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The TACR3 gene locus encoding neurokinin 3 receptor has been implicated as forming the genetic basis of menopausal vasomotor symptoms. However, a new genomic study reports that the genomic variants reducing the levels of neurokinin 3 receptor levels are not implicated in the modification of these symptoms.

Vasomotor symptoms in women undergoing menopause often lead to significant impairment of the quality of life. The onset of these symptoms is associated with an increase in neurokinin 3 receptor signaling, which may have a genetic basis. 

This study performed a genome-wide association study (GWAS) of vasomotor symptoms in a population-based cohort. The study also investigated the association of vasomotor symptoms with rare genomic variants and utilized Mendelian randomization analysis to explore the reasons underlying the use of hormone replacement therapy. The findings are published in the journal BMC Medical Genomics.

Study Characteristics

A total of 14,261 women with vasomotor symptoms and 77,767 controls were included in this GWAS. The mean age of cases and controls was 56.08 ± 7.37 years and 60.55 ± 5.39 years, respectively. The mean body mass index (BMI) of cases and controls was 27.25 ± 5.03 kg/m2 and 27.31 ± 5.11 kg/m2, respectively.

Vasomotor Symptom Phenotype

In the GWAS, a single independent gene signal (lead variant rs34867104) was identified and was related to lower odds of occurrence of vasomotor symptoms. The most likely gene to be present in this region is the TACR3 gene.

Genetic Variants of Vasomotor Symptoms and Levels of Neurokinin 3 Receptor

There was little evidence to support the association between vasomotor symptoms and loss-of-function (LOF) of the TACR3 gene; however, this gene variant was associated with delayed menarche. The allele carriers were heterozygous and had reduced TACR3 protein levels. The gene analysis also indicated that rs34867104 was not an independent signal for the timing of menarche.

Menopause Timing and Hormone Replacement Therapy Proxy Phenotype

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The genetic analysis revealed that the use of the HRT proxy phenotype captures the vasomotor symptoms non-specifically.

Role of Genetics in Capturing Hormone Replacement Therapy Usage

The study observed changes in the characteristics of women utilizing HRT before and after the publication of a clinical trial reporting the adverse outcomes associated with HRT administration in the year 2002. Genetically predicted earlier menopause was associated with increased odds of use of HRT before 2002, which did not hold true for the use of HRT after 2002.

Source:

Ruth, K. S., Beaumont, R. N., Locke, J. M., Tyrrell, J., Crandall, C. J., Hawkes, G., Frayling, T. M., Prague, J., Patel, K., Wood, A. R., Weedon, M. N., & Murray, A. (2023). Insights into the genetics of menopausal vasomotor symptoms: genome-wide analyses of routinely-collected primary care health records. BMC Medical Genomics, 16(1). https://doi.org/10.1186/s12920-023-01658-w