Heritability and genome-wide association study of benign prostatic hyperplasia (BPH) in the eMERGE network

Abstract

Benign prostatic hyperplasia (BPH) results in a significant public health burden due to the morbidity caused by the disease and many of the available remedies. As much as 70% of men over 70 will develop BPH. Few studies have been conducted to discover the genetic determinants of BPH risk. Understanding the biological basis for this condition may provide necessary insight for development of novel pharmaceutical therapies or risk prediction. We have evaluated SNP-based heritability of BPH in two cohorts and conducted a genome-wide association study (GWAS) of BPH risk using 2,656 cases and 7,763 controls identified from the Electronic Medical Records and Genomics (eMERGE) network. SNP-based heritability estimates suggest that roughly 60% of the phenotypic variation in BPH is accounted for by genetic factors. We used logistic regression to model BPH risk as a function of principal components of ancestry, age, and imputed genotype data, with meta-analysis performed using METAL. The top result was on chromosome 22 in SYN3 at rs2710383 (p-value = 4.6 × 10 −7 ; Odds Ratio = 0.69, 95% confidence interval = 0.55–0.83). Other suggestive signals were near genes GLGC , UNCA13 , SORCS1 and between BTBD3 and SPTLC3 . We also evaluated genetically-predicted gene expression in prostate tissue. The most significant result was with increasing predicted expression of ETV4 (chr17; p-value = 0.0015). Overexpression of this gene has been associated with poor prognosis in prostate cancer. In conclusion, although there were no genome-wide significant variants identified for BPH susceptibility, we present evidence supporting the heritability of this phenotype, have identified suggestive signals, and evaluated the association between BPH and genetically-predicted gene expression in prostate.

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

“…Autopsy studies have shown a histological prevalence of the disease of 8%, 50%, and 80% in the fourth, sixth, and ninth decades of life, respectively. Genome-wide association studies suggest the existence of a genetic component in the development of BPH, showing that some single nucleotide polymorphisms reveal a correlation with BPH and serum levels of PSA [504,505,506]. Various pathogenic mechanisms have been proposed to explain the origin of BPH, including alterations at the level of the prostate stem cell compartment.…”

Benign prostatic hyperplasia – what do we know?

“…Other SNPs located near genes associated with increased prostate cancer risk (iroquois homeobox 4 [ IRX4 ], integrin subunit alpha 5 [ ITGA5 ], and regulatory factor X6 [ RFX6 ]) have been linked with more aggressive BPH disease (high IPPS) [18], whilst SNPs linked to metabolic syndromes have correlated with increased prostate volumes [19]. Despite these discoveries, a recent large genome‐wide association study was unable to identify significant susceptibility loci for BPH development [20].…”

TNF Blockade Reduces Prostatic Hyperplasia and Inflammation while Limiting BPH Diagnosis in Patients with Autoimmune Disease

“…The only definitive risk factors for developing BPH are male sex and increasing age, but BPH has been linked to decreased systemic androgen:estrogen ratios, obesity, type 2 diabetes, metabolic syndrome, and inflammation ( 3–9 ). There is a paucity of studies investigating possible genetic determinants of BPH, although, more recently, there has been greater interest in this area ( 10–12 ). The medical therapeutic options used for men with LUTS related to BPH are limited (e.g.…”