rs117585797 (ANO2): Sex Hormone Genetics

Key takeaways

• rs117585797 is located near the ANO2 gene and was identified in a genome-wide scan of sex hormone levels across nearly 7.9 million genetic variants
• The study found eight genome-wide significant signals (P<5x10-8) for nine sex hormone-related traits in a cohort of 2,913 European individuals
• Novel associations were reported for progesterone (P=7.68x10-12), oestradiol (P=1.63x10-8), and free androgen index (P=1.50x10-8) among other hormones
• All known sex hormone GWAS signals together explain under 10% of variance in most hormones, meaning many other genetic and non-genetic factors contribute
• Evidence is from a single study in one cohort; independent replication is not reported in the available study text

What the research says A genome-wide association study (GWAS, a large-scale scan of the genome for variants linked to a trait) used 1000 Genomes-imputed genotypes in up to 2,913 individuals of European ancestry from the TwinsUK registry to test associations with nine sex hormone-related phenotypes: dehydroepiandrosterone sulphate (DHEAS), oestradiol, free androgen index (FAI, calculated as testosterone divided by sex hormone-binding globulin multiplied by 100), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, progesterone, sex hormone-binding globulin (SHBG, a glycoprotein that binds and transports sex hormones including oestradiol and testosterone), and testosterone. Eight independent variants reached genome-wide significance with minor allele frequencies ranging from 1.3% to 23.9%. Prior GWAS had explained under 10% of variance in oestradiol and SHBG, and under 5% for testosterone, DHEAS, and FSH, motivating this study to identify additional contributing loci.

Reported associations

• Progesterone (novel signal): Genome-wide significant association at P=7.68x10-12, identified as a novel finding in this GWAS
• Oestradiol (novel signal): Genome-wide significant association at P=1.63x10-8, identified as a novel finding
• Free androgen index (FAI, novel signal): Genome-wide significant association at P=1.50x10-8, a novel finding; FAI reflects bioavailable testosterone (testosterone divided by SHBG, times 100)
• Follicle-stimulating hormone (FSH) and luteinizing hormone (LH): A variant near the FSHB gene was associated with FSH at P=1.74x10-8 and with LH at P=3.94x10-9
• DHEAS and progesterone (shared locus): A separate locus on chromosome 7 was associated with DHEAS (P=1.82x10-14) and with progesterone at the same locus (P=6.09x10-14)

Evidence quality The study included 2,913 individuals of European ancestry from the TwinsUK twin registry, a modest sample for contemporary GWAS. The cohort was predominantly female, with a maximum of 294 males included, limiting generalisability to male populations. Approximately 7.9 million autosomal SNPs were tested using genotypes imputed from the 1000 Genomes reference panel. Phenotypes were standardised for age, sex, BMI, menstrual cycle phase, and menopausal status; individuals on hormone therapy or oral contraceptives were excluded. The study identified eight genome-wide significant signals in total, but the full results section specifying which signal corresponds to rs117585797 was not available in the provided text excerpt, so direct effect-size attribution to this specific variant is limited. The authors note that cumulative GWAS findings explain under 10% of variance in most sex hormone traits, consistent with a highly polygenic architecture where many variants each contribute small effects. No independent replication cohort results are reported in the available text.

Lifestyle considerations No lifestyle considerations on file for this variant.