 Derek W. Morris41,89 Ole Mors8,9,159 Kieran C. Murphy160 Robin M. Murray161 Inez Myin-Germeys162 Bertram Muller-Myhsok163,164,165 Mari Nelis156 Igor Nenadic166 Deborah A. Nertney167 Gerald Nestadt168 Kristin K. Nicodemus169 Liene Nikitina-Zake130 Laura Nisenbaum170 Annelie Nordin171 Eadbhard O’Callaghan172 Colm O’Dushlaine38 F. Anthony O’Neill173 Sang-Yun Oh174 Ann Olincy126 Line Olsen8,64 Jim Van Os162,175 Christos Pantelis68,176 George N. Papadimitriou86 Sergi Papiol55 Elena Parkhomenko3 Michele T. Pato131 Tiina Paunio177,178 Milica Pejovic-Milovancevic179 Diana O. Perkins180 Olli Pietiläinen178,181 Jonathan Pimm81 Andrew J. Pocklington6 John Powell161 Alkes Price39,182 Ann E. Pulver168 Shaun M. Purcell1 Digby Quested183 Henrik B. Rasmussen30,43 Abraham Reichenberg3 Mark A. Reimers184 Alexander L. Richards6 Joshua L. Roffman62,64 Panos Roussos1,4 Douglas M. Ruderfer1,5,6 Veikko Salomaa97 Alan R. Sanders90,91 Ulrich Schall68,141 Christian R. Schubert185 Thomas G. Schulze103,186 Sibylle G. Schwab187 Edward M. Scolnick38 Rodney J. Scott68,188,189 Larry J. Seidman144,155 Jianxin Shi190 Engilbert Sigurdsson191 Teimuraz Silagadze192 Jeremy M. Silverman3,193 Kang Sim75 Petr Slominsky129 Jordan W. Smoller38,40 Hon-Cheong So72 Chris C. A. Spencer194 Eli A. Stahl1,2,3,4 Hreinn Stefansson195 Stacy Steinberg195 Elisabeth Stogmann196 Richard E. Straub197 Eric Strengman66,198 Jana Strohmaier103 T. Scott Stroup140 Mythily Subramaniam75 Jaana Suvisaari143 Dragan M. Svrakic76 Jin P. Szatkiewicz79 Erik Soderman47 Srinivas Thirumalai199 Draga Toncheva124 Sarah Tosato200 Juha Veijola201,202 John Waddington203 Dermot Walsh204 Dai Wang111 Qiang Wang138 Bradley T. Webb54 Mark Weiser82 Dieter B. Wildenauer205 Nigel M. Williams6 Stephanie Williams79 Stephanie H. Witt103 Aaron R. Wolen184 Emily H. M. Wong72 Brandon K. Wormley54 Hualin Simon Xi206 Clement C. Zai126,127 Xuebin Zheng207 Fritz Zimprich196 Naomi R. Wray112 Kari Stefansson195 Peter M. Visscher112 Rolf Adolfsson171 Ole A. Andreassen49,154 Douglas H. R. Blackwood153 Elvira Bramon208 Joseph D. Buxbaum2,3,24,25 Anders D. Børglum7,8,9,159 Sven Cichon83,84,117,209 Ariel Darvasi210 Enrico Domenici211 Hannelore Ehrenreich55 Tonu Esko39,46,118,156 Pablo V. Gejman90,91 Michael Gill41 Hugh Gurling81 Christina M. Hultman58 Nakao Iwata119 Assen V. Jablensky68,123,205,212 Erik G. Jonsson47,49 Kenneth S. Kendler213 George Kirov6 Jo Knight125,127,128 Todd Lencz214,215,216 Douglas F. Levinson51 Qingqin S. Li111 Jianjun Liu207,217 Anil K. Malhotra214,215,216 Steven A. McCarroll38,118 Andrew McQuillin81 Jennifer L. Moran38 Preben B. Mortensen8,32,33 Bryan J. Mowry112,218 Markus M. Nothen83,84 Roel A. Ophoff10,66,105 Michael J. Owen6,42 Aarno Palotie38,40,181 Carlos N. Pato131 Tracey L. Petryshen38,149,219 Danielle Posthuma220,221,222 Marcella Rietschel103 Brien P. Riley213 Dan Rujescu107,108 Pak C. Sham72,73,137 Pamela Sklar1,2,3,4,25 David St Clair223 Daniel R. Weinberger197,224 Jens R. Wendland185 Thomas Werge8,30,225 Mark J. Daly37,38,39 Patrick F. Sullivan58,79,180 Michael C. O’Donovan6,42 20Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan. 21Neuropsychiatry Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 22Neuropsychiatric Signaling Program, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 23Psychiatry, JJ Peters Virginia Medical Center, Bronx, NY, USA. 24Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA. 25Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 26Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 27CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan. 28F. Hoffman-La Roche Ltd, Basel, Switzerland. 29Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark. 30Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark. 31Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. 32National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark. 33Centre for Integrated Registerbased Research, Aarhus University, Aarhus, Denmark. 34Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark. 35Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark. 36Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark. 37Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. 38Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 39Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 40Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. 41Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland. 42NationalCentre for Mental Health, Cardiff University, Cardiff, UK. 43Eli Lilly and Company Limited, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, UK. 44Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, London, UK. 45Center for BiologicalSequence Analysis, Department of Systems Biology, Technical University of Denmark, Kongens Lyngby, Denmark. 46Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA, USA. 47Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden. 48Department of Psychiatry, Diakonhjemmet Hospital, Oslo, Norway. 49NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 50State Mental Hospital, Haar, Germany. 51Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. 52Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, Atlanta, GA, USA. 53Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA. 54Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA. 55Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Gottingen, Germany. 56Department of Medical Genetics, University of Pécs, Pécs, Hungary. 57Szentagothai Research Center, University of Pécs, Pécs, Hungary. 58Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 59Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA. 60University Medical Center Groningen, Department of Psychiatry, University of Groningen, Groningen, the Netherlands. 