An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype.
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- 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; Jan Hottenga, Jouke; 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, Ole; 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 B; Weir, David R; Weissman, Myrna M; Willemsen, Gonneke; Yang, Jingyun; Zhao, Wei; Tiemeier, Henning; Sullivan, Patrick F
- Year
- 2017
- Journal
- Biological psychiatry
- PMID
- 28049566
- DOI
- 10.1016/j.biopsych.2016.11.013
- PMCID
- PMC5462867
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) 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). 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.
Manhattan PlotX-axis represents the chromosomal position for each SNP, and y-axis the −log10 P value for association with depression.
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