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

Abstract

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 sex hormone binding globulin (SHBG) by menopausal status in women of European and African ancestry. Methods Using data on 229,966 women from UK Biobank, we conducted genome-wide association studies (GWAS) 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 four 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 one locus for testosterone (7q22.1) in the CYP3A7 gene, and one 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.

Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis

“…The gonadal phenotypes from XY mutant mice range from ovotestes to ovaries, thus mimicking those found in human patients carrying coding mutations on FGF9 43 , or in FGFR2 that encodes its gonadal receptor 63 . Remarkably, this novel regulatory region also contains several human GWAS hits associated with fluctuations in testosterone levels [44][45][46] , a phenotype that is consistent with altered FGF9 regulation. Overall, METALoci revealed important insights into the process of sex determination, going from fundamental mechanisms of gene regulation to their relevance in vivo.…”

“…Specifically, we identified a noncoding region located approximately 250 Kb downstream of Fgf9, whose deletion was predicted to be disruptive of its HH metaloci. Interestingly, the human homologous region contains GWAS hits associated with abnormal testosterone levels [44][45][46] , a phenotype that is consistent with alterations in FGF9 expression (Extended Data Table 2). To validate the METALoci predictions, we generated a 306 Kb homozygous deletion (Δ306) within the 1.15 Mb TAD of Fgf9, in mouse embryonic stem cells (mESC).…”

Better together against genetic effect heterogeneity: a sex-combined interaction analysis of testosterone levels in the UK Biobank data

“…Finally, we evaluated whether the 27 novel genome-wide significant loci, uniquely identified by T SG Q but missed by T SG F , T SG M and T SG L in the UK Biobank data, are biologically relevant to the testosterone level phenotype. According to the GWAS catalog (Buniello et al, 2018), nine out of the 27 loci were previously reported to be associated with either testosterone level or steroid biosynthesis pathway where testosterone is synthesized (Haas et al (2022); Ruth et al (2020); Richardson et al (2022);Hoffmann et al (2018)). Furthermore, we used Ensembl Variant Effect Predictor (McLaren et al, 2016) to extract a list of genes affected by the top SNPs in these loci, of which multiple genes were previously reported to be associated with testosterone or the cholesterol level (Table 1).…”

Better together against genetic effect heterogeneity: a sex-combined interaction analysis of testosterone levels in the UK Biobank data

“…Finally, we evaluated whether the 27 novel genome-wide significant loci, uniquely identified by TSG Q but missed by TSG F , TSG M and TSG L in the UK Biobank data, are biologically relevant to the testosterone level phenotype. According to the GWAS catalog (Buniello et al, 2018), nine out of the 27 loci were previously reported to be associated with either testosterone level or steroid biosynthesis pathway where testosterone is synthesized (Haas et al (2022); Ruth et al (2020);Richardson et al (2022);Hoffmann et al (2018)). Furthermore, we used Ensembl Variant Effect Predictor (McLaren et al, 2016) to extract a list of genes affected by the top SNPs in these loci, of which multiple genes were previously reported to be associated with testosterone or the cholesterol level (Table 1).…”