Genome-wide association study in Chinese cohort identifies one novel hypospadias risk associated locus at 12q13.13

Zhongzhong Chen,Yunping Lei,Hua Xie,Yaping Wang,Xiaoling Lin,Richard H Finnell,Daru Lu,Fang Chen,Haitao Chen,Jianfeng Xu

doi:10.1186/s12920-019-0642-0

Abstract

BackgroundHypospadias risk–associated gene variants have been reported in populations of European descent using genome-wide association studies (GWASs). There is little known at present about any possible hypospadias risk associations in Han Chinese populations.MethodsTo systematically investigate hypospadias risk–associated gene variants in Chinese patients, we performed the first GWAS in a Han Chinese cohort consisting of 197 moderate-severe hypospadias cases and 933 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 and protein-protein interactions (PPIs) were then conducted for the functional analyses of candidate variants.ResultsWe 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 locus (cis-eQTL). Protein SP1 could affect the risk of hypospadias via PPIs.ConclusionsWe 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 and subsequent PPIs. This study complements known common hypospadias risk-associated variants and provides the possible role of cis-acting regulatory variant in causing hypospadias.

Highlights

Hypospadias risk–associated gene variants have been reported in populations of European descent using genome-wide association studies (GWASs)
These GWASs or association analysis were performed in individuals of European descent or Japanese population, no GWAS analysis of hypospadias has yet been conducted in Chinese populations
Association analysis of ~ 3.0 million genetic variants with hypospadias in the discovery stage in the Han Chinese population demonstrated little evidence of global test statistic inflation caused by population stratification (Fig. 2). This result was further supported by principal component analysis (PCA) (Additional file 7: Figure S1)

Summary

Introduction

Hypospadias risk–associated gene variants have been reported in populations of European descent using genome-wide association studies (GWASs). The Hypospadias is considered to be a complex congenital disorder stemming from multiple genetic and environmental interacting factors [8]. Despite the large number of genes contributing to the etiology of hypospadias, the majority of genetic risk factors remain largely unknown. SNPs in HAAO and IRX6 genes were found to be associated with hypospadias in Japanese population [15]. These GWASs or association analysis were performed in individuals of European descent or Japanese population, no GWAS analysis of hypospadias has yet been conducted in Chinese populations

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Discussion

Conclusion