Preprint
Genomic dissection of bipolar disorder and schizophrenia including 28 subphenotypes
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- (1) Vanderbilt University Medical Center, grid.412807.8
- (2) Charité, grid.6363.0
- (3) Broad Institute, grid.66859.34
- (4) Massachusetts General Hospital, grid.32224.35
- (5) University College London, grid.83440.3b
- (6) University of California, Los Angeles, grid.19006.3e
- (7) Icahn School of Medicine at Mount Sinai, grid.59734.3c
- (8) University of Queensland, grid.1003.2
- (9) King's College London, grid.13097.3c
- (10) University of Trento, grid.11696.39
- (11) Cardiff University, grid.5600.3
- (12) Department of Psychiatry and Psychotherapy, Ludwig Maximillian University, Munich, Germany
- (13) Ludwig Maximilian University of Munich, grid.5252.0
- (14) Umeå University, grid.12650.30
- (15) Diakonhjemmet Hospital, grid.413684.c
- (16) NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- (17) Karolinska Institute, grid.4714.6
- (18) Aarhus University, grid.7048.b, AU
- (19) Lundbeck Foundation, grid.452548.a
- (20) University of Michigan, grid.214458.e
- (21) Mario Negri Institute for Pharmacological Research, grid.4527.4
- (22) State Mental Hospital, Haar, Germany
- (23) National Institute of Mental Health, grid.447902.c
- (24) Dalhousie University, grid.55602.34
- (25) Stanford University, grid.168010.e
- (26) Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois, USA
- (27) Atlanta VA Medical Center, grid.414026.5
- (28) Emory University, grid.189967.8
- (29) Berkshire Healthcare NHS Foundation Trust, grid.439510.a
- (30) University of Barcelona, grid.5841.8
- (31) Virginia Commonwealth University, grid.224260.0
- (32) Rush University Medical Center, grid.240684.c
- (33) State Serum Institute, grid.6203.7
- (34) University Medical Center Utrecht, grid.7692.a
- (35) Wellcome Centre for Human Genetics, grid.270683.8
- (36) Cornell University, grid.5386.8
- (37) Wellcome Sanger Institute, grid.10306.34
- (38) Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany
- (39) University of Adelaide, grid.1010.0
- (40) Max Planck Institute of Experimental Medicine, grid.419522.9
- (41) Paris Bipolar and TRD Expert Centres, FondaMental Foundation, Paris, France
- (42) Paris Diderot University, grid.7452.4
- (43) French Institute of Health and Medical Research, grid.7429.8
- (44) Assistance Publique -Hopitaux De Paris, grid.50550.35
- (45) TU Dresden, grid.4488.0
- (46) Section for Experimental Psychopathology, General Psychiatry, Heidelberg, Germany
- (47) University of Pecs, grid.9679.1
- (48) University of Pennsylvania, grid.25879.31
- (49) Mayo Clinic, grid.66875.3a
- (50) University of Iowa, grid.214572.7
- (51) Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, subiaco, Western Australia, Australia
- (52) University of Cambridge, grid.5335.0
- (53) University of Edinburgh, grid.4305.2
- (54) Diamantina Institute of Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia
- (55) University Medical Center Groningen, Department of Psychiatry, University of Groningen, RB, The Netherlands
- (56) Louisiana State University Health Sciences Center New Orleans, grid.279863.1
- (57) Harvard University, grid.38142.3c
- (58) University of California, Irvine, grid.266093.8
- (59) University of California, San Francisco, grid.266102.1
- (60) University of Newcastle Australia, grid.266842.c
- (61) Schizophrenia Research Institute, grid.419558.4
- (62) Centre Hospitalier du Rouvray and INSERM U 1079Faculty of Medicine, Rouen, France
- (63) UNSW Sydney, grid.1005.4
- (64) London School of Hygiene & Tropical Medicine, grid.8991.9
- (65) Autonomous University of Barcelona, grid.7080.f
- (66) Hospital Universitari Vall d'Hebron, grid.411083.f
- (67) Institute of Health Carlos III, grid.413448.e
- (68) Royal Brisbane and Women’s Hospital, University of Queensland, Brisbane, Australia
- (69) McGill University Health Centre, grid.63984.30
- (70) Institute of Psychology, grid.454868.3
- (71) University of Hong Kong, grid.194645.b
- (72) University of North Carolina at Chapel Hill, grid.10698.36
