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

TitleAn Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype.
Publication TypeJournal Article
Year of Publication2017
AuthorsDirek, N, Williams, S, Smith, JA, Ripke, S, Air, T, Amare, AT, Amin, N, Baune, BT, Bennett, DA, Blackwood, DHR, Boomsma, DI, Breen, G, Buttenschøn, HN, Byrne, EM, Børglum, AD, Castelao, E, Cichon, S, Clarke, T-K, Cornelis, MC, Dannlowski, U, de Jager, PL, Demirkan, A, Domenici, E, van Duijn, CM, Dunn, EC, Eriksson, JG, Esko, T, Faul, J, Ferrucci, L, Fornage, M, de Geus, EJC, Gill, M, Gordon, SD, Grabe, H-J, van Grootheest, G, Hamilton, SP, Hartman, CA, Heath, AC, Hek, K, Hofman, A, Homuth, G, Horn, C, Hottenga, J-J, Kardia, SLR, Kloiber, S, Koenen, KC, Kutalik, Z, Ladwig, K-H, Lahti, J, Levinson, DF, Lewis, CM, Lewis, G, Li, QS, Llewellyn, DJ, Lucae, S, Lunetta, KL, MacIntyre, DJ, Madden, PAF, Martin, NG, McIntosh, AM, Metspalu, A, Milaneschi, Y, Montgomery, GW, Mors, O, Mosley, TH, Murabito, JM, Müller-Myhsok, B, Nöthen, MM, Nyholt, DR, O'Donovan, MC, Penninx, BWJH, Pergadia, ML, Perlis, R, Potash, JB, Preisig, M, Purcell, SM, Quiroz, JA, Räikkönen, K, Rice, JP, Rietschel, M, Rivera, M, Schulze, TG, Shi, J, Shyn, S, Sinnamon, GC, Smit, JH, Smoller, JW, Snieder, H, Tanaka, T, Tansey, KE, Teumer, A, Uher, R, Umbricht, D, Van der Auwera, S, Ware, EB, Weir, DR, Weissman, MM, Willemsen, G, Yang, J, Zhao, W, Tiemeier, H, Sullivan, PF
JournalBiological Psychiatry
Volume82
Issue5
Pagination322-329
ISSN Number1873-2402
KeywordsAcid Anhydride Hydrolases, depression, Depressive Disorder, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Neoplasm Proteins, Phenotype, Whites
Abstract

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.

DOI10.1016/j.biopsych.2016.11.013
Citation Key12135
PubMed ID28049566
PubMed Central IDPMC5462867
Grant ListR01 MH095034 / MH / NIMH NIH HHS / United States
U01 AG009740 / AG / NIA NIH HHS / United States
G0200243 / MRC_ / Medical Research Council / United Kingdom
076113 / / Wellcome Trust / United Kingdom
G0701420 / / Medical Research Council / United Kingdom
U24 MH068457 / MH / NIMH NIH HHS / United States
U01 MH094421 / MH / NIMH NIH HHS / United States
090355 / / Wellcome Trust / United Kingdom
U01 MH109528 / MH / NIMH NIH HHS / United States
MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom
RC2 MH089951 / MH / NIMH NIH HHS / United States
RC4 AG039029 / AG / NIA NIH HHS / United States
R01 MH081802 / MH / NIMH NIH HHS / United States
RF1 AG015819 / AG / NIA NIH HHS / United States
RC2 MH089995 / MH / NIMH NIH HHS / United States
R01 MH077139 / MH / NIMH NIH HHS / United States
104036 / / Wellcome Trust / United Kingdom
R01 AG017917 / AG / NIA NIH HHS / United States
/ / Department of Health / United Kingdom
085475 / / Wellcome Trust / United Kingdom
P30 AG010161 / AG / NIA NIH HHS / United States
K01 MH102403 / MH / NIMH NIH HHS / United States
RC2 AG036495 / AG / NIA NIH HHS / United States
/ / Wellcome Trust / United Kingdom