rs116173394 (GOLPH3L): Prostate Cancer Risk Locus

Key takeaways

• rs116173394 in the ENSA-GOLPH3L region was identified as a novel prostate cancer risk variant in one of the largest genetic studies of the disease ever conducted.
• The study analyzed over 156,000 prostate cancer cases and 788,000 controls across European, African, Asian, and Hispanic populations.
• This variant is one of 187 newly discovered risk loci that raised the total count of known prostate cancer genetic risk factors to 451.
• The ALT allele at this position is linked to increased expression of both HORMAD1 and GOLPH3L genes across multiple body tissues.
• Evidence for this variant comes from a single large study; independent replication specific to this locus is not yet documented.

What the research says rs116173394, in the ENSA-GOLPH3L region (a chromosomal area containing the ENSA and GOLPH3L genes), was reported as one of 187 novel prostate cancer risk variants in a multi-ancestry genome-wide association study (GWAS - a method that scans millions of genomic positions to find variants statistically linked to a trait) of 156,319 cases and 788,443 controls drawn from European, African, Asian, and Hispanic populations. The study used genome-wide significance thresholds (p<5x10^-8, a stringent statistical bar to limit false positives) and forward-selection conditional analysis to confirm 451 independent prostate cancer risk variants in total. Expression data from GTEx v11 (953 donors, FDR<0.05) additionally shows that the ALT allele at this locus is associated with increased expression of HORMAD1 across six tissue types - with the strongest effect in esophagus mucosa - and increased expression of GOLPH3L in nerve and sun-exposed skin tissue GTEx Portal.

Reported associations

• Prostate cancer risk: Identified as a novel susceptibility locus in a multi-ancestry GWAS of 156,319 prostate cancer cases and 788,443 controls spanning four ancestry groups; the individual effect size (odds ratio) for this specific variant is not stated in the available study text.

Evidence quality The prostate cancer association for rs116173394 derives from a single large multi-ancestry GWAS of 156,319 cases and 788,443 controls, using genome-wide significance (p<5x10^-8) and conditional analysis to confirm independence. While the overall study design is rigorous and the sample size is very large, the individual odds ratio for this specific locus is not reported in the available text. Independent replication of this particular variant's association is also not documented in the materials provided, which limits confidence at the single-variant level. The GTEx eQTL (expression quantitative trait locus - a variant that predicts the expression level of a nearby gene) data for HORMAD1 and GOLPH3L come from 953 GTEx v11 donors with FDR<0.05 significance thresholds, providing statistically robust evidence for expression-level effects; however, eQTL associations describe a molecular correlation and do not on their own confirm that this variant causally drives disease risk.

Tissue-specific expression effects

• HORMAD1: The ALT allele is associated with increased expression in esophagus mucosa, tibial nerve, suprapubic skin (non-sun-exposed), sun-exposed lower leg skin, subcutaneous adipose tissue, and cultured fibroblasts; the effect is strongest in esophagus mucosa GTEx Portal
• GOLPH3L: The ALT allele is associated with increased expression in tibial nerve and sun-exposed lower leg skin GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.