rs11155787 (ZBTB2): Testosterone & Sex Hormone GWAS

Key takeaways

• rs11155787 sits near ZBTB2 (Zinc Finger and BTB Domain Containing 2, a transcriptional repressor - a protein that suppresses the activity of other genes) and was identified in a genome-wide study of testosterone and sex hormone levels covering up to 425,000 participants.
• Testosterone genetics research shows opposite effects on Type 2 diabetes risk in men versus women, based on a multi-variant genetic analysis that includes this variant among thousands of others.
• The ALT allele of rs11155787 is associated with reduced expression of a nearby gene (ENSG00000297566) in thyroid tissue and increased AKAP12 expression in tibial nerve tissue.
• This variant was also studied in a cross-population atlas spanning 220 human traits across Japanese and European ancestry cohorts totaling up to 628,000 participants.

What the research says A genome-wide association study in up to 425,097 UK Biobank participants identified 2,571 genome-wide significant associations for sex hormone traits including total testosterone, sex hormone-binding globulin (SHBG, a protein that carries sex hormones in the bloodstream), and bioavailable testosterone, with rs11155787 near ZBTB2 among the identified signals. PMID 32042192 Using these variants collectively as a genetic instrument in Mendelian randomization (a method that uses inherited genetic variants to estimate causal effects, reducing confounding from lifestyle and ageing), the study found sex-specific metabolic effects: in women, a 1-standard-deviation increase in genetically determined testosterone raised Type 2 diabetes risk (OR 1.37, 95% CI 1.22 to 1.53) and polycystic ovary syndrome risk (OR 1.51, 95% CI 1.33 to 1.72), while in men the same increase reduced Type 2 diabetes risk (OR 0.86, 95% CI 0.76 to 0.98). PMID 32042192 A separate cross-population atlas analyzed this locus across 220 phenotypes in BioBank Japan combined with UK Biobank and FinnGen (up to 628,000 participants), identifying approximately 5,000 new genetic loci across diseases, biomarkers, and medication usage. PMID 34385711

Reported associations

• Sex hormone traits (GWAS discovery): rs11155787 near ZBTB2 was identified among 2,571 genome-wide significant genetic associations for testosterone, SHBG, bioavailable testosterone, and estradiol in up to 425,097 participants; the study noted that genetic determinants of testosterone levels differ substantially between men and women. PMID 32042192
• Type 2 diabetes (Mendelian randomization): Using all identified sex-hormone variants as a collective genetic instrument (which includes this variant), genetically higher testosterone increased T2D risk in women (OR 1.37, 95% CI 1.22 to 1.53) and reduced it in men (OR 0.86, 95% CI 0.76 to 0.98); these effect estimates reflect the aggregate of 2,571 variants, not this variant in isolation. PMID 32042192
• Polycystic ovary syndrome (Mendelian randomization): Using the same collective genetic instrument, genetically higher testosterone increased PCOS risk in women (OR 1.51, 95% CI 1.33 to 1.72). PMID 32042192
• Cancer outcomes (Mendelian randomization): The same analysis identified adverse effects of genetically higher testosterone on breast and endometrial cancers in women, and on prostate cancer in men; specific odds ratios for these outcomes are not reported in the available study summary. PMID 32042192
• Multiple human phenotypes (cross-population): This locus was included in a cross-population atlas spanning 220 phenotypes across BioBank Japan, UK Biobank, and FinnGen, as part of approximately 5,000 newly identified genetic loci in a combined sample of up to 628,000 participants. PMID 34385711

Evidence quality The testosterone GWAS used up to 425,097 UK Biobank participants and reported genome-wide significant findings, with replication conducted in three external datasets; heritability was demonstrable for testosterone and SHBG traits. PMID 32042192 The cross-population atlas combined up to 628,000 participants across Japanese and European ancestry cohorts, improving generalizability beyond predominantly European samples. PMID 34385711 Critically, the Mendelian randomization effect estimates for T2D, PCOS, and cancer outcomes reflect the combined effect of 2,571 genetic variants acting as a group, not the independent contribution of rs11155787 alone; the specific proportion of sex hormone variance attributable to this single variant is not reported in the available study summaries. The GTEx tissue-specific expression associations (FDR below 0.05, 953 donors, GTEx v11) are statistical correlations between genotype and gene expression and do not establish a causal biological mechanism or a clinical outcome. No direct conflicts were identified between the two GWAS studies, as they examined different primary phenotypes.

Tissue-specific expression effects

• ENSG00000297566: The rs11155787 ALT allele is associated with reduced expression of this gene in thyroid tissue. GTEx Portal
• AKAP12: The ALT allele is associated with increased expression in tibial nerve tissue. GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.