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

Jonathan R.I. Coleman, Héléna A. Gaspar, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Julien Bryois

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116 Citations (Scopus)

Abstract

Background: Mood disorders (including major depressive disorder and bipolar disorder) affect 10% to 20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Multiple approaches have shown considerable sharing of risk factors across mood disorders despite their diagnostic distinction. Methods: To clarify the shared molecular genetic basis of major depressive disorder and bipolar disorder and to highlight disorder-specific associations, we meta-analyzed data from the latest Psychiatric Genomics Consortium genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; nonoverlapping N = 609,424). Results: Seventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More loci from the Psychiatric Genomics Consortium analysis of major depression than from that for bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single-episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment—the relationship is positive in bipolar disorder but negative in major depressive disorder. Conclusions: The mood disorders share several genetic associations, and genetic studies of major depressive disorder and bipolar disorder can be combined effectively to enable the discovery of variants not identified by studying either disorder alone. However, we demonstrate several differences between these disorders. Analyzing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum.

Original languageEnglish
Pages (from-to)169-184
Number of pages16
JournalBiological Psychiatry
Volume88
Issue number2
DOIs
Publication statusPublished - 15 Jul 2020

Bibliographical note

Funding Information:
This study represents independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley National Health Service (NHS) Foundation Trust and King’s College London . High-performance computing facilities were funded with capital equipment grants from the Guy's and St. Thomas' Charity (Grant No. TR130505 ) and Maudsley Charity (Grant No. 980 ). The PGC has received major funding from the United States National Institute of Mental Health (NIMH) and the United States National Institute of Drug Abuse of the National Institutes of Health (NIH) (Grant Nos. U01 MH109528 [to PFS], U01MH109514 [to MCO], and U01 MH1095320 [to A Agrawal]). We acknowledge the continued support of the NL Genetic Cluster Computer ( http://www.geneticcluster.org/ ) hosted by SURFsara in the management and curation of PGC data, with funding from Scientific Organization Netherlands (Grant No. 480-05-003 [to DP]). Central analysis of PGC data was funded by UK Medical Research Council (MRC) Centre and Program Grants (Grant Nos. G0801418 and G0800509 [to PAH, MCO, MJO]) and grants from the Australian National Health and Medical Research Council (NHMRC) (Grant Nos. 1078901 and 108788 [to NRW]). GB, JRIC, HAG, and CL were supported in part by the NIHR as part of the Maudsley BRC. DP is funded by the Dutch Brain Foundation and the VU University Amsterdam Netherlands. PFS receives support from the Swedish Research Council ( Vetenskapsrådet ) (Grant No. D0886501 ).

