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A mega-analysis of genome-wide association studies for major depressive disorder

Abstract

Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 × 10−8), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083–53 822 102, minimum P=5.9 × 10−9 at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.

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Acknowledgements

We thank the thousands of people with MDD who donated time and effort to make this research possible. The PGC was funded by NIMH Grants MH085520 (lead PI PFS) and MH080403. We thank our colleagues in the PGC Bipolar Disorder Working Group who allowed pre-publication access to their GWAS mega-analysis results for the MDD-BIP cross-disorder analyses. The Bonn/Mannheim (BoMa) GWAS was supported by the German Federal Ministry of Education and Research, within the context of the National Genome Research Network 2 (NGFN-2), the National Genome Research Network plus (NGFNplus) and the Integrated Genome Research Network (IG) MooDS (Grant 01GS08144 to S Cichon and MM Nöethen, and Grant 01GS08147 to M Rietschel). The work at deCODE was funded by European Union Grants LSHM-CT-2006-037761 (Project SGENE), PIAP-GA-2008-218251 (Project PsychGene) and HEALTH-F2-2009-223423 (Project PsychCNVs). GenPod was funded by the Medical Research Council (UK) and supported by the Mental Health Research Network. Genotyping of the GenPod sample was funded by the Innovative Medicines Initiative Joint Undertaking under Grant Agreement number 115008 (NEWMEDS). The GenRED GWAS project was supported by NIMH R01 Grants MH061686 (DF Levinson), MH059542 (WH Coryell), MH075131 (WB Lawson), MH059552 (JB Potash), MH059541 (WA Scheftner) and MH060912 (MM Weissman). We acknowledge the contributions of Dr George S Zubenko and Dr Wendy N Zubenko, Department of Psychiatry, University of Pittsburgh School of Medicine, to the GenRED I project. The NIMH Cell Repository at Rutgers University and the NIMH Center for Collaborative Genetic Studies on Mental Disorders made essential contributions to this project. Genotyping was carried out by the Broad Institute Center for Genotyping and Analysis with support from Grant U54 RR020278 (which partially subsidized the genotyping of the GenRED cases). Collection and quality control analyses of the control data set were supported by grants from NIMH and the National Alliance for Research on Schizophrenia and Depression. We are grateful to Knowledge Networks (Menlo Park, CA, USA) for assistance in collecting the control data set. We express our profound appreciation to the families who participated in this project, and to the many clinicians who facilitated the referral of participants to the study. The Depression Genes and Networks ARRA grant was funded by RC2MH089916. Funding for the Harvard i2b2 sample was provided by a subcontract to RH Perlis and JW Smoller as part of the i2b2 Center (Informatics for Integrating Biology and the Bedside), an NIH-funded National Center for Biomedical Computing based at Partners HealthCare System (U54LM008748, PI: IS Kohane), and by an NIMH Grant to RH Perlis (MH086026). Max Planck Institute of Psychiatry MARS study was supported by the BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression (01ES0811). Genotyping was supported by the Bavarian Ministry of Commerce, and the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN2 and NGFN-Plus, FKZ 01GS0481 and 01GS08145). The Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR) contributed to GAIN-MDD and to MDD2000. Funding was from: the Netherlands Organization for Scientific Research (MagW/ZonMW Grants 904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, 912-100-20; Spinozapremie 56-464-14192; Geestkracht program Grant 10-000-1002); the Center for Medical Systems Biology (NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure, VU University's Institutes for Health and Care Research and Neuroscience Campus Amsterdam, NBIC/BioAssist/RK (2008.024); the European Science Foundation (EU/QLRT-2001-01254); the European Community's Seventh Framework Program (FP7/2007-2013); ENGAGE (HEALTH-F4-2007-201413); and the European Science Council (ERC, 230374). Genotyping was funded in part by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the NIMH (MH081802). CM Middeldorp was supported by the Netherlands Organization for Scientific Research (NOW-VENI grant 916-76-125). The PsyCoLaus study was supported by grants from the Swiss National Science Foundation (#3200B0–105993, #3200B0-118′308, 33CSC0-122661) and from GlaxoSmithKline (Psychiatry Center of Excellence for Drug Discovery and Genetics Division, Drug Discovery - Verona, R&D). We express our gratitude to the Lausanne inhabitants who volunteered to participate in the PsyCoLaus study. We also thank V Mooser, G Weaber and P Vollenweider who initiated the CoLaus project. Funding for the QIMR samples was provided by the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674, 619667), the Australian Research Council (FT0991360, FT0991022), the FP-5 GenomEUtwin Project (QLG2-CT- 2002-01254) and the US National Institutes of Health (AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951), and the Center for Inherited Disease Research (Baltimore, MD, USA). We thank the twins and their families registered at the Australian Twin Registry for their participation in the many studies that have contributed to this research. RADIANT was funded by: a joint grant from the UK Medical Research Council and GlaxoSmithKline (G0701420); the National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King's College London; and the UK Medical Research Council (G0000647). The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grants no. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (Grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the ‘Center of Knowledge Interchange’ program of the Siemens AG. SHIP-LEGEND is funded by the German Research Foundation (DFG: GR 1912/5-1). Genotyping of STAR*D was supported by an NIMH Grant to SP Hamilton (MH072802). STAR*D was funded by the National Institute of Mental Health (contract N01MH90003) to the University of Texas Southwestern Medical Center at Dallas (AJ Rush, principal investigator). The TwinGene study was supported by the Swedish Ministry for Higher Education, the Swedish Research Council (M-2005-1112), GenomEUtwin (EU/QLRT-2001-01254; QLG2-CT-2002-01254), the Swedish Foundation for Strategic Research and the US National Institutes of Health (U01 DK066134). This study makes use of data generated by the Wellcome Trust Case–Control Consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under awards 076113 and 085475.

