Genome-wide association study in Chinese cohort reveals a new susceptibility locus within the 12q13.13 region for hypospadias

Abstract

Hypospadias risk–associated gene variants have been reported in populations of European descent using genome-wide association studies (GWAS). There is little known at present about any possible hypospadias risk associations in Han Chinese populations. To systematically investigate hypospadias risk–associated gene variants in Chinese patients, we performed the first GWAS in a Han Chinese cohort consisting of 200 moderate-severe hypospadias cases and 1008 unaffected controls. Suggestive loci (p<1×10−4) were replicated in 118 cases and 383 controls, as well as in a second independent validation population of 137 cases and 190 controls. Regulatory were then conducted for the functional analyses of candidate variants. We identified rs11170516 with the risk allele G within the SP1/SP7 region that was independently associated with moderate-severe Hypospadias [SP1/SP7, rs11170516, Pcombine = 3.5×10-9, odds ratio (OR) = 1.96 (1.59-2.44)]. Results also suggested that rs11170516 is associated with the expression of SP1 as a cis-expression quantitative trait loci (cis-eQTL). We performed the first GWAS of moderate-severe hypospadias in a Han Chinese cohort, and identified one novel susceptibility cis-acting regulatory locus at 12q13.13, which may regulate a variety of hypospadias-related pathways by affecting proximal SP1 gene expression. This study complements known common hypospadias risk-associated variants and provides the possible role of cis-acting regulatory variant in causing hypospadias.