A 2-stage genome-wide association study to identify single nucleotide polymorphisms associated with development of erectile dysfunction following radiation therapy for prostate cancer

Abstract

Purpose: To identify single nucleotide polymorphisms (SNPs) associated with development of erectile dysfunction (ED) among prostate cancer patients treated with radiation therapy.

Methods and materials: A 2-stage genome-wide association study was performed. Patients were split randomly into a stage I discovery cohort (132 cases, 103 controls) and a stage II replication cohort (128 cases, 102 controls). The discovery cohort was genotyped using Affymetrix 6.0 genome-wide arrays. The 940 top ranking SNPs selected from the discovery cohort were genotyped in the replication cohort using Illumina iSelect custom SNP arrays.

Results: Twelve SNPs identified in the discovery cohort and validated in the replication cohort were associated with development of ED following radiation therapy (Fisher combined P values 2.1×10(-5) to 6.2×10(-4)). Notably, these 12 SNPs lie in or near genes involved in erectile function or other normal cellular functions (adhesion and signaling) rather than DNA damage repair. In a multivariable model including nongenetic risk factors, the odds ratios for these SNPs ranged from 1.6 to 5.6 in the pooled cohort. There was a striking relationship between the cumulative number of SNP risk alleles an individual possessed and ED status (Sommers' D P value=1.7×10(-29)). A 1-allele increase in cumulative SNP score increased the odds for developing ED by a factor of 2.2 (P value=2.1×10(-19)). The cumulative SNP score model had a sensitivity of 84% and specificity of 75% for prediction of developing ED at the radiation therapy planning stage.

Conclusions: This genome-wide association study identified a set of SNPs that are associated with development of ED following radiation therapy. These candidate genetic predictors warrant more definitive validation in an independent cohort.

Figure 1

Study design.

Figure 2

ROC curves from multivariable logistic regression models. Clinical-only model contains age, ADT, and treatment; SNP-only model contains 12 SNPs and PCs; Clinical+SNP model contains age, ADT, treatment, 12 SNPs and PCs.