Genetic Exploration of Depression Onset in Females from Menarche to Menopause

Depression risk in females is markedly elevated during hormonal transitions such as menarche, the perinatal period, and menopause; yet the genetic basis of depression onset during these windows remains uncharacterized. We conducted GWAS meta-analyses (including the X chromosome) in females from Generation Scotland and UK Biobank, running the first GWAS of depression onset around menarche (ncases = 3,089; ncontrols = 25,558) and around natural menopause (ncases = 3,754; ncontrols = 14,079), and the largest female-specific GWAS of continuous age at onset of depression (N = 29,735). We identified one locus for depression onset around menarche and two for depression onset around menopause, including one mapping onto CDKAL1, a gene implicated in metabolic disorders, and no genome-wide significant findings for continuous age at onset. Genetic correlation analyses revealed moderate to strong positive correlations among depression onset around menarche, around menopause, and postpartum depression (rg = 0.47-0.95), suggesting possible shared genetic pathways of reproductive-related depressions. Mendelian randomization demonstrated a causal effect of earlier menarche on depression onset around menarche; by contrast, age at menopause did not causally influence depression onset around menopause. Together, these findings establish a partly shared and partly distinct genetic architecture across reproductive-related depression subtypes, implicate possible metabolic pathways in depression onset around menopause, and provide a genetic framework for understanding why hormonal transitions confer differential depression risk across the female lifespan. By shifting focus from lifetime risk to hormonally defined onset windows, this study advances a timing informed genetic framework for understanding sex differences in depression.