Trans-ancestry GWAS of hot flashes reveals potent treatment target and overlap with psychiatric disorders

Most women experience hot flashes (hot flushes) during the menopause transition. Menopausal hot flashes typically persist for years, and for a sizeable minority of women, are substantially impairing. Genetic investigations can improve understanding of hot flash etiology. We conducted a trans-ancestry genome-wide association study (GWAS) of hot flashes (N = 149,560) among post-menopausal women age 35-88. The outcome variable was self-reported hot flashes in four samples (total n = 42,489) and menopausal hormone therapy as a proxy in one sample (n = 107,071). We estimated the heritability of hot flashes and genetic correlations with psychiatric phenotypes using linkage disequilibrium score regression. In our trans-ancestry meta-analysis, the top locus lies on chromosome 4 in the neurokinin 3 receptor gene (TACR3, p = 7.2×10-41). We also identify another locus on chromosome 4 with top SNP rs13107507 (p = 3.5×10-8). Gene results implicate TACR3, GRID1, NUDT4, and PHF21B. SNP heritability is estimated to be 8% (h2liab = .08, h2SNP = .04, se = .02). Genetic correlations are statistically significant between hot flashes and PTSD (rg = 0.25, p = 0.01), schizophrenia (rg = 0.17, p = 0.02), depression (rg = 0.21, p = 0.01), and ADHD (rg = .22, p = 0.03). These genomic findings are consistent with independent, robust basic science research which led to a recently developed treatment for hot flashes, namely, a neurokinin 3 receptor antagonist. This non-hormonal class of hot flash drugs blocks the receptor coded for by the top locus reported here (TACR3, the neurokinin 3 receptor gene). Hot flash GWAS results provide an example of how GWAS findings can point to potent treatment targets for complex brain phenotypes. Hot flashes are sudden sensations of heat that are often accompanied by sweating, flushing, and chills. Most women experience hot flashes during the menopause transition, and for some, they occur for many years, are severe, impact sleep patterns and impair functioning in everyday life. This study aimed to investigate genetic influences on hot flashes to gain insight into their causal mechanisms and potential treatment targets. Using data from a large sample of post-menopausal women, we identified a genetic risk factor on chromosome 4 in the TACR3 gene that is significantly associated with hot flashes. This gene encodes a receptor, which is the target of a recent FDA approved drug that effectively treats hot flashes (fezolinetan/Veozah). These results provide an example of how genetic analyses that scan the human genome can point to mechanisms and clinically useful treatment targets. Werwath, Lawn et al. conduct a large trans-ancestry genome-wide association study (GWAS) of hot flashes among post-menopausal women age 35-88. The findings reveal a locus on chromosome 4 and multiple genes linked to hot flashes, suggesting potential mechanisms and treatment targets.