Hot flash gwas reveals substantial genetic overlap with psychiatric disorders and a top locus that signals a highly effective and novel treatment target

The term “hot flash” refers to the sudden experience of heat in the upper body and face. Approximately 80% of women experience hot flashes during the menopause transition, and these symptoms typically persist for years. Some men also experience hot flashes, and for a minority of individuals hot flashes are severe and substantially impairing. Hot flashes and other menopause symptoms have historically been undertreated and deprioritized in healthcare. We conducted the largest GWAS meta-analysis of hot flashes available to date (N=145,854) using direct assessment of hot flashes in four samples (n=32,974) and assessment of a proxy variable in one sample (UK Biobank, n=103,370). Genetic correlations were estimated using linkage disequilibrium score regression (LDSR) in ancestrally homogeneous samples. In component analyses as well as our trans-ancestry meta-analysis, the top locus was on chromosome 4 in the neurokinin B receptor gene (TACR3, chromosome 4, position 104,557,400, trans-ancestry p=2.8e-34). Genetic correlations between hot flashes and multiple psychiatric phenotypes including neuroticism, schizophrenia, and cannabis use disorder were positive and statistically significant, the largest of which was with post-traumatic stress disorder, PTSD (rg=.54, p=.003). The top hot flash locus is notable because the neurokinin B receptor, expressed prominently in a thermoregulatory center of the brain (hypothalamus), is known to mediate hot flashes. Moreover, blocking this receptor is an effective treatment for hot flashes; the FDA approved a neurokinin B receptor antagonist as a novel, non-hormonal treatment for hot flashes in May of 2023. In sum, this GWAS of hot flashes provides evidence of a genetic component underlying the long-known epidemiological observation of higher psychiatric symptoms among women experiencing hot flashes, and it also provides a rare example of how a GWAS locus could be translated into a novel, effective treatment for a brain-based phenotype.