- (73) Castle Peak Hospital, grid.460827.f
- (74) Institute of Mental Health, grid.414752.1
- (75) Washington University in St. Louis, grid.4367.6
- (76) Blue Note Biosciences, Princeton, New Jersey, USA
- (77) Eli Lilly (United Kingdom), grid.418786.4
- (78) Trinity College Dublin, grid.8217.c
- (79) University of Iowa Hospitals and Clinics, grid.412584.e
- (80) Translational Genomics, USAC, Phoenix, Arizona, USA
- (81) Centro de Investigación Biomédica en Red de Salud Mental, grid.469673.9
- (82) University Hospital Marques de Valdecilla, Instituto de Formacion e Investigacion Marques de Valdecilla, University of Cantabria, Santander, Spain
- (83) Max Planck Institute of Psychiatry, grid.419548.5
- (84) Queen Mary University of London, grid.4868.2
- (85) Poznan University of Medical Sciences, grid.22254.33
- (86) University of California, San Diego, grid.266100.3
- (87) University of Münster, grid.5949.1
- (88) Department of Genetics, The Hebrew University of Jer USA lem, JerUSAlem, Israel
- (89) Sheba Medical Center, grid.413795.d
- (90) VU Amsterdam, grid.12380.38
- (91) University of Bonn, grid.10388.32
- (92) University of Antwerp, grid.5284.b
- (93) VA Boston Healthcare System, grid.410370.1
- (94) Johns Hopkins University, grid.21107.35
- (95) National and Kapodistrian University of Athens, grid.5216.0
- (96) University College Cork, grid.7872.a
- (97) Oslo University Hospital, grid.55325.34
- (98) University of Oxford, grid.4991.5
- (99) National University of Ireland, Galway, grid.6142.1
- (100) NorthShore University HealthSystem, grid.240372.0
- (101) Wellcome Trust, grid.52788.30
- (102) Indiana University – Purdue University Indianapolis, grid.257413.6
- (103) University of Regensburg, grid.7727.5
- (104) Department of General Practice, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
- (105) Folkhälsans Forskningscentrum, grid.428673.c
- (106) National Institute for Health and Welfare, grid.14758.3f
- (107) Boston Children's Hospital, grid.2515.3
- (108) University of Tartu, grid.10939.32
- (109) Translational Technologies and Bioinformatics, Pharma Research and Early Development, F.Hoffman-La Roche, Basel, Switzerland
- (110) Heidelberg University, grid.7700.0
- (111) Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
- (112) University of Colorado Anschutz Medical Campus, grid.430503.1
- (113) Neuroscience Research Australia, grid.250407.4
- (114) University Medical Center Göttingen, grid.411984.1
- (115) Martin Luther University Halle-Wittenberg, grid.9018.0
- (116) Pitié-Salpêtrière Hospital, grid.411439.a
- (117) Janssen (United States), grid.497530.c
- (118) QIMR Berghofer Medical Research Institute, grid.1049.c
- (119) University of Worcester, grid.189530.6
- (120) Peninsula College of Medicine and Dentistry, grid.467855.d
- (121) Spitalul Clinic de Psihiatrie Alexandru Obregia, grid.440274.1
- (122) University of Minnesota System, grid.437349.e
- (123) Instituto de Investigación Biomédica de Málaga, grid.452525.1
- (124) Academic Medical Center, grid.5650.6
- (125) Mclean Hospital, Harvard Medical School, 115 Mill St, Belmont Massachusetts, USA
- (126) Illumina (United States), grid.185669.5
- (127) Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Denmark
- (128) J.J. Peters VA Medical Center, Bronx, New York, New York, USA
- (129) Department of Psychology, Eberhard Karls Universitat Tobingen, Tubingen, Germany
- (130) University of Basel, grid.6612.3
- (131) Howard University Hospital, grid.411399.7
- (132) University Hospital of Basel, grid.410567.1
- (133) Fujita Health University, grid.256115.4
- (134) University of Western Australia, grid.1012.2
- (135) Mondor Institute of Biomedical Research, grid.462410.5
- (136) Paris 12 Val de Marne University, grid.410511.0
- (137) Plymouth University, grid.11201.33
- (138) Stavanger University Hospital, grid.412835.9
- (139) Vall d'Hebron Research Institute, grid.430994.3
- (140) Medical University of Sofia, grid.410563.5
- (141) University of Colorado Boulder, grid.266190.a
- (142) Centre for Addiction and Mental Health, grid.155956.b
