An analysis of two genome-wide association meta-analyses identifies a new locus for broad depression phenotype

Direk, Nese, Williams, Stephanie, Smith, Jennifer A., Ripke, Stephan, Air, Tracy, Amare, Azmeraw T., Amin, Najaf, Baune, Bernhard T., Bennett, David A., Blackwood, Douglas H.R., Boomsma, Dorret, Breen, Gerome, Buttenschøn, Henriette N., Byrne, Enda M., Børglum, Anders D., Castelao, Enrique, Cichon, Sven, Clarke, Toni-Kim, Cornelis, Marilyn C., Dannlowski, Udo, De Jager, Philip L., Demirkan, Ayse, Domenici, Enrico, van Duijn, Cornelia M., Dunn, Erin C., Eriksson, Johan G., Esko, Tonu, Faul, Jessica D., Ferrucci, Luigi, Fornage, Myriam, de Geus, Eco, Gill, Michael, Gordon, Scott D., Grabe, Hans Jörgen, van Grootheest, Gerard, Hamilton, Steven P., Hartman, Catharina A., Heath, Andrew C., Hek, Karin, Hofman, Albert, Homuth, Georg, Horn, Carsten, Hottenga, Jouke Jan, Kardia, Sharon L.R., Kloiber, Stefan, Koenen, Karestan, Kutalik, Zoltán, Ladwig, Karl-Heinz, Lahti, Jari, Levinson, Douglas F., Lewis, Cathryn M., Lewis, Glyn, Li, Qingqin S., Llewellyn, David J., Lucae, Susanne, Lunetta, Kathryn L., MacIntyre, Donald J., Madden, Pamela, Martin, Nicholas G., McIntosh, Andrew M., Metspalu, Andres, Milaneschi, Yuri, Montgomery, Grant W., Mors, Oles, Mosley, Thomas H., Murabito, Joanne M., Müller-Myhsok, Bertram, Nöthen, Markus M., Nyholt, Dale R., O'Donovan, Michael C., Penninx, Brenda W., Pergadia, Michele L., Perlis, Roy, Potash, James B., Preisig, Martin, Purcell, Shaun M., Quiroz, Jorge A., Räikkönen, Katri, Rice, John P., Rietschel, Marcella, Rivera, Margarita, Schulze, Thomas G., Shi, Jianxin, Shyn, Stanley, Sinnamon, Grant C., Smit, Johannes H., Smoller, Jordan W., Snieder, Harold, Tanaka, Toshiko, Tansey, Katherine E., Teumer, Alexander, Uher, Rudolf, Umbricht, Daniel, Van der Auwera, Sandra, Ware, Erin, Weir, David R., Weissman, Myrna M., Willemsen, Gonneke, Yang, Jingyun, Zhao, Wei, Tiemeier, Henning, and Sullivan, Patrick F. (2017) An analysis of two genome-wide association meta-analyses identifies a new locus for broad depression phenotype. Biological Psychiatry, 82 (5). pp. 322-329.

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Background: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder.

Methods: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures.

Results: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 x 10(-9)) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 x 10(-9)).

Conclusions: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.

Item ID: 50353
Item Type: Article (Research - C1)
ISSN: 1873-2402
Keywords: CHARGE consortium, depressive symptoms, FHIT gene, genome-wide association study, major depressive disorder, psychiatric genomics consortium
Funders: US National Institute of Mental Health (NIMH), National Institute on Aging (NIA), GlaxoSmithKline (GSK), Faculty of Biology and Medicine of Lausanne, Switzerland, Swiss National Science Foundation (SNSF), German Research Foundation (GRF), Innovative Madizinische Forschung of the Medical Faculty of Muenster (MF), Chief Scientist Office, Scotland (CSO), Wellcome Trust (WT), Dr Mortimer and Theresa Sackler Foundation, Medical Research Council, UK (MRC), European Union (EU), European Federation of Pharmaceutical Industries and Associations (EF), Netherlands Organization for Scientific Research (NWO), Center for Medical Systems Biology (NWO Genomics), Netherlands Bioinformatics Centre (NBC), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI), VU University's Institute for Health and Care Research, Neuroscience Campus Amsterdam, European Science Foundation (ESF), European Network of Genomic and Genetic Epidemiology (EN), European Science Council (ESC), Rutgers University Cell and DNA Repository (RU), Avera Institute, National Institute of Health (NIH), USA, Foundation for the National Institutes of Health (FNIH), National Health Service (NHS), Kings College London, European Commission (EC), Danish Strategic Research Council, Stanley Research Foundation, H. Lundbeck, Federal Ministry Education and Research, Germany (FMER), University of Adelaide
Projects and Grants: NIMH U01MH094421, NIMH R01MH094421, NIA U01AG009740, NIA RC2 AG036495, NIA RC4 AG039029, SNSF 3200B0-105993, SNSF 3200B0-118308, SNSF 33CSCO-122661, SNSF 33CS30-139468, SNSF 33CS30-148401, GRF grant no. FOR2107, GRF grant no. DA1151/5-1, MF grant no. DA120903, MF grant no. DA111107, MF grant no. DA211012, CSO NRS Research Fellow, WT 104036/Z/14/Z, MRC G0200243, WT 076113, WT 085475, WT 090355, EU and EF Innovative Medicine Initiative Joint Undertaking 115008, EU Seventh Framework Program FP7/2007-2013, NBC BioAssist/RK(2008.024), BBMRI-NL 184.021.007, ESF EU/QLRT-2001-01254, EN HEALTH-F4-2007-201413, ESC ERC Advanced 230374, RU NIMH U24 MH068457-06, NIH R01D0042157-01A, NIH MH081802, NIH Grand Opportunity Grant 1RC2 MH089951, NIH Grand Opportunity Grant 1RC2 MH089995, FNIH Genetic Association Information Network, MRC and GSK joint grant G0701420, NHS Foundation Trust, EC Framework 6 grant LSHB-CT-2003-503428, FMER grant 01ZZ9603, FMER grant 01ZZ0103, FMER grant 01ZZ0403, FMER grant 031S2061A, FMER grant 03ZIK012, GRF GR1912/5-1
Date Deposited: 20 Sep 2017 08:13
FoR Codes: 31 BIOLOGICAL SCIENCES > 3105 Genetics > 310509 Genomics @ 50%
42 HEALTH SCIENCES > 4203 Health services and systems > 420313 Mental health services @ 50%
SEO Codes: 92 HEALTH > 9204 Public Health (excl. Specific Population Health) > 920410 Mental Health @ 50%
97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 50%
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