Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435 291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and is important in monoaminergic neurotransmission in the brain) with P-values of 7.7 × 10−7 for rs2715148 and 1.2 × 10−6 for rs2522833. We undertook replication of SNPs in this region in five independent samples (6079 MDD independent cases and 5893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded P=6.4 × 10−8 for the nonsynonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.
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We acknowledge support from NWO: genetic basis of anxiety and depression (904-61-090); resolving cause and effect in the association between exercise and well-being (904-61-193); twin-family database for behavior genomic studies (480-04-004); twin research focusing on behavior (400-05-717), Center for Medical Systems Biology (NWO Genomics); Spinozapremie (SPI 56-464-14192); Centre for Neurogenomics and Cognitive Research (CNCR-VU); genome-wide analyses of European twin and population cohorts (EU/QLRT-2001-01254); genome scan for neuroticism (NIMH R01 MH059160); Geestkracht program of ZonMW (10-000-1002); matching funds from universities and mental health care institutes involved in NESDA (GGZ Buitenamstel-Geestgronden, Rivierduinen, University Medical Center Groningen, GGZ Lentis, GGZ Friesland, GGZ Drenthe). Genotyping was funded 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). Genotype data were obtained from dbGaP (http://www.ncbi.nlm.nih.gov/dbgap, accession number phs000020.v1.p1). Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) which is financially supported by the NWO (480-05-003). Dr Sullivan was also supported by R01s MH074027 and MH077139. Dr Schosser was supported by an Austrian Science Fund Erwin-Schrödinger-Fellowship. We express our thanks to: the GAIN Genotyping group (Dr Gonçalo Abecasis, chair) for help with quality control; Dr Gonçalo Abecasis and Dr Jun Li for assistance with MACH; Dr Shaun Purcell for PLINK; Troy Dumenil (QIMR) for expert assistance with the replication genotyping; Dr Dina Ruano (Portuguese Foundation for Science and Technology, SFRH/BPD/28725/2006); and Dr Pam Madden (DA012854) and Dr Richard Todd (AA013320) for supplying some of the phenotypes used in the Australian sample. Replication genotyping of the STAR*D samples was supported by a grant from the Bowman Family Foundation and the Sidney R Baer, Jr Foundation. We gratefully acknowledge NARSAD for funding the PCLO follow-up genotyping.
Conflict of interest/disclosure (past 3 years)
Dr Baune has received honoraria for educational training of psychiatrists and general practitioners from Lundbeck, AstraZeneca and Pfizer Pharmaceuticals and travel grants from AstraZeneca, Bristol-Meyrs Squibb, Janssen and Pfizer Pharmaceuticals. Dr Fava has received: research support from Abbott Laboratories, Alkermes, Aspect Medical Systems, AstraZeneca, Bristol-Myers Squibb Company, Cephalon, Eli Lilly & Company, Forest Pharmaceuticals Inc., GlaxoSmithKline, J&J Pharmaceuticals, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Novartis, Organon Inc., PamLab, LLC, Pfizer Inc., Pharmavite, Roche, Sanofi-Aventis, Solvay Pharmaceuticals Inc., Synthelabo, Wyeth-Ayerst Laboratories; advisory/consulting fees from Abbott Laboratories, Amarin, Aspect Medical Systems, AstraZeneca, Auspex Pharmaceuticals, Bayer AG, Best Practice Project Management Inc., Biovail Pharmaceuticals Inc., BrainCells Inc., Bristol-Myers Squibb Company, Cephalon, CNS Response, Compellis, Cypress Pharmaceuticals, Dov Pharmaceuticals, Eli Lilly & Company, EPIX Pharmaceuticals, Fabre-Kramer Pharmaceuticals Inc., Forest Pharmaceuticals Inc., GlaxoSmithKline, Grunenthal GmBH, Janssen Pharmaceutica, Jazz Pharmaceuticals, J&J Pharmaceuticals, Knoll Pharmaceutical Company, Lorex Pharmaceuticals, Lundbeck, MedAvante Inc., Merck, Neuronetics, Novartis, Nutrition 21, Organon Inc., PamLab, LLC, Pfizer Inc., PharmaStar, Pharmavite, Precision Human Biolaboratory, Roche, Sanofi-Aventis, Sepracor, Solvay Pharmaceuticals Inc., Somaxon, Somerset Pharmaceuticals, Synthelabo, Takeda, Tetragenex, Transcept Pharmaceuticals, Vanda Pharmaceuticals Inc., Wyeth-Ayerst Laboratories; speaking fees from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb Company, Cephalon, Eli Lilly & Company, Forest Pharmaceuticals Inc., GlaxoSmithKline, Novartis, Organon Inc., Pfizer Inc., PharmaStar, Primedia, Reed-Elsevier, Wyeth-Ayerst Laboratories; has equity holdings in Compellis, MedAvante; and has royalty/patent, other income for patent applications for SPCD and for a combination of azapirones and bupropion in MDD, copyright royalties for the MGH CPFQ, DESS and SAFER. Dr. Nolen has received: speaking fees from AstraZeneca, Eli Lilly, Pfizer, Servier, Wyeth; unrestricted research funding from AstraZeneca, Eli Lilly, GlaxoSmithKline, Wyeth; and served on advisory boards for AstraZeneca, Cyberonics, Eli Lilly, GlaxoSmithKline, Pfizer, Servier. Dr Perlis has received consulting fees or honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Pfizer and Proteus; he is a stockholder in Concordant Rater Systems, LLC, and the holder of a patent related to the monitoring of raters in clinical trials. Dr Smoller has consulted to Eli Lilly, received honoraria from Hoffman-La Roche Inc., Enterprise Analysis Corp. and MPM Capital, and has served on an advisory board for Roche Diagnostics Corporation. Dr Sullivan has received unrestricted research support from Eli Lilly.
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Sullivan, P., de Geus, E., Willemsen, G. et al. Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo. Mol Psychiatry 14, 359–375 (2009). https://doi.org/10.1038/mp.2008.125
- major depressive disorder
- genome-wide association
- Netherlands study of depression and anxiety
- Netherlands twin registry
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