Trans-Ancestry GWAS of Hot Flashes Reveals Potent Treatment Target and Overlap with Psychiatric Disorders

Abstract

Background: Most women experience hot flashes (hot flushes) during the menopause transition. Menopausal hot flashes typically persist for years. For a sizeable minority of women, hot flashes are severe and substantially impairing. It is worthwhile to further investigate the genetic underpinnings of hot flashes. Method: We conducted the largest trans-ancestry genome-wide association study (GWAS) of hot flashes available to date (N=149,560). We used self-assessment of hot flashes in the Nurses' Health Study, Nurses' Health Study II, Women's Health Initiative, and Queensland Institute of Medical Research samples (total n=42,489). In one sample (UK Biobank, n=107,071) direct assessment of hot flashes was not available, so menopausal hormone therapy was used as a proxy variable. We estimated the heritability of hot flashes and genetic correlations with psychiatric phenotypes using linkage disequilibrium score regression (LDSR). Results: In component analyses and our trans-ancestry meta-analysis, the top locus was on chromosome 4 in the neurokinin 3 receptor gene (TACR3, position 104,556,732, trans-ancestry p=7.2x10-41). A second novel locus was identified (LINC02428, p=3.5x10-8). Gene results implicated TACR3, GRID1, NUDT4, and PHF21B. Using the hot flash GWAS meta-analysis (n=42,489; i.e., no proxy variable), SNP heritability was estimated: h2liab=.08 (h2SNP=.04, se=.02). Genetic correlations were statistically significant between hot flashes and posttraumatic stress disorder (PTSD, rg=0.25, p=0.01), schizophrenia (rg=0.17, p=0.02), and depression (rg=0.21, p=0.01). Discussion: These genomic findings are consistent with independent, robust basic science research which led to a novel treatment for hot flashes, namely, neurokinin 3 receptor antagonists. This new class of hot flash drugs blocks the receptor (neurokinin 3 receptor) coded for by the top locus for hot flashes (TACR3). This GWAS of hot flashes provides an uncommonly clear example of how GWAS findings can point to potent treatment targets for complex brain phenotypes. We also found that the proxy variable (menopausal hormone therapy) pointed to the same target (TACR3), and that exclusively intronic and intergenic variants signaled this target.