Genetic stratification of depression in UK Biobank suggests a subgroup linked to age of natural menopause

Depression is a common and clinically heterogeneous mental health disorder that is frequently comorbid with other diseases and conditions. Stratification of depression may align sub-diagnoses more closely with their underling aetiology and provide more tractable targets for research and effective treatment. In the current study, we investigated whether genetic data could be used to identify subgroups within people with depression using the UK Biobank. Examination of cross-locus correlations was used to test for evidence of subgroups by examining whether there was clustering of independent genetic variants associated with eleven other complex traits and disorders in people with depression. We found evidence of a subgroup within depression using age of natural menopause variants ( P = 1.69 × 10 −3 ) and this effect remained significant in females ( P = 1.18 × 10 −3 ), but not males ( P = 0.186). However, no evidence for this subgroup ( P > 0.05) was found in Generation Scotland, iPSYCH, a UK Biobank replication cohort or the GERA cohort. In the UK Biobank, having depression was also associated with a later age of menopause (beta = 0.34, standard error = 0.06, P = 9.92 × 10 −8 ). A potential age of natural menopause subgroup within depression and the association between depression and a later age of menopause suggests that they partially share a developmental pathway.