Exploring the Genetic Basis of Chronic Prostatitis/Chronic Pelvic Pain Syndrome: Insights from a Large-Scale Multi-Ancestry Study

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common, debilitating condition affecting up to 10% of men. The genetic basis of CP/CPPS remains largely unknown. Using Million Veteran Program and EHR data from over 580,000 participants across European (EUA; 430,306), African (AFR; 106,081), and Hispanic (HIS; 47,008) ancestral backgrounds, including 14,575 CP/CPPS cases, we conducted the first study to explore the genetic underpinnings of CP/CPPS. The EUA GWAS uncovered three loci with a genome-wide significant (GWS) association with CP/CPPS, substantially advancing our understanding of the genetic basis of CP/CPPS. The top SNP was rs10886893 (p=3x10-8, OR=1.2 [1.1-1.4]) in the FGFR2 gene. A locus on chromosome 19 is associated with a suite of genes, including LRRC4B, KLK2, KLK4, KLK7, and CLDND2, each with noteworthy expression quantitative trait loci (eQTL) associations. Cross-ancestry analyses revealed three additional GWS loci on chromosomes 5, 10, and 13, linked to genes (SLC6A19, TERT, RAB18, and TRIM13) associated with prostate-specific antigen levels and benign prostatic hyperplasia (BPH). The observed scale CP/CPPS heritability was estimated at 6.7% (SE: 0.12). Network analyses revealed clusters of interlinked SNPs and genes, emphasizing key biological pathways underlying CP/CPPS. An unbiased screen of genetic correlations with 1,466 public GWAS phenotypes revealed a significant genetic correlation with 12 other phenotypes, including BPH, genitourinary diseases, back pain, depression, and anxiety. These findings provide a foundation for future research into the genetic basis of CP/CPPS, explore areas of overlap with other conditions, and suggest new avenues for investigating disease mechanisms and therapeutic strategies. Funded by IK2 CX002107.