Chronic kidney disease affects approximately 10% of the global population and represents a major cause of morbidity and mortality. Progression to end-stage renal disease necessitates dialysis or kidney transplantation, imposing substantial burdens on patients and healthcare systems. Understanding the genetic basis of kidney disease could improve risk prediction, illuminate disease mechanisms, and identify therapeutic targets.

Genome-wide association studies (GWAS) have successfully identified numerous genetic loci associated with kidney function and kidney disease risk. However, the majority of GWAS have focused on autosomal chromosomes, often excluding the X chromosome due to analytical challenges related to sex differences in chromosome dosage and X-inactivation. This exclusion means that potentially important genetic variants on the X chromosome have been overlooked.

The X chromosome contains over 800 protein-coding genes, many of which are involved in immune function, cellular metabolism, and development. Several Mendelian kidney diseases map to the X chromosome, including Alport syndrome and Dent disease. These observations suggest that the X chromosome may harbor variants influencing susceptibility to common forms of kidney disease as well.

This X chromosome-wide association study (XWAS) systematically examined genetic variants on the X chromosome for association with ESRD risk. The study included tens of thousands of cases and controls from multiple cohorts, providing adequate statistical power to detect associations. Rigorous quality control procedures were implemented to account for the unique characteristics of X chromosome data.

Key findings identified several loci on the X chromosome significantly associated with ESRD risk. Some of these loci contain genes with known roles in kidney biology, while others implicate novel pathways that warrant further investigation. The identified variants collectively explain a portion of ESRD heritability, contributing to a more complete understanding of the genetic architecture of kidney disease.

Sex-specific analyses revealed differences in the effects of certain variants between men and women. These differences may reflect the distinct X chromosome dosage in each sex (XY in men, XX in women) and the complex patterns of X-inactivation in women. Understanding sex-specific genetic effects is important for precision medicine approaches that account for biological sex as a key variable.

Functional characterization of the identified loci provided insights into potential disease mechanisms. Several implicated genes are involved in immune regulation, consistent with the recognized role of inflammation in kidney disease progression. Other genes relate to cellular stress responses, metabolic pathways, and structural components of the kidney.

The clinical implications of these findings include potential improvements in genetic risk prediction for ESRD. Incorporating X chromosome variants into polygenic risk scores could enhance predictive accuracy, particularly for populations underrepresented in previous GWAS. Additionally, the identified genes and pathways represent candidates for therapeutic targeting.

Several limitations should be acknowledged. The study focused on common variants, and rare variants on the X chromosome may also contribute to ESRD risk. The findings were primarily derived from populations of European and East Asian ancestry, and additional studies in diverse populations are needed. Functional validation of the identified loci will require further experimental work.

Future research directions include fine-mapping of the identified loci to identify causal variants, investigation of gene-environment interactions on the X chromosome, and extension of XWAS to other kidney-related traits and diseases.
DOI:10.1007/s11684-026-1205-3