An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype

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

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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 × 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 × 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.

Original languageEnglish
Pages (from-to)322-329
Number of pages8
JournalBiological Psychiatry
Issue number5
StatePublished - Sep 1 2017


  • CHARGE consortium
  • Depressive symptoms
  • FHIT gene
  • Genome-wide association study
  • Major depressive disorder
  • Psychiatric Genomics Consortium


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