61School of Nursing, Louisiana State University Health Sciences Center, New Orleans, LA, USA. 62Athinoula A. Martinos Center, Massachusetts General Hospital, Boston, MA, USA. 63Center for Brain Science, Harvard University, Cambridge, MA, USA. 64Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. 65Department of Psychiatry, University of California at San Francisco, San Francisco, CA, USA. 66University Medical Center Utrecht, Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, Utrecht, the Netherlands. 67Centre Hospitalier du Rouvray and INSERM U1079 Faculty of Medicine, Rouen, France. 68Schizophrenia Research Institute, Sydney, New South Wales, Australia. 69School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia. 70Royal Brisbane and Women’s Hospital, University of Queensland, Brisbane, Queensland, Australia. 71Institute of Psychology, Chinese Academy of Science, Beijing, China. 72Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. 73State Key Laboratory for Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. 74Castle Peak Hospital, Hong Kong, China. 75Institute of Mental Health, Singapore, Singapore. 76Department of Psychiatry, Washington University, St. Louis, MO, USA. 77Department of Child and Adolescent Psychiatry, Assistance Publique Hopitaux de Paris, Pierre and Marie Curie Faculty of Medicine and Institute for Intelligent Systems and Robotics, Paris, France. 78Blue Note Biosciences, Princeton, NJ, USA. 79Department of Genetics, University of North Carolina, Chapel Hill, NC, USA. 80Department of Psychological Medicine, Queen Mary University of London, London, UK. 81Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK. 82Sheba Medical Center, Tel Hashomer, Israel. 83Department of Genomics, Life and Brain Center, Bonn, Germany. 84Institute of Human Genetics, University of Bonn, Bonn, Germany. 85AppliedMolecular Genomics Unit, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium. 86First Department of Psychiatry, University of Athens Medical School, Athens, Greece. 87Department of Psychiatry, University College Cork, Co, Cork, Ireland. 88Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. 89Cognitive Genetics and Therapy Group, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Co, Galway, Ireland. 90Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA. 91Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, IL, USA. 92Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK. 93Department of Child and Adolescent Psychiatry, University Clinic of Psychiatry, Skopje, Republic of Macedonia. 94Department of Psychiatry, University of Regensburg, Regensburg, Germany. 95Department of General Practice, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland. 96Folkhälsan Research Center, Helsinki, Finland, Biomedicum Helsinki, Helsinki, Finland. 97National Institute for Health and Welfare, Helsinki, Finland. 98Translational Technologies and Bioinformatics, Pharma Research and Early Development, F. Hoffman-La Roche, Basel, Switzerland. 99Department of Psychiatry, Georgetown University School of Medicine, Washington, DC, USA. 100Department of Psychiatry, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. 101Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. 102Mental Health Service Line, Washington VA Medical Center, Washington, DC, USA. 103Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Mannheim, Germany. 104Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands. 105Department of Psychiatry, University of Colorado Denver, Aurora, CO, USA. 106Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA. 107Department of Psychiatry, University of Halle, Halle, Germany. 108Department of Psychiatry, University of Munich, Munich, Germany. 109Departments of Psychiatry and Human and Molecular Genetics, INSERM, Institut de Myologie, Hôpital de la Pitiè-Salpêtrière, Paris, France. 110Mental Health Research Centre, Russian Academy of Medical Sciences, Moscow, Russia. 111Neuroscience Therapeutic Area, Janssen Research and Development, Raritan, NJ, USA. 112Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. 113Academic Medical Centre University of Amsterdam, Department of Psychiatry, Amsterdam, the Netherlands. 114Illumina, La Jolla, CA, USA. 115Priority Research Centre for Health Behaviour, University of Newcastle, Newcastle, New South Wales, Australia. 116School of Electrical Engineering and Computer Science, University of Newcastle, Newcastle, New South Wales, Australia. 117Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland. 118Department of Genetics, Harvard Medical School, Boston, MA, USA. 119Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan. 120Regional Centre for Clinical Researchin Psychosis, Department of Psychiatry, Stavanger University Hospital, Stavanger, Norway. 121Rheumatology Research Group, Vall d’Hebron Research Institute, Barcelona, Spain. 122Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia. 123The Perkins Institute for Medical Research, The University of Western Australia, Perth, Western Australia, Australia. 124Department of Medical Genetics, Medical University, Sofia, Bulgaria. 125Department of Psychology, University of Colorado Boulder, Boulder, CO, USA. 126Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. 127Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. 128Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. 129Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia. 130Latvian Biomedical Research and Study Centre, Riga, Latvia. 131Department of Psychiatry and Zilkha Neurogenetics Institute, Keck School of Medicine at University of Southern California, Los Angeles, CA, USA. 132Faculty of Medicine, Vilnius University, Vilnius, Lithuania. 133Department of Biology and Medical Genetics, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic. 134Department of Child and Adolescent Psychiatry, Pierre and Marie Curie Faculty of Medicine, Paris, France. 