Genetic factors for reproductive aging and vasomotor symptoms

Contemporary OB/GYN JournalVol 66 No 6
Volume 66
Issue 06

Genetic factors predictive of reproductive aging also are linked to vasomotor symptoms (VMS), indicative of VMS having a polygenic architecture, according to an analysis of the Study of Women’s Health Across the Nation (SWAN) Genomic Substudy.

The analysis of a multiracial/ethnic cohortinthe journal Menopausefound that in White women only, there was an association between the protein-coding gene tachykinin receptor 3 (TACR3) and VMS.

But among Chinese and Japanese women, all 14 TACR3 single-nucleotide polymorphisms (SNPs) were monomorphic or extremely rare.

Sioban Harlow, PhD

Sioban Harlow, PhD

“Most women experience some VMS as they transition through menopause,” said principal investigator Sioban Harlow, PhD, a professor of epidemiology and global public health at the University of Michigan in Ann Arbor. “And a subset of women experiences severe and bothersome hot flashes that last on average more than 5 years.”

The investigators created polygenic risk scores (PRSs) from genome-wide association studies of VMS and ages at menarche and menopause for 702 White, 306 Black, 126 Chinese, and 129 Japanese women.

Since enrollment in SWAN across 7 sites in 1996 and 1997, participants have had on average 15 follow-up visits. The study also remains in contact with 75% of surviving participants.

At each visit, women completed an interviewer-administered and self-administered questionnaires on a broad range of topics, including menstrual characteristics and current use of hormone therapy (HT) for menopausal symptoms, and symptom experience.

“Genetic factors associated with age at menopause and age at menarche were associated with VMS in some but not all race/ethnic groups, suggesting that VMS has a polygenic architecture,” Harlow told Contemporary OB/GYN®. “Specifically, in Black women, a higher PRS for older age at menarche was associated with a 45% reduction in the odds of frequent VMS (VMS ≥6 days in the past 2 weeks at any visit) and of experiencing a sustained high-frequency VMS trajectory.”

But in White women, a higher PRS for older age at menarche was connected to only a 25% reduction in the odds of having a frequent VMS trajectory with onset at final menstrual period.

“Chinese women with a higher PRS for older age at menopause had a two-fold increase in the odds of having frequent VMS,” Harlow said.

The authors expected to replicate findings of a link between VMS and TACR3. “However, findings of associations with PRSs for age at menopause and age at menarche are novel,” Harlow said.

The proportion of women who ever used HT during follow-up ranged from 33.3% for Chinese women to 52.7% for White women, with 6.1% to 25.0% reporting HT use at any given visit.

Frequent VMS were ever reported by 70.7% of White, 79.4% of Black, 51.6% of Chinese and 52.7% of Japanese women.

“Increasing scientific understanding of the different biological pathways that underlie hot flashes is critical for innovation in the prevention and treatment of bothersome vasomotor symptoms,” said Harlow, director of the Center for Midlife Science at the University of Michigan. “Validation of the casual effects of specific SNPs in vitro could also provide support for new targets for VMS alleviation, such as the use of neurokinin B (NKB) pathway agents. Replication in larger samples in diverse populations is needed as well.”



Harlow reports no relevant financial disclosures.


Zhao W, Smith JA, Yu M, et al. Genetic variants predictive of reproductive aging are associated with vasomotor symptoms in a multiracial/ethnic cohort. Menopause. Published online April 26, 2021.


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