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

Abstract

BackgroundMajor 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.MethodsDiscovery 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.ResultsWe 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.ConclusionsWe 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.

Age of onset and family history as indicators of polygenic risk for major depression

“…Moreover, research on recurrent cases here is consistent with sampling methods from the previous molecular studies on AO. 27-29 …”

“…A potential implication of this finding is an increased genetic loading for MD in earlier-onset cases. 29 …”

Machine learning in major depression: From classification to treatment outcome prediction

“…For example, MDD workgroup has been a part of the PGC since 2007, and now it covers over 100 000 people with depression. The PGC MDD group has published a paper confronting the notably challenges in genetic dissection of MDD and keeps increasing sample size and expanding their studies . The ENIGMA MDD working group includes brain scans of around >5000 MDD patients and >9000 controls from 35 research samples of 14 different countries worldwide.…”

Genome‐wide association studies of bipolar disorder: A systematic review of recent findings and their clinical implications

“…However, it is of note that RPS analyses could potentially identify clinical subtypes or treatment responses in psychiatric patients, including those with BD; for example, early‐onset MDD had a higher polygenic score based on the BD risk. This finding suggests that clinicians should consider that patients with early‐onset MDD may be at risk for development of BD, and it is reasonable in a clinical sense …”