135Duke-NUS Graduate Medical School, Singapore, Singapore. 136Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 137Centre for Genomic Sciences, The University of Hong Kong, Hong Kong, China. 138Mental Health Centre and Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, China. 139Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA. 140Department of Psychiatry, Columbia University, New York, New York, NY, USA. 141Priority Centre for Translational Neuroscience and Mental Health, University of Newcastle, Newcastle, New South Wales, Australia. 142Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, Szczecin, Poland. 143Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland. 144Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. 145Department of Psychiatry, University of Bonn, Bonn, Germany. 146Centre National de la Recherche Scientifique, Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodénégératifs, Hôpital de la Pitiè-Salpêtrière, Paris, France. 147Department of Genomics Mathematics, University of Bonn, Bonn, Germany. 148Research Unit, Sørlandet Hospital, Kristiansand, Norway. 149Department of Psychiatry, Harvard Medical School, Boston, MA, USA. 150VA Boston Health Care System, Brockton, MA, USA. 151Department of Psychiatry, National University of Ireland Galway, Co, Galway, Ireland. 152Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK. 153Division of Psychiatry, University of Edinburgh, Edinburgh, UK. 154Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. 155Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston, MA, USA. 156Estonian Genome Center, University of Tartu, Tartu, Estonia. 157School of Psychology, University of Newcastle, Newcastle, New South Wales, Australia. 158First Psychiatric Clinic, Medical University, Sofia, Bulgaria. 159Department P, Aarhus University Hospital, Risskov, Denmark. 160Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland. 161King’s College London, London, UK. 162Maastricht University Medical Centre, South Limburg Mental Health Research and TeachingNetwork, EURON, Maastricht, the Netherlands. 163Institute of Translational Medicine, University of Liverpool, Liverpool, UK. 164Max Planck Institute of Psychiatry, Munich, Germany. 165Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. 166Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. 167Department of Psychiatry, Queensland Brain Institute and Queensland Centre for Mental Health Research, University of Queensland, Brisbane, Queensland, Australia. 168Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 169Department of Psychiatry, Trinity College Dublin, Dublin, Ireland. 170Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA. 171Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden. 172DETECT Early Intervention Service for Psychosis, Blackrock, Co, Dublin, Ireland. 173Centre for Public Health, Institute of Clinical Sciences, Queen’s University Belfast, Belfast, UK. 174Lawrence Berkeley National Laboratory, University of California at Berkeley, Berkeley, CA, USA. 175Institute of Psychiatry, King’s College London, London, UK. 176Melbourne Neuropsychiatry Centre, University of Melbourne & Melbourne Health, Melbourne, Victoria, Australia. 177Department of Psychiatry, University of Helsinki, Helsinki, Finland. 178Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland. 179Medical Faculty, University of Belgrade, Belgrade, Serbia. 180Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA. 181Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland. 182Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA. 183Department of Psychiatry, University of Oxford, Oxford, UK. 184Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA. 185Pharma Therapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, USA. 186Department of Psychiatry and Psychotherapy, University of Gottingen, Göttingen, Germany. 187Psychiatry and Psychotherapy Clinic, University of Erlangen, Erlangen, Germany. 188Hunter New England Health Service, Newcastle, New South Wales, Australia. 189School of Biomedical Sciences, University of Newcastle, Newcastle, New South Wales, Australia. 190Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. 191University of Iceland, Landspitali, National University Hospital, Reykjavik, Iceland. 192Department of Psychiatry and Drug Addiction, Tbilisi State Medical University (TSMU), Tbilisi, Georgia. 193Research and Development, Bronx Veterans Affairs Medical Center, New York, NY, USA. 194WellcomeTrust Centre for Human Genetics, Oxford, UK. 195deCODE Genetics, Reykjavik, Iceland. 196Department of Clinical Neurology, Medical University of Vienna, Wien, Austria. 197Lieber Institute for Brain Development, Baltimore, MD, USA. 198Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands. 199Berkshire Healthcare NHS Foundation Trust, Bracknell, UK. 200Section of Psychiatry, University of Verona, Verona, Italy. 201Department of Psychiatry, University of Oulu, Oulu, Finland. 202University Hospital of Oulu, Oulu, Finland. 203Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland. 204Health Research Board, Dublin, Ireland. 205School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, Western Australia, Australia. 206Computational Sciences CoE, Pfizer Worldwide Research and Development, Cambridge, MA, USA. 207Human Genetics, Genome Institute of Singapore, A*STAR, Singapore, Singapore. 208University College London, London, UK. 209Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany. 210Department of Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel. 211NeuroscienceDiscovery and Translational Area, Pharma Research and Early Development, F. Hoffman-La Roche, Basel, Switzerland. 212Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Medical Research Foundation Building, Perth, Western Australia, Australia. 213Virginia Institute for Psychiatric and Behavioral Genetics, Departments of Psychiatry and Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA. 214The Feinstein Institute for Medical Research, Manhasset, NY, USA. 215The Hofstra NS-LIJ School of Medicine, Hempstead, NY, USA. 216The Zucker Hillside Hospital, Glen Oaks, NY, USA. 217Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore. 218Queensland Centre for Mental Health Research, University of Queensland, Brisbane, Queensland, Australia. 219Center for HumanGenetic Research and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. 220Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre, Rotterdam, the Netherlands. 221Department of Complex Trait Genetics, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, Amsterdam, the Netherlands. 222Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands. 223University of Aberdeen, Institute of Medical Sciences, Aberdeen, UK. 224Departments of Psychiatry, Neurology, Neuroscience and Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA. 225Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

Published
2019

4. Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept

Author

Franke, Barbara, Stein, Jason L, McIntosh, Andrew M, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Lee, Phil, Friedman, Joseph I, Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Gershon, Elliot S, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Gopal, Srihari, McMahon, Francis J, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Henskens, Frans A, Herms, Stefan L, Meyer-Lindenberg, Andreas, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V, Hougaard, David M, Ikeda, Masashi, Joa, Inge, Julià, Antonio, Kähler, Anna K, Kahn, René S, Mattheisen, Manuel, Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C, Kelly, Brian J, Kennedy, James L, Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Andreassen, Ole A, Knowles, James A, Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Laurent, Claudine, Lee, S Hong, Keong, Jimmy Lee Chee, Legge, Sophie E, Lerer, Bernard, Gruber, Oliver, Li, Miaoxin, Li, Tao, Liang, Kung-Yee, Lieberman, Jeffrey, Limborska, Svetlana, Lönnqvist, Jouko, Loughland, Carmel M, Lubinski, Jan, Macek, Milan, Magnusson, Patrik K E, Sachdev, Perminder S, Maher, Brion S, Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattingsdal, Morten, McCarley, Robert W, McDonald, Colm, Meier, Sandra, Roiz-Santiañez, Roberto, Meijer, Carin J, Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I, Metspalu, Andres, Michie, Patricia T, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W, Saykin, Andrew J, Mors, Ole, Müller-Myhsok, Bertram, Murphy, Kieran C, Murray, Robin M, Myin-Germeys, Inez, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A, Nestadt, Gerald, Nicodemus, Kristin K, Ripke, Stephan, Ehrlich, Stefan, Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, O'Neill, F Anthony, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, Van Os, Jim, Mather, Karen A, Pantelis, Christos, Papadimitriou, George N, Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T, Paunio, Tiina, Perkins, Diana O, Pietiläinen, Olli, Pimm, Jonathan, Pocklington, Andrew J, Turner, Jessica A, Powell, John, Price, Alkes, Pulver, Ann E, Purcell, Shaun M, Quested, Digby, Rasmussen, Henrik B, Reichenberg, Abraham, Reimers, Mark A, Richards, Alexander L, Roffman, Joshua L, Schwarz, Emanuel, Roussos, Panos, Ruderfer, Douglas M, Salomaa, Veikko, Sanders, Alan R, Schall, Ulrich, Schubert, Christian R, Schulze, Thomas G, Schwab, Sibylle G, Scolnick, Edward M, Scott, Rodney J, Thalamuthu, Anbupalam, Seidman, Larry J, Shi, Jianxin, Silverman, Jeremy M, Sim, Kang, Slominsky, Petr, Smoller, Jordan W, So, Hon-Cheong, Söderman, Erik, Spencer, Chris C A, Stahl, Eli A, Shugart, Yin Yao, Stogmann, Elisabeth, Straub, Richard E, Strengman, Eric, Strohmaier, Jana, Stroup, T Scott, Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M, Szatkiewicz, Jin P, Thirumalai, Srinivas, Ho, Yvonne Yw, Toncheva, Draga, Tooney, Paul A, Veijola, Juha, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T, Weiser, Mark, Wildenauer, Dieter B, Martin, Nicholas G, Williams, Nigel M, Williams, Stephanie, Witt, Stephanie H, Wolen, Aaron R, Wong, Emily H M, Wormley, Brandon K, Wu, Jing Qin, Xi, Hualin Simon, Zai, Clement C, Zheng, Xuebin, Wright, Margaret J, Zimprich, Fritz, Wray, Naomi R, Visscher, Peter M, Adolfsson, Rolf, Blackwood, Douglas H R, Børglum, Anders D, Bramon, Elvira, Buxbaum, Joseph D, Cichon, Sven, Consortium, Schizophrenia Working Group of the Psychiatric Genomics, Darvasi, Ariel, Domenici, Enrico, Ehrenreich, Hannelore, Esko, Tõnu, Gejman, Pablo V, Gill, Michael, Gurling, Hugh, Hultman, Christina M, Iwata, Nakao, Jablensky, Assen V, Anttila, Verneri, Consortium, ENIGMA, Jönsson, Erik G, Kendler, Kenneth S, Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F, Li, Qingqin S, Liu, Jianjun, Malhotra, Anil K, McCarroll, Steven A, O'Donovan, Michael C, McQuillin, Andrew, Moran, Jennifer L, Mortensen, Preben B, Mowry, Bryan J, Nöthen, Markus M, Ophoff, Roel A, Owen, Michael J, Palotie, Aarno, Pato, Carlos N, Petryshen, Tracey L, Thompson, Paul M, Posthuma, Danielle, Rietschel, Marcella, Riley, Brien P, Rujescu, Dan, Sham, Pak C, Sklar, Pamela, Clair, David St, Weinberger, Daniel R, Wendland, Jens R, Werge, Thomas, Neale, Benjamin M, Daly, Mark J, Sullivan, Patrick F, Hibar, Derrek P, Renteria, Miguel E, Arias-Vasquez, Alejandro, Desrivières, Sylvane, Jahanshad, Neda, Toro, Roberto, Medland, Sarah E, Wittfeld, Katharina, Abramovic, Lucija, Andersson, Micael, Aribisala, Benjamin S, Armstrong, Nicola J, Bernard, Manon, Bohlken, Marc M, Boks, Marco