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.
Conflict of interest statement
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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