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Purpose <p>X-chromosome variants contribute significantly to hypospadias risk but have not been fully elucidated in the Chinese population. Here we aim to assess how X-chromosome variants contribute to hypospadias susceptibility in the Chinese population.</p> Methods <p>We recruited 1,073 boys with hypospadias and 5,150 controls in a southern Chinese population. Single-variant and gene/pathway-based association analyses were conducted for the distal and proximal hypospadias. Haplotype analysis was performed on top susceptibility genes. Additionally, we performed a multi-ancestral comparison between the East Asian and European populations.</p> Results <p>We performed an X-chromosome-wide association study on 987 patients and 4,761 controls that met quality control standards. We confirmed <i>DGKK</i> variants as multi-ancestral susceptibility loci for distal hypospadias (lead SNP: rs5961181, <i>P</i> = 1.82 × 10<sup>− 7</sup>), but not for the proximal subtype. Distinct association signals were identified for distal hypospadias (<i>DGKK-CCNB3-AKAP4</i>, <i>PNPLA4</i>, <i>AR-OPHN1</i>, <i>TAF7L</i>, <i>IL1RAPL1</i>) and proximal hypospadias (<i>SMIM10L2A</i>, <i>PRR32</i> and Xq28 gene cluster). Pathway analysis revealed that distal hypospadias is associated with male gamete generation, epithelial cell polarity, and lipid/sterol metabolism, while proximal hypospadias is linked to amino acid metabolism and gastrulation. Except for <i>DGKK</i>, all candidate genes showed population-favored associations compared to European studies. Haplotype analysis of <i>DGKK</i>, <i>PNPLA4</i>, <i>OPHN1</i> and <i>IL1RAPL1</i> showed increased risk for specific risk haplotypes (<i>OR</i> ranged from 4.35 to 6.25).</p> Conclusion <p>Our findings highlight the importance of X chromosome variants in hypospadias etiology and reveal subtype- and population-specific genetic architecture. Our results improve the understanding of genetic susceptibility for hypospadias risk and provide insights into risk prediction and personalized prevention strategies in hypospadias management.</p>

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X-chromosome association study reveals genetic susceptibility loci of hypospadias in southern Chinese population

  • 期刊论文

  • 发表日期：

    2025年5月7日

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  • Yanqing Liu,
  • Binyao Li,
  • Fuming Deng,
  • Xinying Zhao,
  • Zhihai Liu,
  • Jinglu Zhao,
  • Wen Fu,
  • Yan Zhang,
  • Xiaoyu Zuo

摘要

Purpose

X-chromosome variants contribute significantly to hypospadias risk but have not been fully elucidated in the Chinese population. Here we aim to assess how X-chromosome variants contribute to hypospadias susceptibility in the Chinese population.

Methods

We recruited 1,073 boys with hypospadias and 5,150 controls in a southern Chinese population. Single-variant and gene/pathway-based association analyses were conducted for the distal and proximal hypospadias. Haplotype analysis was performed on top susceptibility genes. Additionally, we performed a multi-ancestral comparison between the East Asian and European populations.

Results

We performed an X-chromosome-wide association study on 987 patients and 4,761 controls that met quality control standards. We confirmed DGKK variants as multi-ancestral susceptibility loci for distal hypospadias (lead SNP: rs5961181, P = 1.82 × 10− 7), but not for the proximal subtype. Distinct association signals were identified for distal hypospadias (DGKK-CCNB3-AKAP4, PNPLA4, AR-OPHN1, TAF7L, IL1RAPL1) and proximal hypospadias (SMIM10L2A, PRR32 and Xq28 gene cluster). Pathway analysis revealed that distal hypospadias is associated with male gamete generation, epithelial cell polarity, and lipid/sterol metabolism, while proximal hypospadias is linked to amino acid metabolism and gastrulation. Except for DGKK, all candidate genes showed population-favored associations compared to European studies. Haplotype analysis of DGKK, PNPLA4, OPHN1 and IL1RAPL1 showed increased risk for specific risk haplotypes (OR ranged from 4.35 to 6.25).

Conclusion

Our findings highlight the importance of X chromosome variants in hypospadias etiology and reveal subtype- and population-specific genetic architecture. Our results improve the understanding of genetic susceptibility for hypospadias risk and provide insights into risk prediction and personalized prevention strategies in hypospadias management.