P, Bralten, Janita, Brown, Andrew A, Chakravarty, M Mallar, Chen, Qiang, Ching, Christopher R K, Cuellar-Partida, Gabriel, den Braber, Anouk, Giddaluru, Sudheer, Goldman, Aaron L, Grimm, Oliver, Guadalupe, Tulio, Hass, Johanna, Woldehawariat, Girma, Holmes, Avram J, Hoogman, Martine, Janowitz, Deborah, Jia, Tianye, Kim, Sungeun, Klein, Marieke, Kraemer, Bernd, Loohuis, Loes M Olde, Luciano, Michelle, Macare, Christine, Milaneschi, Yuri, Nho, Kwangsik, Papmeyer, Martina, Ramasamy, Adaikalavan, Risacher, Shannon L, Corvin, Aiden, Rose, Emma J, Salami, Alireza, Sämann, Philipp G, Schmaal, Lianne, Schork, Andrew J, Shin, Jean, Strike, Lachlan T, Teumer, Alexander, van Donkelaar, Marjolein M J, van Eijk, Kristel R, Walters, James T R, Walters, Raymond K, Westlye, Lars T, Whelan, Christopher D, Winkler, Anderson M, Zwiers, Marcel P, Alhusaini, Saud, Athanasiu, Lavinia, Hakobjan, Marina M H, Hartberg, Cecilie B, Farh, Kai-How, Haukvik, Unn, Heister, Angelien J G A M, Höhn, David, Kasperaviciute, Dalia, Liewald, David C M, Lopez, Lorna M, Makkinje, Remco R R, Matarin, Mar, Naber, Marlies A M, McKay, David R, Holmans, Peter A, Needham, Margaret, Nugent, Allison C, Pütz, Benno, Royle, Natalie A, Shen, Li, Sprooten, Emma, Trabzuni, Daniah, van der Marel, Saskia S L, van Hulzen, Kimm J E, Walton, Esther, Wolf, Christiane, Almasy, Laura, Ames, David, Arepalli, Sampath, Assareh, Amelia A, Bastin, Mark E, Brodaty, Henry, Bulayeva, Kazima B, Carless, Melanie A, Bulik-Sullivan, Brendan, Curran, Joanne E, Czisch, Michael, de Zubicaray, Greig I, Dillman, Allissa, Duggirala, Ravi, Dyer, Thomas D, Erk, Susanne, Fedko, Iryna O, Ferrucci, Luigi, Collier, David A, Foroud, Tatiana M, Fox, Peter T, Fukunaga, Masaki, Gibbs, Raphael, Göring, Harald H H, Green, Robert C, Guelfi, Sebastian, Hansell, Narelle K, Hartman, Catharina A, Hegenscheid, Katrin, Huang, Hailiang, Heinz, Andreas, Hernandez, Dena G, Heslenfeld, Dirk J, Hoekstra, Pieter J, Holsboer, Florian, Homuth, Georg, Hottenga, Jouke-Jan, Jack, Clifford R, Jenkinson, Mark, Pers, Tune H, Johnson, Robert, Kanai, Ryota, Keil, Maria, Kent, Jack W, Kochunov, Peter, Kwok, John B, Lawrie, Stephen M, Liu, Xinmin, Longo, Dan L, McMahon, Katie L, Agartz, Ingrid, Meisenzahl, Eva, Mohnke, Sebastian, Montgomery, Grant W, Mostert, Jeanette C, Mühleisen, Thomas W, Nalls, Michael A, Nichols, Thomas E, Nilsson, Lars G, Agerbo, Esben, Ohi, Kazutaka, Olvera, Rene L, Perez-Iglesias, Rocio, Pike, G Bruce, Potkin, Steven G, Reinvang, Ivar, Reppermund, Simone, Romanczuk-Seiferth, Nina, Rosen, Glenn D, Albus, Margot, Schnell, Knut, Schofield, Peter R, Smith, Colin, Steen, Vidar M, Sussmann, Jessika E, Toga, Arthur W, Traynor, Bryan, Troncoso, Juan, Alexander, Madeline, Hernández, Maria C Valdés, van 't Ent, Dennis, van der Brug, Marcel, van der Wee, Nic J A, van Tol, Marie-Jose, Veltman, Dick J, Wassink, Thomas H, Westman, Eric, Zielke, Ronald H, Amin, Farooq, Zonderman, Alan, Ashbrook, David G, Hager, Reinmar, Lu, Lu, Williams, Robert W, Brunner, Han G, Buckner, Randy L, Buitelaar, Jan K, Bacanu, Silviu A, Cahn, Wiepke, Calhoun, Vince D, Cavalleri, Gianpiero L, Crespo-Facorro, Benedicto, Dale, Anders M, Davies, Gareth E, Delanty, Norman, Depondt, Chantal, Djurovic, Srdjan, Drevets, Wayne C, Begemann, Martin, Espeseth, Thomas, Gollub, Randy L, Ho, Beng-Choon, Hoffmann, Wolfgang, Hosten, Norbert, LeHellard, Stephanie, Nauck, Matthias, Belliveau, Richard A, Nyberg, Lars, Pandolfo, Massimo, Penninx, Brenda W J H, Sisodiya, Sanjay M, van Bokhoven, Hans, van Haren, Neeltje E M, Völzke, Henry, Walter, Henrik, Bene, Judit, Weiner, Michael W, Wen, Wei, White, Tonya, Blangero, John, Boomsma, Dorret I, Brouwer, Rachel M, Cannon, Dara M, Cookson, Mark R, Bergen, Sarah E, de Geus, Eco J C, Deary, Ian J, Donohoe, Gary, Fernández, Guillén, Fisher, Simon E, Francks, Clyde, Glahn, David C, Grabe, Hans J, Hardy, John, Bevilacqua, Elizabeth, Hashimoto, Ryota, Hulshoff Pol, Hilleke E, Kloszewska, Iwona, Lovestone, Simon, Mattay, Venkata S, Mecocci, Patrizia, Bigdeli, Tim B, Paus, Tomas, Pausova, Zdenka, Ryten, Mina, Simmons, Andy, Singleton, Andrew, Soininen, Hilkka, Wardlaw, Joanna M, Weale, Michael E, Black, Donald W, Adams, Hieab H H, Launer, Lenore J, Seiler, Stephan, Schmidt, Reinhold, Chauhan, Ganesh, Satizabal, Claudia L, Becker, James T, Yanek, Lisa, van der Lee, Sven J, Bruggeman, Richard, Ebling, Maritza, Fischl, Bruce, Longstreth, W. T., Greve, Douglas, Schmidt, Helena, Nyquist, Paul, Vinke, Louis N, van Duijn, Cornelia M, Luting, Xue, Mazoyer, Bernard, Buccola, Nancy G, Bis, Joshua C, Gudnason, Vilmundur, Seshadri, Sudha, Ikram, M Arfan, Schumann, Gunter, Byerley, William F, Cai, Guiqing, Cairns, Murray J, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberley D, Chan, Raymond C K, Chen, Eric Y H, Chen, Ronald Y L, Cheng, Wei, Cheung, Eric F C, Chong, Siow Ann, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Neale, Michael C, Del Favero, Jurgen, DeLisi, Lynn E, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Franke, Barbara, Stein, Jason L, Ripke, Stephan, Anttila, Verneri, Hong Lee, S, Ikram, M Arfan, Schizophrenia Working Group of the Psychiatric Genomics Consortium, ENIGMA Consortium, Radboud University Medical Center [Nijmegen], University of Southern California (USC), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], University of Warwick [Coventry], University of Oxford [Oxford], Virginia Commonwealth University (VCU), University of Edinburgh, National Institutes of Health [Bethesda] (NIH), Chinese PLA General Hospital, University of Missouri [Columbia], University of Missouri System, Cardiff University, Aarhus University [Aarhus], Stanford University [Stanford], Max-Planck-Institut, University of Iowa [Iowa City], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Schizophrenia Research