全基因组关联研究在中国人群中鉴定出一个新的尿道下裂风险相关位点位于 12q13.13。
Genome-wide association study in Chinese cohort identifies one novel hypospadias risk associated locus at 12q13.13.
机构信息
Department of Urology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, China.
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200438, China.
出版信息
BMC Med Genomics. 2019 Dec 19;12(1):196. doi: 10.1186/s12920-019-0642-0.
BACKGROUND
Hypospadias 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.
METHODS
To 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) 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.
RESULTS
We identified rs11170516 with the risk allele G within the SP1/SP7 region that was independently associated with moderate-severe hypospadias [SP1/SP7, rs11170516, P = 3.5 × 10, 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.
CONCLUSIONS
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 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.
背景
全基因组关联研究（GWAS）已经在欧洲血统的人群中报道了与尿道下裂风险相关的基因变异。目前，关于汉族人群中任何可能的尿道下裂风险关联知之甚少。
方法
为了系统地研究中国患者尿道下裂风险相关基因变异，我们在一个由 197 例中度至重度尿道下裂病例和 933 例无异常对照组成的汉族队列中进行了首次 GWAS。在 118 例病例和 383 例对照中，以及在另一个独立的验证人群 137 例病例和 190 例对照中，对提示性基因座（p < 1 × 10）进行了复制。然后对候选变异进行了调控和蛋白-蛋白相互作用（PPIs）分析，以进行功能分析。
结果
我们在 SP1/SP7 区域内发现了与风险等位基因 G 相关的 rs11170516，该基因与中度至重度尿道下裂独立相关 [SP1/SP7，rs11170516，P = 3.5 × 10，优势比（OR）= 1.96（1.59-2.44）]。结果还表明，rs11170516 与 SP1 的表达相关，是一个顺式表达数量性状基因座（cis-eQTL）。蛋白 SP1 可能通过 PPIs 影响尿道下裂的风险。
结论
我们在汉族人群中进行了首次中度至重度尿道下裂的 GWAS，在 12q13.13 上发现了一个新的易感性顺式作用调节位点，该位点可能通过影响近端 SP1 基因的表达和随后的 PPIs，调节多种与尿道下裂相关的通路。这项研究补充了已知的常见尿道下裂风险相关变异，并提供了顺式作用调节变异导致尿道下裂的可能作用。
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