Cross-ancestry Genome-wide Association Studies of Sex Hormone Concentrations in Pre- and Postmenopausal Women.

Objective: Concentrations of circulating sex hormones have been associated with a variety of diseases in women and are strongly influenced by menopausal status. We investigated the genetic architectures of circulating concentrations of estradiol, testosterone, and SHBG by menopausal status in women of European and African ancestry.
Methods: Using data on 229 966 women from the UK Biobank, we conducted genome-wide association studies (GWASs) of circulating concentrations of estradiol, testosterone, and SHBG in premenopausal and postmenopausal women. We tested for evidence of heterogeneity of genetic effects by menopausal status and genetic ancestry. We conducted gene-based enrichment analyses to identify tissues in which genes with GWAS-enriched signals were expressed.
Results: We identified 4 loci (5q35.2, 12q14.3, 19q13.42, 20p12.3) that were associated with detectable concentrations of estradiol in both pre- and postmenopausal women of European ancestry. Heterogeneity analysis identified 1 locus for testosterone (7q22.1) in the CYP3A7 gene and 1 locus that was strongly associated with concentrations of SHBG in premenopausal women only (10q15.1) near the AKR1C4 gene. Gene-based analysis of testosterone revealed evidence of enrichment of GWAS signals in genes expressed in adipose tissue for postmenopausal women. We did not find any evidence of ancestry-specific genetic effects for concentrations of estradiol, testosterone, or SHBG.
Conclusions: We identified specific loci that showed genome-wide significant evidence of heterogeneity by menopausal status for testosterone and SHBG. We also observed support for a more prominent role of genetic variants located near genes expressed in adipose tissue in determining testosterone concentrations among postmenopausal women.
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