Institute [Sydney], Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Mathematics [CUHK], The Chinese University of Hong Kong [Hong Kong], The University of Hong Kong (HKU), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Castle Peak Hospital [Hong Kong], Institute of Mental Health [Singapore], Service de psychiatrie des enfants et adultes [CHU Pitié-Salpêtrière ], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Queen Mary University of London (QMUL), Open University of Israël, University of Antwerp (UA), Harvard Medical School [Boston] (HMS), University of Athens Medical School [Athens], University College Cork (UCC), University of Oslo (UiO), London School of Hygiene and Tropical Medicine (LSHTM), Universität Regensburg (UR), Biomedicum Helsinki, Roche Pharma Research and Early Development [Basel] (pRED), F. Hoffmann-La Roche [Basel], Universität Heidelberg [Heidelberg], University Medical Center Groningen [Groningen] (UMCG), Haverford College, Service de Pharmacologie, toxicologie et pharmacovigilance [CHU Limoges], CHU Limoges, University of Queensland [Brisbane], James J. Peters VA Medical Center [New York], Martin-Luther-University Halle-Wittenberg, University of Newcastle [Australia] (UoN), University of Basel (Unibas), Division of Medical Genetics [Seattle], University of Washington [Seattle], Statens Serum Institut [Copenhagen], Tohoku University [Sendai], University of Stavanger, Institut de biologie structurale (IBS - UMR 5075), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), University of Sofia, Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), Universität Stuttgart [Stuttgart], Russian Academy of Sciences [Moscow] (RAS), Latvian Biomedical Research and Study Centre [Rīga], Vilnius University [Vilnius], University Hospital Motol [Prague], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hadassah Hebrew University Medical Center [Jerusalem], Karolinska Institutet [Stockholm], University of Bonn, Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Vall d'Hebron University Hospital [Barcelona], Department of Life Sciences, Imperial College London, Deutscher Wetterdienst [Offenbach] (DWD), Eli Lilly and Company Limited [Windlesham], Trinity College Dublin, Royal College of Surgeons in Ireland (RCSI), Université de Lausanne (UNIL), University of Tartu, Johns Hopkins University School of Medicine [Baltimore], Stockholm University, Queen's University [Belfast] (QUB), Lawrence Berkeley National Laboratory [Berkeley] (LBNL), Universidade de São Paulo (USP), Department of Mathematics [Nanticoke], Luzerne County Community College, National Institute for Health and Welfare [Helsinki], King‘s College London, University of Chicago, Fraunhofer Heinrich Hertz Institute [Berlin] (HHI), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), National Cancer Institute [Bethesda] (NCI-NIH), The Wellcome Trust Centre for Human Genetics [Oxford], Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, The Natural History Museum [London] (NHM), University of Calgary, Department of Medical Epidemiology and Biostatistics (MEB), The University of Western Australia (UWA), Rheinische Friedrich-Wilhelms-Universität Bonn, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Montreal Neurological Institute and Hospital, McGill University, Universidade do Algarve (UAlg), Beijing Normal University, Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Dpt of Psychiatry [New Haven], Yale University School of Medicine, Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Bijvoet Center of Biomolecular Research, Utrecht University [Utrecht], School of Psychology, University of Queensland, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Department of Mathematics, University of Colorado, University of Colorado [Boulder], VU University Amsterdam, Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Health and Human Services, McConnell Brain Imaging Centre (MNI), McGill University-McGill University, Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Computer Science and Artificial Intelligence Laboratory [Cambridge] (CSAIL), Massachusetts Institute of Technology (MIT), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Del-Favero, Jurgen, Enigma Consortium, School of Medicine / Clinical Medicine, University of Oxford, University of Missouri [Columbia] (Mizzou), Stanford University, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universität Heidelberg [Heidelberg] = Heidelberg University, University of Newcastle [Callaghan, Australia] (UoN), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Софийски университет = Sofia University, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universität Bonn = University of Bonn, Université de Lausanne = University of Lausanne (UNIL), Universidade de São Paulo = University of São Paulo (USP), Fraunhofer Institute for Telecommunications - Heinrich Hertz Institute (Fraunhofer HHI), Fraunhofer (Fraunhofer-Gesellschaft), Universität Heidelberg [Heidelberg] = Heidelberg University-Central Institute of Mental Health Mannheim, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), McGill University = Université McGill [Montréal, Canada], Beijing Normal University (BNU), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Yale School of Medicine [New Haven, Connecticut] (YSM), Centre épigénétique et destin cellulaire (EDC), Bijvoet Center of Biomolecular Research [Utrecht], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Vrije Universiteit Amsterdam [Amsterdam] (VU), McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Biological Psychology, EMGO+ - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Other departments, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, Adult Psychiatry, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, MUMC+: MA Psychiatrie (3), and MUMC+: Hersen en Zenuw Centrum (3)