Funding Information:
This study represents independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley National Health Service (NHS) Foundation Trust and King's College London. High-performance computing facilities were funded with capital equipment grants from the Guy's and St. Thomas' Charity (Grant No. TR130505) and Maudsley Charity (Grant No. 980). The PGC has received major funding from the United States National Institute of Mental Health (NIMH) and the United States National Institute of Drug Abuse of the National Institutes of Health (NIH) (Grant Nos. U01 MH109528 [to PFS], U01MH109514 [to MCO], and U01 MH1095320 [to A Agrawal]). We acknowledge the continued support of the NL Genetic Cluster Computer (http://www.geneticcluster.org/) hosted by SURFsara in the management and curation of PGC data, with funding from Scientific Organization Netherlands (Grant No. 480-05-003 [to DP]). Central analysis of PGC data was funded by UK Medical Research Council (MRC) Centre and Program Grants (Grant Nos. G0801418 and G0800509 [to PAH, MCO, MJO]) and grants from the Australian National Health and Medical Research Council (NHMRC) (Grant Nos. 1078901 and 108788 [to NRW]). GB, JRIC, HAG, and CL were supported in part by the NIHR as part of the Maudsley BRC. DP is funded by the Dutch Brain Foundation and the VU University Amsterdam Netherlands. PFS receives support from the Swedish Research Council (Vetenskapsr?det) (Grant No. D0886501). Acknowledgments and funding for individual cohorts follow (full expansions of individual cohort names can be found in the original PGC publications) (15,16). BD_TRS: This work was funded by the Deutsche Forschungsgemeinschaft (Grant Nos. FOR2107 DA1151/5-1, SFB-TRR58, and Project C09 [to UD]) and the Interdisciplinary Center for Clinical Research of the medical faculty of M?nster (Grant No. Dan3/012/17 [to UD]). BiGS: Research was funded by the NIMH for work at 4 locations: Chicago (Grant No. R01 MH103368 [to ESG]), NIMH (Grant Nos. R01 MH061613 and ZIA MH002843 [to FJM]), Pittsburgh (Grant No. MH63480 [to VN]), and University of California?San Diego (Grant Nos. MH078151, MH081804, and MH59567 [to JK]). FJM was supported by the NIMH Intramural Research Program, NIH, and Department of Health and Human Services. BOMA-Australia: Funding was supplied by the Australian NHMRC (Grant Nos. 1037196, 1066177, and 1063960 [to JMF], Grant No. 1103623 [to SEM], Grant No. 1037196 [to PBM], Grant No. 1078399 [to GWM], Grant No. 1037196 [to PRS]). BOMA-Germany I, BOMA-Germany II, BOMA-Germany III, PsyCourse, and M?nster MDD Cohort: This work was supported by the German Ministry for Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med program (Grant No. 01ZX1314A/01ZX1614A [to MMN and SC], Grant No. 01ZX1314G/01ZX1614G [to MR], Grant No. 01ZX1314K [to TGS]) and through NGFNplus MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia) (Grant Nos. 01GS08144 and 01GS08147 [to MMN, MR, and SC]). This work was also supported by the Deutsche Forschungsgemeinschaft (Grant Nos. NO246/10-1 to MMN [FOR 2107], RI 908/11-1 to MR [FOR 2107], and WI 3429/3-1 [to SHW], and Grant Nos. SCHU 1603/4?1, SCHU 1603/5?1 [KFO 241], and SCHU 1603/7?1 [PsyCourse] [to TGS]), the Swiss National Science Foundation (Grant No. 156791 [to SC]), and the European Union (Grant No. N Health-F2?2008?222963 [to BTB and VA]). MMN is supported through the Excellence Cluster ImmunoSensation. TGS is supported by an unrestricted grant from the Dr. Lisa-Oehler Foundation. AJF received support from the BONFOR Programme of the University of Bonn, Germany. MH was supported by the Deutsche Forschungsgemeinschaft. BOMA-Romania: The work was supported by Unitatea Executiva Pentru Finantarea Invatamantului Superior a Cercetarii (Grant No. 89/2012 [to MG-S]). Bulgarian Trios: Recruitment was funded by the Janssen Research Foundation (Grant No. 045856), and genotyping was funded by multiple grants to the Stanley Center for Psychiatric Research at the Broad Institute from the Stanley Medical Research Institute, The Merck Genome Research Foundation, and the Herman Foundation (to GK). CoFaMS?Adelaide: Research was funded by the Australian NHMRC (Grant No. APP1060524 [to BTB]). CONVERGE: Research was funded by the Wellcome Trust (Grant Nos. WT090532/Z/09/Z, WT083573/Z/07/Z, and WT089269/Z/09/Z [to J Flint]) and the NIMH (Grant No. MH100549 [to KSK]). Danish RADIANT: Research was funded by H?jteknologifonden (Grant No. 0001-2009-2 [to TW]) and the Lundbeck Foundation (Grant No. R24-A3242 [to TW]). deCODE: Research was funded by FP7-People-2011-IAPP grant agreement PsychDPC (Grant No. 286213 [to KS]) and the United States National Institute of Drug Abuse (Grant No. R01 DA017932 [to KS] and Grant No. R01 DA034076 [to TT]). Edinburgh: Genotyping was conducted at the Genetics Core Laboratory at the Clinical Research Facility (University of Edinburgh). Research was funded by the Wellcome Trust (Grant No. 104036/Z/14/Z [to AMM, T-KC, and DJP]). DJM is supported by a National Health Services Research Scotland Clinical Fellowship funded by the Chief Scientist Office. EGCUT: Research was funded by European Union Project (Grant Nos. EstRC-IUT20-60, 2014-2020.4.01.15-0012, and 692145 [to AM]). Fran: This research was supported by Foundation FondaMental, Cr?teil, France, and by the Investissements d'Avenir Programs managed by the Agence Nationale de la Recherche (Grant Nos. ANR-11-IDEX-0004?02 and ANR-10-COHO-10?01 [to ML]). GenPOD/Newmeds: Research was funded by MRC (Grant No. G0200243 [to GL and MCO]), EU 6th Framework, (Grant No. LSHB-CT-2003-503428 [to RH]), IMI-JU (Grant No. 15008 [to GL]). GenScot: Research was funded by the UK Chief Scientist Office (Grant No. CZD/16/6 [to DJP]) and the Scottish Funding Council (Grant No. HR03006 [to DJP]). Genotyping was conducted at the Genetics Core Laboratory at the Clinical Research Facility (University of Edinburgh). GERA: Participants in the Genetic Epidemiology Research on Adult Health and Aging Study are part of the Kaiser Permanente Research Program on Genes, Environment, and Health, supported by the National Institute on Aging, NIMH, Office of the Director (Grant No. RC2 AG036607 [to CS, N Risch]) and the Wayne and Gladys Valley Foundation, the Ellison Medical Foundation, the Robert Wood Johnson Foundation, and the Kaiser Permanente Regional and National Community Benefit Programs. GSK_Munich: Halifax: Halifax data were obtained with support from the Canadian Institutes of Health Research (Grant No. 64410 [to MA]). Harvard i2b2: Research was funded by NIMH (Grant No. R01 MH085542 [to JWS], Grant No. R01 MH086026 [to RHP]). iPSYCH: The iPSYCH (the Lundbeck Foundation Initiative for Integrative Psychiatric Research) team acknowledges funding from the Lundbeck Foundation (Grant Nos. R102-A9118 and R155-2014-1724, R129-A3973, and R24-A3243 [to TW, ADB, OM, MN, DH, and PBM]), the Stanley Medical Research Institute, the European Research Council (Grant No. 294838 [to TW, ADB, OM, MN, DH, and PBM]), the Novo Nordisk Foundation for supporting the Danish National Biobank resource, the Capital Region of Denmark (Grant No. R144-A5327 [to TW, ADB, OM, MN, DH, and PBM]), and grants from Aarhus and Copenhagen Universities and University Hospitals, including support to the iSEQ Center, the GenomeDK HPC facility, and the CIRRAU Center (to TW, ADB, OM, MN, DH, and PBM). Janssen: Funded by Janssen Research and Development, LLC. MARS/BiDirect: This work was funded by the Max Planck Society, by the Max Planck Excellence Foundation, and by a grant from the BMBF in the National Genome Research Network framework (NGFN2 and NGFN-Plus) (Grant No. FKZ 01GS0481), and by the BMBF Program (Grant No. FKZ01ES0811). Controls were from the Dortmund Health Study that was supported by the German Migraine and Headache Society, and by unrestricted grants to the University of M?nster from Almirall, AstraZeneca, Berlin Chemie, Boehringer, Boots Health Care, GlaxoSmithKline, Janssen Cilag, McNeil Pharma, MSD Sharp and Dohme, and Pfizer. Blood collection was funded by the Institute of Epidemiology and Social Medicine, University of M?nster. Genotyping was supported by the BMBF (Grant Nos. 01ER0816 and 01ER1506 [to KB]). Mayo Bipolar Disorder Biobank: Research was funded by grants from the Marriot Foundation and the Mayo Clinic Center for Individualized Medicine (to JMB and MF). Michigan (NIMH/Pritzker Neuropsychiatric Disorders Research Consortium): Research was funded by NIMH (Grant Nos. R01 MH09414501A1 and MH105653 [to MB]). Many of the authors are members of the Pritzker Neuropsychiatric Disorders Research Consortium, which is supported by the Pritzker Neuropsychiatric Disorders Research Fund, LLC. A shared intellectual property agreement exists between this philanthropic fund and the University of Michigan, Stanford University, the Weill Medical College of Cornell University, HudsonAlpha Institute of Biotechnology, the Universities of California at Davis, and at Irvine, to encourage the development of appropriate findings for research and clinical applications. Mount Sinai: This work was funded in part by a NARSAD Young Investigator award (to EAS), and by NIH (Grant Nos. R01MH106531 and R01MH109536 [to PS and EAS]). NeuRA-CASSI-Australia: This work was funded by the New South Wales Ministry of Health, Office of Health and Medical Research, and by the NHMRC (Grant No. 568807 [to CSW and TWW]). CSW was a recipient of NHMRC fellowships (Fellowship Nos. 1117079 and 1021970). NeuRA-IGP-Australia: Research was funded by the NHMRC (Grant Nos. 630471, 1061875, and 1081603 [to MJG]). NESDA: Research was funded by Nederlandse Organisatie voor Wetenschappelijk (ZonMW Geestkracht grant [to PWJHP]). Norway: Research was funded by the Vetenskapsr?det (to IA), the Western Norway Regional Health Authority (to KJO), the Research Council of Norway (Grant No. 421716 [to IM] and Grant Nos. 249711, 248778, 223273, and 217776 [to OAA]), the South-East Norway Regional Health Authority (Grant Nos. 2012-132 and 2012-131 [to OAA], Grant No. 2016-064 [to OBS], Grant No. 2017-004 [to OAA and OBS], Grant Nos. 2013-088, 2014-102, and 2011-085 [to IM]), and the KG Jebsen Stiftelsen (to OAA). TE was funded by the South-East Norway Regional Health Authority (Grant No. 2015-078) and a research grant from