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

BACKGROUND

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.

METHODS

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.

RESULTS

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).

CONCLUSIONS

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.