- (143) University of Toronto, grid.17063.33
- (144) Institute of Molecular Genetics, grid.418826.1
- (145) University Hospital Frankfurt, grid.411088.4
- (146) Latvian Biomedical Research and Study Centre, grid.419210.f
- (147) University of Cincinnati, grid.24827.3b
- (148) University of Southern California, grid.42505.36
- (149) Center for Research in Environmental Epidemiology, grid.417617.2
- (150) Vilnius University, grid.6441.7
- (151) GGZ inGeest, grid.420193.d
- (152) VU University Medical Center, grid.16872.3a
- (153) University Hospital in Motol, grid.412826.b
- (154) University of Gothenburg, grid.8761.8
- (155) Department of Child and Adolescent Psychiatry, Pierre and Marie Curie Faculty of Medicine, Paris, France
- (156) North East London NHS Foundation Trust, grid.451079.e
- (157) University Hospital Cologne, grid.411097.a
- (158) Duke-NUSA Graduate Medical School, Singapore, Singapore
- (159) Hofstra University, grid.257060.6
- (160) Feinstein Institute for Medical Research, grid.250903.d
- (161) The Hofstra NS-LIJ School of Medicine, Hempstead, New York, USA
- (162) Hadassah Medical Center, grid.17788.31
- (163) HudsonAlpha Institute for Biotechnology, grid.417691.c
- (164) Mental Health Centre and Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- (165) Columbia University, grid.21729.3f
- (166) Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- (167) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
- (168) University of Illinois at Chicago, grid.185648.6
- (169) National University of Singapore, grid.4280.e
- (170) Genome Institute of Singapore, grid.418377.e
- (171) Pomeranian Medical University, grid.107950.a
- (172) National Health Service Scotland, grid.422655.2
- (173) Brigham and Women's Hospital, grid.62560.37
- (174) Zucker Hillside Hospital, grid.440243.5
- (175) Centre National de la Recherche Scientifique, Laboratoire de Genetique Moleculaire de la Neurotransmission et des Processus Neurodegeneratifs, Hopital de la Pitie Salpetriere, Paris, France
- (176) Research and Education, Division of Clinical Neuroscience, Oslo Universitetssykehus, Oslo, Norway
- (177) St George's, University of London, grid.264200.2
- (178) Stockholm Health Care Services, grid.467087.a
- (179) Sørlandet Sykehus, grid.417290.9
- (180) Churchill Hospital, grid.415719.f
- (181) Lindner Center of HOPE, grid.490303.d
- (182) International Agency For Research On Cancer, grid.17703.32
- (183) National Institute of Mental Health, grid.416868.5
- (184) Beth Israel Deaconess Medical Center, grid.239395.7
- (185) St Olav's University Hospital, grid.52522.32
- (186) Norwegian University of Science and Technology, grid.5947.f
- (187) Forschungszentrum Jülich, grid.8385.6
- (188) Munich Cluster for Systems Neurology, grid.452617.3
- (189) University of Liverpool, grid.10025.36
- (190) Royal College of Surgeons in Ireland, grid.4912.e
- (191) Maastricht University Medical Centre, grid.412966.e
- (192) Jena University Hospital, grid.275559.9
- (193) VA San Diego Healthcare System, grid.410371.0
- (194) University of Pittsburgh, grid.21925.3d
- (195) Eli Lilly (United States), grid.417540.3
- (196) Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark
- (197) DETECT Early Intervention Service for Psychosis, Blackrock, Co. Dublin, Ireland
- (198) Queen's University Belfast, grid.4777.3
- (199) Haukeland University Hospital, grid.412008.f
- (200) University of Bergen, grid.7914.b
- (201) University of California, Berkeley, grid.47840.3f
- (202) Clinical Center University of Sarajevo, grid.411735.5
- (203) Pfizer (United States), grid.410513.2
- (204) Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, UK
- (205) University of Helsinki, grid.7737.4
- (206) Melbourne Health, grid.429299.d
- (207) Technical University of Denmark, grid.5170.3, DTU
- (208) Erasmus University Medical Center, grid.5645.2
- (209) Amsterdam Neuroscience, grid.484519.5
- (210) Altrecht GGZ, grid.413664.2
- (211) University of Granada, grid.4489.1
- (212) Montreal Neurological Institute and Hospital, grid.416102.0
- (213) McGill University, grid.14709.3b
