hide
Free keywords:
Age at onset, GWAS, Heterogeneity, Major depressive disorder, Polygenic scoring, Stratification
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 x 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.
