Hirsutism beyond PCOS: Genome-wide evidence for genetic factors

Hirsutism is a condition characterized by excessive hair growth in women, with a prevalence of 5-10 %. The diagnostic criteria usually include hair appearing in male-pattern areas, such as the face, abdomen, and chest. The contributing factors for hirsutism symptoms are heterogeneous and vary from genetic and ethnic backgrounds to diverse endocrinological causes, most commonly polycystic ovary syndrome. In this cross-ancestry GWAS, including 4834 cases and 352,966 controls, we explored the genetic background of hirsutism and identified 7 loci associated with the condition, 4 of which have not, to our knowledge, been previously reported in GWAS. To capture low-frequency variants, we analyzed the Finnish FinnGen cohort separately, leveraging its bottleneck history, which enriches for rare variants with larger effects. A missense variant, rs199649605 (effect allele frequency = 0.005), enriched in the Finnish population near FGF5, a gene regulating the hair follicle cycle, showed a particularly strong effect (P = 1.39 × 10^-10, OR = 5.02, 95 % confidence interval = 3.06-8.21). Genetic correlation analyses revealed a shared genetic architecture between hirsutism, polycystic ovary syndrome, and metabolic traits such as obesity and type 2 diabetes. These findings uncover genetic contributors to hirsutism beyond polycystic ovary syndrome, suggesting that both androgen-dependent and independent mechanisms underlie excessive hair growth in women.