- (214) Scripps Health, grid.419722.b
- (215) Faculty of Science, Medicine & Health, Univeristy of Wollogong, Australia
- (216) Hunter New England Health, grid.3006.5
- (217) University of Bologna, grid.6292.f
- (218) National Cancer Institute, grid.48336.3a
- (219) University of Iceland, grid.14013.37
- (220) James J Peters VA Medical Center, grid.274295.f
- (221) PsyQ, grid.491389.e
- (222) University of Aberdeen, grid.7107.1
- (223) CODE Genetics / Amgen, Reykjavik, Iceland
- (224) Medical University of Vienna, grid.22937.3d
- (225) Department of Psychiatry, Hospital Namsos, Namsos, Norway
- (226) Lieber Institute for Brain Development, grid.429552.d
- (227) Neurogenomics, TGen, Los Angeles, AZ, USA
- (228) University of Verona, grid.5611.3
- (229) Dept of Psychiatry, Sankt Olavs Hospital Universitetssykehuset i Trondheim, Trondheim, Norway
- (230) Psychiatry, Psychiatrisches Zentrum Nordbaden, Wiesloch, Germany
- (231) Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain
- (232) National Institute for Health Research, grid.451056.3
- (233) Health Research Board, grid.413895.2
- (234) University of Oslo, grid.5510.1
- (235) University of Copenhagen, grid.5254.6, KU
- (236) Department of Psychiatry, University Medical Center Groningen, University of Groningen, The Netherlands
- (237) Princess Margaret Cancer Centre, grid.415224.4
- (238) State University of New York, grid.189747.4
- (239) Departments of Psychiatry and Human Genetics, University of Chicago, Chicago, Illinois, USA
- (240) Universidad Autonoma de Nuevo Leon, Department of Psychiatry, Monterrey, Mexico; Department of Psychiatry, Mayo Clinic, MN, USA
- (241) Universidad Autónoma de Nuevo León, grid.411455.0
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Description
Abstract Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable disorders that share a significant proportion of common risk variation. Understanding the genetic factors underlying the specific symptoms of these disorders will be crucial for improving diagnosis, intervention and treatment. In case-control data consisting of 53,555 cases (20,129 BD, 33,426 SCZ) and 54,065 controls, we identified 114 genome-wide significant loci (GWS) when comparing all cases to controls, of which 41 represented novel findings. Two genome-wide significant loci were identified when comparing SCZ to BD and a third was found when directly incorporating functional information. Regional joint association identified a genomic region of overlapping association in BD and SCZ with disease-independent causal variants indicating a fourth region contributing to differences between these disorders. Regional SNP-heritability analyses demonstrated that the estimated heritability of BD based on the SCZ GWS regions was significantly higher than that based on the average genomic region (91 regions, p = 1.2×10 −6 ) while the inverse was not significant (19 regions, p=0.89). Using our BD and SCZ GWAS we calculated polygenic risk scores and identified several significant correlations with: 1) SCZ subphenotypes: negative symptoms (SCZ, p=3.6×10 −6 ) and manic symptoms (BD, p=2×10 −5 ), 2) BD subphenotypes: psychotic features (SCZ p=1.2×10 −10 , BD p=5.3×10 −5 ) and age of onset (SCZ p=7.9×10 −4 ). Finally, we show that psychotic features in BD has significant SNP-heritability (h 2 snp =0.15, SE=0.06), and a significant genetic correlation with SCZ (r g =0.34) in addition there is a significant sign test result between SCZ GWAS and a GWAS of BD cases contrasting those with and without psychotic features (p=0.0038, one-side binomial test). For the first time, we have identified specific loci pointing to a potential role of 4 genes ( DARS2 , ARFGEF2 , DCAKD and GATAD2A ) that distinguish between BD and SCZ, providing an opportunity to understand the biology contributing to clinical differences of these disorders. Our results provide the best evidence so far of genomic components distinguishing between BD and SCZ that contribute directly to specific symptom dimensions.
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