Identification of end stage renal disease associated loci in X chromosome: an X chromosome-wide association study

Abstract

X-chromosomal genetic variants have been understudied in end stage renal disease (ESRD), which holds the promise to provide valuable insights into sexually dimorphic traits and diseases. Here we performed an X chromosome-wide association study (XWAS) in a Chinese cohort (N = 2750), comprising 1489 cases with ESRD and 1261 controls, to identify locus associated with ESRD risk. One locus showing a consistent effect direction across sex but primarily supported by the male cohort was identified in COL4A5 (P = 2.43 × 10^-6) in the meta-analysis combining summary statistics from the sex-stratified XWAS. COL4A5 codes for the alpha chain of type IV collagen, which is essential for the integrity of the glomerular basement membrane and normal glomerular function. Two male-specific loci, MIR3202-2 (P = 6.85× 10^-5) and SYTL4 (P = 1.71× 10^-5), were identified in the sex-stratified XWAS in males, and expression of SYTL4, TSPAN6, NOX1, CSTF2, and PCDH19 were found to be influenced by the ESRD loci near SYTL4 based on expression quantitative trait loci (eQTL) results from the Genotype-Tissue Expression (GTEx) project. In summary, our finding revealed three X-chromosome loci linked to ESRD risk, which provided foundational knowledge for genetic risk prediction and advanced our understanding of the molecular underpinnings of ESRD.

Keywords

end stage renal disease / genotype / single nucleotide polymorphism / sexually dimorphic traits / X chromosome-wide association study

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Higher Education Press 2026

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