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Background <p>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.</p> Methods <p>We conducted a trans-ancestry genome-wide association study (GWAS) of hot flashes (<i>N</i> = 149,560) among post-menopausal women age 35-88. The outcome variable was self-reported hot flashes in four samples (total <i>n</i> = 42,489) and menopausal hormone therapy as a proxy in one sample (<i>n</i> = 107,071). We estimated the heritability of hot flashes and genetic correlations with psychiatric phenotypes using linkage disequilibrium score regression.</p> Results <p>In our trans-ancestry meta-analysis, the top locus lies on chromosome 4 in the neurokinin 3 receptor gene (<i>TACR3</i>, <i>p</i> = 7.2×10<sup>-41</sup>). We also identify another locus on chromosome 4 with top SNP rs13107507 (<i>p</i> = 3.5×10<sup>-8</sup>). Gene results implicate <i>TACR3</i>, <i>GRID1</i>, <i>NUDT4</i>, and <i>PHF21B</i>. SNP heritability is estimated to be 8% (<i>h</i><sup><i>2</i></sup><sub>liab</sub> = .08, <i>h</i><sup><i>2</i></sup><sub>SNP</sub> = .04, <i>se</i> = .02). Genetic correlations are statistically significant between hot flashes and PTSD (<i>rg</i> = 0.25, <i>p</i> = 0.01), schizophrenia (<i>rg</i> = 0.17, <i>p</i> = 0.02), depression (<i>rg</i> = 0.21, <i>p</i> = 0.01), and ADHD (<i>rg</i> = .22, <i>p</i> = 0.03).</p> Conclusions <p>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 (<i>TACR3</i>, 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月6日

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  • Kathryn E. Werwath,
  • Rebecca B. Lawn,
  • Madeleine T. Salem,
  • Tayden Li,
  • Brittany L. Mitchell,
  • Hanyang Shen,
  • Scott D. Gordon,
  • Benson Kung,
  • Ciera Stafford,
  • Mytilee Vemuri,
  • Andrew Ratanatharathorn,
  • Joeri Meijsen,
  • Aladdin H. Shadyab,
  • Charles Kooperberg,
  • Karestan C. Koenen,
  • Carolyn J. Crandall,
  • Nicholas G. Martin,
  • Laramie E. Duncan

摘要

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.