rs11130329 (STIMATE): Puberty Timing and Adiposity

Key takeaways

• rs11130329 is linked to idiopathic central precocious puberty (ICPP), with the highest polygenic risk group showing an odds ratio above 11 for early puberty in a Taiwanese Han Chinese cohort
• This locus appears in cross-trait genomic analyses connecting adiposity measures to cancers including colorectal, breast, and endometrial cancer
• GTEx data show this variant strongly increases ITIH4 expression in brain and testis while reducing STIMATE expression in immune cells
• A 22-variant polygenic score including this locus achieved AUC 0.713 for distinguishing early puberty cases from controls

What the research says A genome-wide association study (GWAS, a method for scanning the genome to find genetic variants linked to traits) of 321 Taiwanese Han Chinese girls with idiopathic central precocious puberty (ICPP, a condition where puberty begins abnormally early) and 148 controls identified 105 variants associated with ICPP risk; 33 of these replicated prior GWAS associations for pubertal timing, and a 22-variant weighted polygenic risk score (a combined genetic score) built from this set achieved an area under the ROC curve of 0.713 for predicting early puberty, with the third quartile showing an odds ratio of 11.67 (95% CI: 2.44-55.83). A separate large-scale cross-trait analysis of nine adiposity measures and five obesity-related cancers, drawing on European-ancestry datasets each exceeding 20,000 participants, identified 464 pleiotropic loci (genomic regions whose variants influence multiple traits simultaneously) and 409 candidate shared genes, with 128 of those genes replicated in transcriptome-wide association analyses and Mendelian randomization (a genetic method for estimating causal effects) indicating stronger cancer associations for genetically elevated BMI and waist-to-hip ratio than for other fat distribution measures.

Reported associations

• Idiopathic central precocious puberty and early puberty risk: Variants in this locus were among 33 SNPs (single-letter DNA sequence changes) from pubertal timing GWAS that replicated in an ICPP cohort of 321 cases and 148 controls; a 22-SNP polygenic risk score achieved AUC 0.713, with second-quartile OR 5.00 (95% CI: 1.55-16.16) and third-quartile OR 11.67 (95% CI: 2.44-55.83) for early puberty
• Adiposity and obesity-related cancer: Cross-trait analysis identified this locus among 464 pleiotropic regions shared between adiposity measures, including BMI, waist-to-hip ratio, and MRI-derived fat depots, and cancers including colorectal, breast, endometrial, and ovarian cancer
• ITIH4 expression: The alternate allele is associated with increased ITIH4 expression, most strongly in testis, and also in cerebellum, cerebellar hemisphere, thyroid, and colon sigmoid GTEx Portal
• STIMATE expression: The alternate allele is associated with reduced STIMATE expression in EBV-transformed lymphocytes (a laboratory model of immune cells commonly used in genetics research) and increased STIMATE expression in thyroid GTEx Portal
• ITIH4-AS1 expression: The alternate allele is associated with increased ITIH4-AS1 expression in testis GTEx Portal

Evidence quality The ICPP association draws on a single-ancestry cohort of 321 cases and 148 controls from Taiwan, limiting generalizability to other ancestries and reducing statistical precision; however, the 33-SNP replication set leverages prior large-scale pubertal timing GWAS, adding confidence to the locus. The dose-dependent gradient across polygenic risk quartiles (OR rising from 5.00 to 11.67 across quartiles 2 and 3) supports biological plausibility but should be interpreted cautiously given the small discovery cohort and single-population design. The adiposity-cancer cross-trait evidence uses larger European-ancestry datasets (each exceeding 20,000 participants), applies multiple complementary methods including genome-wide cross-trait analysis, colocalization, transcriptome-wide association analysis (TWAS, which links genetic variants to gene expression and then to traits), and Mendelian randomization, and replicated 128 of 409 candidate genes in independent transcriptome analyses, representing stronger evidence than the ICPP finding. The pleiotropic nature of this locus means the same region may affect multiple traits through distinct mechanisms that are not yet fully characterized. No direct conflicting findings were reported across the provided studies.

Tissue-specific expression effects

• ITIH4: The alternate allele is associated with increased expression in testis (largest magnitude effect), as well as in cerebellum, cerebellar hemisphere, thyroid, and colon sigmoid GTEx Portal
• STIMATE: The alternate allele is associated with reduced expression in EBV-transformed lymphocytes and increased expression in thyroid GTEx Portal
• ITIH4-AS1: The alternate allele is associated with increased expression in testis GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.