Mrs. Throne-Holst. NTR: Research was funded by Netherlands Organization for Scientific Research (Grant No. 480-15-001/674 [to DIB]). Pfizer: Research was funded by the EU Innovative Medicine Initiative Joint Undertaking (Grant No. 115008.5). PsyColaus: PsyCoLaus/CoLaus received additional support from research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (Grant Nos. 3200B0-105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, and 33CS30-148401 [to MP]). QIMR: Research was funded by NHMRC (Grant Nos. 941177, 971232, 3399450, and 443011 [to NGM]) and the National Institute on Alcohol Abuse and Alcoholism (Grant Nos. AA07535, AA07728, and AA10249 [to ACH]). RADIANT: Research was funded by MRC (Grant No. G0701420 [to GB and CML] and Grant No. G0901245 [to GB]) and NIMH (Grant No. U01 MH109528 [to GB]). Rotterdam Study: The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University and Netherlands Organization for Scientific Research (Grant Nos. 175.010.2005.011, 911-03-012 [to AGU]). SHIP-LEGEND/TREND: SHIP is part of the Community Medicine Research net of the University of Greifswald, which is funded by the Deutsche Forschungsgemeinschaft (Grant No. GR 1912/5-1 [to HJG]), Federal Ministry of Education and Research (Grant Nos. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genotyping in SHIP was funded by Siemens Healthineers and the Federal State of Mecklenburg-West Pomerania. Genotyping in SHIP-TREND-0 was supported by the Federal Ministry of Education and Research (Grant No. 03ZIK012). Span2: Research was funded by Instituto de Salud Carlos III (Grant Nos. PI12/01139, PI14/01700, PI15/01789, and PI16/01505), and cofinanced by the European Regional Development Fund, Ag?ncia de Gesti? d'Ajuts Universitaris i de Recerca-AGAUR, Generalitat de Catalunya (Grant No. 2014SGR1357), Departament de Salut, Generalitat de Catalunya, Spain, and a NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation. This project has also received funding from the European Union's Horizon 2020 Research and Innovation Programme (Grant Nos. 667302 and 643051). CSM is a recipient of a Sara Borrell contract (Grant No. CD15/00199) and a mobility grant (Grant No. MV16/00039) from the Instituto de Salud Carlos III, Ministerio de Econom?a, Industria y Competitividad, Spain. MR is a recipient of a Miguel de Servet contract (Grant Nos. CP09/00119 and CPII15/00023) from the Instituto de Salud Carlos III, Ministerio de Econom?a, Industria y Competitividad, Spain. STAR*D: Research was funded by NIMH (Grant No. R01 MH-072802 [to SPH]). SUNY DMC: Research was funded by NIMH (Grant No. R01MH085542 [to CP, MTP, JAK, and HM]). SWEBIC: Research was funded by NIMH (Grant No. MH077139 [to ML]), the Vetenskapsr?det (Grant Nos. K2014-62X-14647-12-51 and K2010-61P-21568-01-4 [to ML]), the Swedish foundation for Strategic Research (Grant No. KF10?0039 [to ML]), and the Stanley Center for Psychiatric Research, Broad Institute from a grant from Stanley Medical Research Institute (to ML). Sweden: This work was funded by the Vetenskapsr?det (Grant No 2010-03631 [to MS and CL]), the Stockholm County Council (to MS, CL, LB, LF, and U?), and the S?derstr?m Foundation (to LB). TwinGene: Research was funded by GenomeEUtwin, (Grant Nos. EU/QLRT-2001?01254 and QLG2-CT-2002?01254 [to NLP]), Heart and Lung Foundation (Grant No. 20070481 [to PKM]), Swedish Foundation for Strategic Research, and Vetenskapsr?det (Grant No. M-2005?1112 [to U de Faire]). UCL: Research was funded by the MRC (Grant No. G1000708 [to AM]). UCLA-Utrecht (Los Angeles): Research was funded by NIMH (Grant Nos. R01MH090553 and U01MH105578 [to NBF, RAO, LMOL, and APSO]). UK-BDRN: Research was funded by MRC Centre and Program Grants (Grant Nos. G0801418 and G0800509 [to MCO and MJO]), the Wellcome Trust (Grant No. 078901 [to NC, IJ, LAJ]), the Stanley Medical Research Institute (Grant No. 5710002223-01 [to NC, IJ, LAJ]), and a European Commission Marie Curie Fellowship (Grant No. 623932 [to ADF]). UK Biobank: This research has been funded by the NIHR under its BRCs funding initiative (Application Nos. 4844, 6818, and 16577 [to GB]) and the Wellcome Trust (Grant No. 04036/Z/14/Z [to AMM]). UNIBO/University of Barcelona, Hospital Clinic, IDIBAPS, CIBERSAM: This work was supported by the Spanish Ministry of Economy and Competitiveness (Grant No. PI15/00283 [to EV]) integrated into the Plan Nacional de I+D+I y cofinanciado por el ISCIII-Subdirecci?n General de Evaluaci?n y el Fondo Europeo de Desarrollo Regional (FEDER); CIBERSAM; and the Comissionat per a Universitats i Recerca del DIUE de la Generalitat de Catalunya to the Bipolar Disorders Group (Grant No. 2014 SGR 398). USC: Research funded by NIH (Grant No. R01MH085542 [to JLS]). WTCCC: The principal funder of this project was the Wellcome Trust (to NC and AHY). For the 1958 Birth Cohort, venous blood collection was funded by the UK MRC. AHY is funded by the NIHR BRC at South London and Maudsley NHS Foundation Trust and King's College London. We are deeply indebted to the investigators who comprise the PGC, and to the hundreds of thousands of participants who have shared their life experiences