Genome-wide associations for benign prostatic hyperplasia reveal a genetic correlation with serum levels of PSA

Abstract

Benign prostatic hyperplasia and associated lower urinary tract symptoms (BPH/LUTS) are common conditions affecting the majority of elderly males. Here we report the results of a genome-wide association study of symptomatic BPH/LUTS in 20,621 patients and 280,541 controls of European ancestry, from Iceland and the UK. We discovered 23 genome-wide significant variants, located at 14 loci. There is little or no overlap between the BPH/LUTS variants and published prostate cancer risk variants. However, 15 of the variants reported here also associate with serum levels of prostate specific antigen (PSA) (at a Bonferroni corrected P < 0.0022). Furthermore, there is a strong genetic correlation, r_g = 0.77 (P = 2.6 × 10^-11), between PSA and BPH/LUTS, and one standard deviation increase in a polygenic risk score (PRS) for BPH/LUTS increases PSA levels by 12.9% (P = 1.6×10^-55). These results shed a light on the genetic background of BPH/LUTS and its substantial influence on PSA levels.

Fig. 1

A Manhattan plot of the combined BPH/LUTS GWAS results. The Manhattan plot shows variants with two-sided P-value < 0.10 (obtained using a logistic regression model) and high imputation information score (info > 0.90) from the BPH/LUTS meta-analysis of GWAS data from 20,621 patients and 280,541 controls of European ancestry, coming from Iceland and the UK. Shown are negative log₁₀-transformed two-sided P-values from the unconditional analysis (y-axis) over 22 autosomes (x-axis). Dots colored in red denote variants that surpass our genome-wide significance thresholds (ranging between 1.9 × 10⁻⁷ and 5.9 × 10⁻¹⁰), defined using a weighted Bonferroni procedure based on functional impact of classes of variants

Fig. 2

GWAS variants intersecting with regulatory regions defined on the basis of acetylation of histone H3 at lysine residue K27 (H3K27ac). Shown are results for two of the loci reported to associate with BPH/LUTS from an analysis of non-coding risk variants intersecting with regulatory regions defined on the basis of acetylation of histone H3 at lysine residue K27 (H3K27ac), indicative of regulatory regions, in primary prostate epithelial cells. The y-axis shows the ChIP-seq signal for the H3K27ac mark represented as negative log₁₀ of the P-value and the x-axis shows the genomic location (hg38). The black tick marks (top of panels a and b) indicate the position of variants found in strong LD (r² > 0.8) with the lead variant, defining an LD class, wherein rs numbers are shown for those residing within H3K27ac significant regions. a At 12q24.21 four variants reside within an H3K27ac marked region (rs71807, rs8853, rs484443, and rs551510). b At 13q14.3, only one variant, rs2274069, belonging to the LD class of the lead variant resides within a H3K27ac marked region. This is the promoter region for RNASEH2B, located within 500 bp from the transcription start site of the gene