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), genetic association, Genome-wide association study, brain imaging, VARIANTS, Genome-wide association studies, Linkage Disequilibrium, 0302 clinical medicine, pathology [Brain], 2.1 Biological and endogenous factors, Psychology, GWAS, genetics [Schizophrenia], genetics, genetics [Genetic Predisposition to Disease], Aetiology, Non-U.S. Gov't, PERSPECTIVE, humans, Schizophrenia Working Group of the Psychiatric Genomics Consortium, neuroimaging, General Neuroscience, Research Support, Non-U.S. Gov't, Brain, Single Nucleotide, Organ Size, Endophenotypes, Genetic Predisposition to Disease, Humans, Magnetic Resonance Imaging, Neuroimaging, Polymorphism, Single Nucleotide, Schizophrenia, Genome-Wide Association Study, Neuroscience (all), Serious Mental Illness, ENIGMA Consortium, 3. Good health, endophenotype, Mental Health, Meta-analysis, Neurological, genetics [Polymorphism, Single Nucleotide], Cognitive Sciences, MRI, Neuroinformatics, DISORDERS, heredity, Schizophrenia (object-oriented programming), brain, Non-P.H.S, Brain Structure and Function, RELATIVES, PHENOTYPES, Research Support, N.I.H, 03 medical and health sciences, Magnetic resonance imaging, ENDOPHENOTYPE, Research Support, N.I.H., Extramural, ddc:570, Journal Article, Polymorphism, GENOME-WIDE ASSOCIATION, pathology [Schizophrenia], METAANALYSIS, genetic predisposition to disease, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Neurology & Neurosurgery, genome-wide association study, [SCCO.NEUR]Cognitive science/Neuroscience, Human Genome, Neurosciences, Extramural, Genetic architecture, Brain Disorders, meta-analysis, schizophrenia, INDIVIDUALS, 030104 developmental biology, Genetic marker, Endophenotype, DISCOVERY, Genetic markers, U.S. Gov't, Human medicine, Neuroscience, genetic predisposition, 030217 neurology & neurosurgery, Research Support, U.S. Gov't, Non-P.H.S, Meta-Analysis
Abstract

Article, Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders., final draft, peerReviewed

Published
2016

5. No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study

Author

Johnson, Emma C., Bjelland, Douglas W., Howrigan, Daniel P., Abdellaoui, Abdel, Breen, Gerome, Borglum, Anders, Cichon, Sven, Degenhardt, Franziska, Forstner, Andreas J., Frank, Josef, Genovese, Giulio, Heilmann-Heimbach, Stefanie, Herms, Stefan, Hoffman, Per, Maier, Wolfgang, Mattheisen, Manuel, Morris, Derek, Mowry, Bryan, Müller-Mhysok, Betram, Neale, Benjamin, Nenadic, Igor, Nöthen, Markus M., O’Dushlaine, Colm, Rietschel, Marcella, Ruderfer, Douglas M., Rujescu, Dan, Schulze, Thomas G., Simonson, Matthew A., Stahl, Eli, Strohmaier, Jana, Witt, Stephanie H., Ripke, Stephan, Neale, Benjamin M., Corvin, Aiden, Walters, James T R, Farh, Kai How, Holmans, Peter A., Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A., Huang, Hailiang, Pers, Tune H., Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A., Begemann, Martin, Belliveau, Richard A., Bene, Judit, Bergen, Sarah E., Bevilacqua, Elizabeth, Bigdeli, Tim B., Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M., Carr, Vaughan J., Carrera, Noa, Catts, Stanley V., Chambert, Kimberly D., Chan, Raymond C K, Chen, Ronald Y L, Chen, Eric Y H, Cheng, Wei, Cheung, Eric F C, Chong, Siow Ann, Robert Cloninger, C., Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J., Curtis, David, Davidson, Michael, Davis, Kenneth L., Del Favero, Jurgen, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H., Farrell, Martilias S., Franke, Lude, Freedman, Robert, Freimer, Nelson B., Friedl, Marion, Friedman, Joseph I., Fromer, Menachem, Georgieva, Lyudmila, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I., Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L., Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M., Henskens, Frans A., Hirschhorn, Joel N., Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V., Hougaard, David M., Ikeda, Masashi, Joa, Inge, Julià, Antonio, Kahn, René S., Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Kennedy, James L., Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Knowles, James A., Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Kähler, Anna K., Laurent, Claudine, Chee Keong, Jimmy Lee, Hong Lee, S., Legge, Sophie E., Lerer, Bernard, Li, Miaoxin, Li, Tao, Liang, Kung Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M., Lubinski, Jan, Lönnqvist, Jouko, Macek, Milan, Magnusson, Patrik K E, Maher, Brion S., Mallet, Jacques, Marsal, Sara, Mattingsdal, Morten, McCarley, Robert W., McDonald, Colm, McIntosh, Andrew M., Meier, Sandra, Meijer, Carin J., Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W., Mors, Ole, Murphy, Kieran C., Murray, Robin M., Myin-Germeys, Inez, Müller-Myhsok, Bertram, Nelis, Mari, Nertney, Deborah A., Nestadt, Gerald, Nicodemus, Kristin K., Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, Anthony O'Neill, F., Oh, Sang Yun, Olincy, Ann, Olsen, Line, Van Os, Jim, Pantelis, Christos, Papadimitriou, George N., Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T., Paunio, Tiina, Pejovic-Milovancevic, Milica, Perkins, Diana O., Pietiläinen, Olli, Pimm, Jonathan, Pocklington, Andrew J., Powell, John, Price, Alkes, Pulver, Ann E., Purcell, Shaun M., Quested, Digby, Rasmussen, Henrik B., Reichenberg, Abraham, Reimers, Mark A., Richards, Alexander L., Roffman, Joshua L., Roussos, Panos, Salomaa, Veikko, Sanders, Alan R., Schall, Ulrich, Schubert, Christian R., Schwab, Sibylle G., Scolnick, Edward M., Scott, Rodney J., Seidman, Larry J., Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M., Sim, Kang, Slominsky, Petr, Smoller, Jordan W., So, Hon Cheong, Spencer, Chris C A, Stahl, Eli A., Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E., Strengman, Eric, Scott