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Correspondence to Patrick F Sullivan.

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Elisabeth Binder received grant support from Pharmaneuroboost. Hans J Grabe reports receiving funding from: German Research Foundation; Federal Ministry of Education and Research Germany; speakers honoraria from Bristol-Myers Squibb, Eli Lilly, Novartis, Eisai, Wyeth, Pfizer, Boehringer Ingelheim, Servier and travel funds from Janssen-Cilag, Eli Lilly, Novartis, AstraZeneca and SALUS-Institute for Trend-Research and Therapy Evaluation in Mental Health. Florian Holsboer is a shareholder of Affectis Pharmaceuticals and co-founder of HolsboerMaschmeyer-NeuroChemie. James A Knowles is on the Scientific Advisory Committee for Next-Generation Sequencing of Life Technologies and is a technical advisor to SoftGenetics. Pierandrea Muglia was a full-time employee of GSK when the work was performed. Bertram Müller-Myhsok consulted for Affectis Pharmaceuticals. Matthias Nauck reports funding from: the Federal Ministry of Education and Research Germany, Bio-Rad Laboratories, Siemens AG, Zeitschrift für Laboratoriumsmedizin, Bruker Daltronics, Abbott, Jurilab Kuopio, Roche Diagnostics, Dade Behring, DPC Biermann and Becton Dickinson. Rudolf Uher has received funding from a number of pharmaceutical companies as part of the European Union Innovative Medicine Initiative funded NEWMEDS project. Federica Tozzi was a full-time employee of GSK when the work was performed. Henry Völzke reports funding from: Sanofi-Aventis, Biotronik, the Humboldt Foundation, the Federal Ministry of Education and Research (Germany) and the German Research Foundation. No other author reports a conflict of interest.

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All collaborators reviewed and approved the final version of the manuscript. Overall coordination: Patrick F Sullivan. Statistical analysis: Mark J Daly (lead), Stephan Ripke, Cathryn M Lewis, Dan-Yu Lin, Naomi R Wray, Benjamin Neale, Douglas F Levinson, Gerome Breen, Enda M Byrne. Phenotype analysis: Naomi R Wray (lead), Douglas F Levinson, Marcella Rietschel, Witte Hoogendijk, Stephan Ripke. Writing committee: Patrick F Sullivan (lead), Steven P Hamilton, Douglas F Levinson, Cathryn M Lewis, Stephan Ripke, Myrna M Weissman, Naomi R Wray.

