Genome-wide Association For Major Depression Through Age At Onset Stratification: Major Depressive Disorder Working Group Of The Psychiatric Genomics Consortium
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 5.2 3 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.
- Power et al. - 2017 - Genome-wide Association for Major Depression Throu.pdf application/pdf 653 KB Download File
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- Biological Psychiatry