Stroup, T., Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M., Szatkiewicz, Jin P., Söderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Veijola, Juha, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T., Weiser, Mark, Wildenauer, Dieter B., Williams, Nigel M., Williams, Stephanie, Wolen, Aaron R., Wong, Emily H M, Wormley, Brandon K., Xi, Hualin Simon, Zai, Clement C., Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R., Stefansson, Kari, Visscher, Peter M., Adolfsson, Rolf, Andreassen, Ole A., Blackwood, Douglas H R, Bramon, Elvira, Buxbaum, Joseph D., Børglum, Anders D., Darvasi, Ariel, Domenici, Enrico, Ehrenreich, Hannelore, Esko, Tõnu, Gejman, Pablo V., Gill, Michael, Gurling, Hugh, Hultman, Christina M., Iwata, Nakao, Jablensky, Assen V., Jönsson, Erik G., Kendler, Kenneth S., Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Malhotra, Anil K., McCarroll, Steven A., McQuillin, Andrew, Moran, Jennifer L., Mortensen, Preben B., Mowry, Bryan J., Ophoff, Roel A., Owen, Michael J., Palotie, Aarno, Pato, Carlos N., Petryshen, Tracey L., Posthuma, Danielle, Riley, Brien P., Sham, Pak C., Sklar, Pamela, Clair, David S., Weinberger, Daniel R., Wendland, Jens R., Werge, Thomas, Daly, Mark J., O'Donovan, Michael C., Sullivan, Patrick F., Keller, Matthew C., Biological Psychology, Johnson, Emma C, Bjelland, Douglas W, Howrigan, Daniel P, Abdellaoui, Abdel, Lee, S Hong, Keller, Matthew C, and Schizophrenia Working Group of the Psychiatric Genomics Consortium

Subjects
0301 basic medicine, Male, Cancer Research, Heredity, Ecology, Evolution, Behavior and Systematics, Molecular Biology, Genetics, Genetics (clinical), Social Sciences, Genome-wide association study, Disease, 030105 genetics & heredity, Runs of Homozygosity, Homozygosity, Consanguinity, Sociology, Polymorphism (computer science), Consortia, Medicine and Health Sciences, Genetics(clinical), Inbreeding, Ecology, Depression, Homozygote, Genomics, 3. Good health, Schizophrenia, Research Design, Physical Sciences, Female, Statistics (Mathematics), Research Article, lcsh:QH426-470, Evolution, Replication Studies, inbreeding, Single-nucleotide polymorphism, Biology, Genome Complexity, Research and Analysis Methods, Polymorphism, Single Nucleotide, 03 medical and health sciences, SDG 17 - Partnerships for the Goals, Behavior and Systematics, SDG 3 - Good Health and Well-being, Mental Health and Psychiatry, medicine, Confidence Intervals, Humans, replication study, Mood Disorders, Genome, Human, Biology and Life Sciences, Computational Biology, medicine.disease, schizophrenia, lcsh:Genetics, 030104 developmental biology, homozygosity, Mathematics, Genome-Wide Association Study
Abstract

It is well known that inbreeding increases the risk of recessive monogenic diseases, but it is less certain whether it contributes to the etiology of complex diseases such as schizophrenia. One way to estimate the effects of inbreeding is to examine the association between disease diagnosis and genome-wide autozygosity estimated using runs of homozygosity (ROH) in genome-wide single nucleotide polymorphism arrays. Using data for schizophrenia from the Psychiatric Genomics Consortium (n = 21,868), Keller et al. (2012) estimated that the odds of developing schizophrenia increased by approximately 17% for every additional percent of the genome that is autozygous (β = 16.1, CI(β) = [6.93, 25.7], Z = 3.44, p = 0.0006). Here we describe replication results from 22 independent schizophrenia case-control datasets from the Psychiatric Genomics Consortium (n = 39,830). Using the same ROH calling thresholds and procedures as Keller et al. (2012), we were unable to replicate the significant association between ROH burden and schizophrenia in the independent PGC phase II data, although the effect was in the predicted direction, and the combined (original + replication) dataset yielded an attenuated but significant relationship between Froh and schizophrenia (β = 4.86,CI(β) = [0.90,8.83],Z = 2.40,p = 0.02). Since Keller et al. (2012), several studies reported inconsistent association of ROH burden with complex traits, particularly in case-control data. These conflicting results might suggest that the effects of autozygosity are confounded by various factors, such as socioeconomic status, education, urbanicity, and religiosity, which may be associated with both real inbreeding and the outcome measures of interest., Author Summary It is well known that mating between relatives increases the risk that a child will have a rare recessive genetic disease, but there has also been increasing interest and inconsistent findings on whether inbreeding is a risk factor for common, complex psychiatric disorders such as schizophrenia. The best powered study to date investigating this theory predicted that the odds of developing schizophrenia increase by approximately 17% for every additional percent of the genome that shows evidence of inbreeding. In this replication, we used genome-wide single nucleotide polymorphism data from 18,562 schizophrenia cases and 21,268 controls to quantify the degree to which they were inbred and to test the hypothesis that schizophrenia cases show higher mean levels of inbreeding. Contrary to the original study, we did not find evidence for distant inbreeding to play a role in schizophrenia risk. There are various confounding factors that could explain the discrepancy in results from the original study and our replication, and this should serve as a cautionary note–careful attention should be paid to issues like ascertainment when using the data from genome-wide case-control association studies for secondary analyses for which the data may not have originally been intended.

Published
2016

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