with PGC investigators. BDRN acknowledges the research participants who continue to give their time to participate in our research. JMF thanks Janette M. O'Neil and Betty C. Lynch for their support. The deCODE authors are thankful to the participants and staff at the Patient Recruitment Center. GenPOD/Newmeds investigators are grateful to all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants, and nurses. GlaxoSmithKline Munich investigators thank all participants in the GSK-Munich study. We also thank numerous people at GSK and Max Planck Institute, BKH Augsburg, and Klinikum Ingolstadt in Germany who contributed to this project. Janssen investigators are grateful to the study volunteers for participating in the research studies and to the clinicians and support staff for enabling patient recruitment and blood sample collection. We also thank the staff in the former Neuroscience Biomarkers of Janssen Research and Development for laboratory and operational support (e.g. biobanking, processing, plating, and sample de-identification), and to the staff at Illumina for genotyping Janssen DNA samples. MARS/BiDirect investigators acknowledge all study participants. We thank numerous people at Max Planck Institute, and all study sites in Germany and Switzerland who contributed to this project. Michigan investigators thank the participants who donated their time and DNA to make this study possible. We thank members of the NIMH Human Genetics Initiative and the University of Michigan Prechter Bipolar DNA Repository for generously providing phenotype data and DNA samples. QIMR investigators thank the twins and their families for their willing participation in our studies. STAR*D authors appreciate the efforts of the STAR*D investigator team for acquiring, compiling, and sharing the STAR*D clinical dataset. SWEBIC investigators are deeply grateful for the participation of all participants contributing to this research, and to the collection team that worked to recruit them. We also wish to thank the Swedish National Quality Register for Bipolar Disorders: Bipol?R. TwinGene investigators thank the Karolinska Institutet for infrastructural support of the Swedish Twin Registry. We thank the 23andMe research participants included in the analysis, all of whom provided informed consent and participated in the research online according to a human subjects protocol approved by an external AAHRPP-accredited institutional review board (Ethical & Independent Review Services), and the employees of 23andMe for making this work possible. 23andMe acknowledges the-invaluable contributions of Michelle Agee, Babak Alipanahi, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, Nicholas A. Furlotte, David A. Hinds, Bethann S. Hromatka, Karen E. Huber, Aaron Kleinman, Nadia K. Litterman, Matthew H. McIntyre, Joanna L. Mountain, Carrie A.M. Northover, Steven J. Pitts, J. Fah Sathirapongsasuti, Olga V. Sazonova, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Joyce Y. Tung, Vladimir Vacic, and Catherine H. Wilson. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. This article was published as a preprint on bioRxiv: doi: https://doi.org/10.1101/383331. Genome-wide association study results from analyses including 23andMe are restricted by a data transfer agreement with 23andMe. For these analyses, linkage disequilibrium?independent sets of 10,000 single nucleotide polymorphisms have been made available via the Psychiatric Genetics Consortium (https://www.med.unc.edu/pgc/results-and-downloads). Summary statistics not including 23andMe have been made available via the Psychiatric Genetics Consortium (https://www.med.unc.edu/pgc/results-and-downloads). O.A. Andreassen has received speaker fees from Lundbeck. A.T.F. Beekman is on speaker's bureaus for Lundbeck and GlaxoSmithKline. G. Breen reports consultancy and speaker fees from Eli Lilly, Otsuka, and Illumina and grant funding from Eli Lilly. G. Crawford is a cofounder of Element Genomics. E. Domenici was formerly an employee of Hoffmann?La Roche and a consultant to Roche and Pierre Fabre. J. Nurnberger is an investigator for Janssen and was an investigator for Assurex. S.A. Paciga is an employee of Pfizer. J.A. Quiroz was formerly an employee of Hoffmann?La Roche. S. Steinberg, H. Stefansson, K. Stefansson, and T.E. Thorgeirsson are employed by deCODE Genetics/Amgen. P.F. Sullivan reports the following potentially competing financial interests: Current: Lundbeck (advisory committee, grant recipient). Past 3 years: Pfizer (scientific advisory board), Element Genomics (consultation fee), and Roche (speaker reimbursement). A.H. Young has given paid lectures and is on advisory boards for the following companies with drugs used in affective and related disorders: AstraZeneca, Eli Lilly, Janssen, Lundbeck, Sunovion, Servier, LivaNova. A.H. Young is lead investigator for Embolden Study (AstraZeneca), BCI Neuroplasticity study, and Aripiprazole Mania Study, which are investigator-initiated studies from AstraZeneca, Eli Lilly, Lundbeck, and Wyeth. All other authors declare no biomedical financial interests or potential conflicts of interest.

