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| PMID |
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| TITLE |
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| Trans-ancestry GWAS of hot flashes reveals potent treatment target and overlap with psychiatric disorders. |
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| ABSTRACT |
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| BACKGROUND |
NlmCategory: 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 |
NlmCategory: METHODS |
| 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. |
| RESULTS |
NlmCategory: RESULTS |
| 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 ). We also identify another locus on chromosome 4 with top SNP rs13107507 (p = 3.5×10 ). Gene results implicate TACR3, GRID1, NUDT4, and PHF21B. SNP heritability is estimated to be 8% (h = .08, h = .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 |
NlmCategory: CONCLUSIONS |
| 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 ). We also identify another locus on chromosome 4 with top SNP rs13107507 (p = 3.5×10 ). Gene results implicate TACR3, GRID1, NUDT4, and PHF21B. SNP heritability is estimated to be 8% (h = .08, h = .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. |
| © 2026. The Author(s). |
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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| received |
2024/09/27 |
| accepted |
2025/12/02 |
| medline |
2026/01/07 01:12 |
| pubmed |
2026/01/07 01:11 |
| entrez |
2026/01/06 23:27 |
| pmc-release |
2026/01/06 |
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| AUTHORS |
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| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Werwath KE |
|
Werwath |
Kathryn E |
KE |
|
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. |
| Lawn RB |
|
Lawn |
Rebecca B |
RB |
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Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Cambridge, MA, USA. |
| Salem MT |
|
Salem |
Madeleine T |
MT |
|
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. |
| Li T |
|
Li |
Tayden |
T |
|
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. |
| Mitchell BL |
|
Mitchell |
Brittany L |
BL |
|
Queensland Institute of Medical Research, Brisbane, QLD, Australia. |
| Shen H |
|
Shen |
Hanyang |
H |
|
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. |
| Gordon SD |
|
Gordon |
Scott D |
SD |
|
Queensland Institute of Medical Research, Brisbane, QLD, Australia. |
| Kung B |
|
Kung |
Benson |
B |
|
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. |
| Stafford C |
|
Stafford |
Ciera |
C |
|
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. |
| Vemuri M |
|
Vemuri |
Mytilee |
M |
|
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. |
| Ratanatharathorn A |
|
Ratanatharathorn |
Andrew |
A |
|
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Cambridge, MA, USA. |
| Meijsen J |
|
Meijsen |
Joeri |
J |
|
Institute for Biological Psychiatry, Copenhagen, Denmark. |
| Shadyab AH |
|
Shadyab |
Aladdin H |
AH |
|
Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA. |
| Kooperberg C |
|
Kooperberg |
Charles |
C |
|
Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA. |
| Koenen KC |
|
Koenen |
Karestan C |
KC |
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Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. |
| Crandall CJ |
|
Crandall |
Carolyn J |
CJ |
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Division of General Internal Medicine and Health Services Research, Dept. of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA. |
| Martin NG |
|
Martin |
Nicholas G |
NG |
|
Queensland Institute of Medical Research, Brisbane, QLD, Australia. |
| Duncan LE |
|
Duncan |
Laramie E |
LE |
|
Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. laramied@stanford.edu. |
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| INVESTIGATORS |
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| JOURNAL |
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| VOLUME: 6 |
| ISSUE: 1 |
| TITLE: Communications medicine |
| ISOABBREVIATION: Commun Med (Lond) |
| YEAR: 2026 |
| MONTH: Jan |
| DAY: 06 |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 2730-664X |
| ISSNTYPE: Electronic |
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| MEDLINE JOURNAL |
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| PUBLICATION TYPE |
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| PUBLICATIONTYPE TEXT |
| Journal Article |
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| COMMENTS AND CORRECTIONS |
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| GRANTS |
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| GRANTID |
AGENCY |
COUNTRY |
| R01 MH123486 |
NIMH NIH HHS |
United States |
| R01 CA067262 |
NCI NIH HHS |
United States |
| U01 CA176726 |
NCI NIH HHS |
United States |
| R21 MH125358 |
NIMH NIH HHS |
United States |
| UM1 CA186107 |
NCI NIH HHS |
United States |
| MH125358 |
U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) |
|
| R01 CA049449 |
NCI NIH HHS |
United States |
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