MDD discovery sample data contributed by: Bonn/Mannheim study—René Breuer, Sven Cichon, Franziska Degenhardt, Josef Frank, Magdalena Gross, Stefan Herms, Susanne Hoefels, Wolfgang Maier, Manuel Mattheisen, Markus M Nöethen, Marcella Rietschel, Thomas G Schulze, Michael Steffens, Jens Treutlein; GAIN MDD study—Dorret I Boomsma, Eco J De Geus, Witte Hoogendijk, Jouke Jan Hottenga, Tzeng Jung-Ying, Dan-Yu Lin, Christel M Middeldorp, Willem A Nolen, Brenda P Penninx, Johannes H Smit, Patrick F Sullivan, Gerard van Grootheest, Gonneke Willemsen, Frans G Zitman; GenRED study—William H Coryell, James A Knowles, William B Lawson, Douglas F Levinson, James B Potash, William A Scheftner, Jianxin Shi, Myrna M Weissman; GlaxoSmithKline study—Florian Holsboer, Pierandrea Muglia, Federica Tozzi; MDD2000 study—Douglas HR Blackwood, Dorret I Boomsma, Eco J De Geus, Jouke Jan Hottenga, Donald J MacIntyre, Andrew McIntosh, Alan McLean, Christel M Middeldorp, Willem A Nolen, Brenda P Penninx, Stephan Ripke, Johannes H Smit, Patrick F Sullivan, Gerard van Grootheest, Gonneke Willemsen, Frans G Zitman, Edwin JCG van den Oord; Max Planck Institute of Psychiatry Study—Florian Holsboer, Susanne Lucae, Elisabeth Binder, Bertram Müller-Myhsok, Stephan Ripke, Darina Czamara, Martin A Kohli, Marcus Ising, Manfred Uhr, Thomas Bettecken; RADIANT study—Michael R Barnes, Gerome Breen, Ian W Craig, Anne E Farmer, Cathryn M Lewis, Peter McGuffin, Pierandrea Muglia; Queensland Institute for Medical Research study—Enda Byrne, Scott D Gordon, Andrew C Heath, Anjali K Henders, Ian B Hickie, Pamela AF Madden, Nicholas G Martin, Grant M Montgomery, Dale R Nyholt, Michele L Pergadia, Naomi R Wray; and STAR*D study—Steven P Hamilton, Patrick J McGrath, Stanley I Shyn, Susan L Slager.

MDD replication sample data contributed by: deCODE Genetics—Högni Oskarsson, Engilbert Sigurdsson, Hreinn Stefansson, Kari Stefansson, Stacy Steinberg, Thorgeir Thorgeirsson; Depression Genes Networks study—Douglas F Levinson, James B Potash, Jianxin Shi, Myrna M Weissman; GENPOD—Michel Guipponi, Glyn Lewis, Michael O’Donovan, Katherine E Tansey, Rudolf Uher; GenRED2 study—William H Coryell, James A Knowles, William B Lawson, Douglas F Levinson, James B Potash, William A Scheftner, Jianxin Shi, Myrna M Weissman; Harvard i2b2 study—Victor M Castro, Susanne E Churchill, Maurizio Fava, Vivian S Gainer, Patience J Gallagher, Sergey Goryachev, Dan V Iosifescu, Isaac S Kohane, Shawn N Murphy, Roy H Perlis, Jordan W Smoller, Jeffrey B Weilburg; PsyCoLaus study—Zoltan Kutalik, Martin Preisig; SHIP-LEGEND study—Hans J Grabe, Matthias Nauck, Andrea Schulz, Alexander Teumer, Henry Völzke; and TwinGene study—Mikael Landen, Paul Lichtenstein, Patrik Magnusson, Nancy Pedersen, Alexander Viktorin.

Supplementary Information accompanies the paper on the Molecular Psychiatry website

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Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium. A mega-analysis of genome-wide association studies for major depressive disorder. Mol Psychiatry 18, 497–511 (2013). https://doi.org/10.1038/mp.2012.21

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Keywords

  • genetics
  • genome-wide association study
  • major depressive disorder
  • mega-analysis
  • meta-analysis

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