Funding Information:
We are deeply indebted to the investigators who comprise the PGC, and to the hundreds of thousands of participants who have shared their life experiences with PGC investigators. BDRN acknowledges the research participants who continue to give their time to participate in our research. JMF thanks Janette M. O'Neil and Betty C. Lynch for their support. The deCODE authors are thankful to the participants and staff at the Patient Recruitment Center. GenPOD/Newmeds investigators are grateful to all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants, and nurses. GlaxoSmithKline Munich investigators thank all participants in the GSK-Munich study. We also thank numerous people at GSK and Max Planck Institute, BKH Augsburg, and Klinikum Ingolstadt in Germany who contributed to this project. Janssen investigators are grateful to the study volunteers for participating in the research studies and to the clinicians and support staff for enabling patient recruitment and blood sample collection. We also thank the staff in the former Neuroscience Biomarkers of Janssen Research and Development for laboratory and operational support (e.g., biobanking, processing, plating, and sample de-identification), and to the staff at Illumina for genotyping Janssen DNA samples. MARS/BiDirect investigators acknowledge all study participants. We thank numerous people at Max Planck Institute, and all study sites in Germany and Switzerland who contributed to this project. Michigan investigators thank the participants who donated their time and DNA to make this study possible. We thank members of the NIMH Human Genetics Initiative and the University of Michigan Prechter Bipolar DNA Repository for generously providing phenotype data and DNA samples. QIMR investigators thank the twins and their families for their willing participation in our studies. STAR*D authors appreciate the efforts of the STAR*D investigator team for acquiring, compiling, and sharing the STAR*D clinical dataset. SWEBIC investigators are deeply grateful for the participation of all participants contributing to this research, and to the collection team that worked to recruit them. We also wish to thank the Swedish National Quality Register for Bipolar Disorders: BipoläR. TwinGene investigators thank the Karolinska Institutet for infrastructural support of the Swedish Twin Registry. We thank the 23andMe research participants included in the analysis, all of whom provided informed consent and participated in the research online according to a human subjects protocol approved by an external AAHRPP-accredited institutional review board (Ethical & Independent Review Services), and the employees of 23andMe for making this work possible. 23andMe acknowledges the-invaluable contributions of Michelle Agee, Babak Alipanahi, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, Nicholas A. Furlotte, David A. Hinds, Bethann S. Hromatka, Karen E. Huber, Aaron Kleinman, Nadia K. Litterman, Matthew H. McIntyre, Joanna L. Mountain, Carrie A.M. Northover, Steven J. Pitts, J. Fah Sathirapongsasuti, Olga V. Sazonova, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Joyce Y. Tung, Vladimir Vacic, and Catherine H. Wilson.

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© 2019 Society of Biological Psychiatry

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