Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium.

Biol Psychiatry
Authors
Abstract

BACKGROUND: Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset.

METHODS: Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer's disease, and coronary artery disease.

RESULTS: We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11-1.21, p = 5.2 × 10(-11)). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD.

CONCLUSIONS: We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder.

Year of Publication
2017
Journal
Biol Psychiatry
Volume
81
Issue
4
Pages
325-335
Date Published
2017 Feb 15
ISSN
1873-2402
DOI
10.1016/j.biopsych.2016.05.010
PubMed ID
27519822
PubMed Central ID
PMC5262436
Links
Grant list
R01 MH059552 / MH / NIMH NIH HHS / United States
U01 MH085520 / MH / NIMH NIH HHS / United States
R01 AA007535 / AA / NIAAA NIH HHS / United States
R01 MH072802 / MH / NIMH NIH HHS / United States
R01 AA014041 / AA / NIAAA NIH HHS / United States
R01 MH081802 / MH / NIMH NIH HHS / United States
R01 MH060912 / MH / NIMH NIH HHS / United States
R01 MH066206 / MH / NIMH NIH HHS / United States
R01 AA013326 / AA / NIAAA NIH HHS / United States
R56 DA012854 / DA / NIDA NIH HHS / United States
R01 MH059541 / MH / NIMH NIH HHS / United States
R01 AA013321 / AA / NIAAA NIH HHS / United States
U01 DK066134 / DK / NIDDK NIH HHS / United States
CZD/16/6/4 / Chief Scientist Office / United Kingdom
N01MH90003 / MH / NIMH NIH HHS / United States
R01 DA012854 / DA / NIDA NIH HHS / United States
K08 DA019951 / DA / NIDA NIH HHS / United States
R01 MH080403 / MH / NIMH NIH HHS / United States
R01 MH059542 / MH / NIMH NIH HHS / United States
R01 MH061686 / MH / NIMH NIH HHS / United States
U54 RR020278 / RR / NCRR NIH HHS / United States
R01 MH075131 / MH / NIMH NIH HHS / United States
R01 AA013320 / AA / NIAAA NIH HHS / United States