Sex-specific and pleiotropic effects underlying kidney function identified from GWAS meta-analysis

Area of Science:

• Genetics
• Nephrology
• Genomics

Background:

• Chronic kidney disease (CKD) affects 10-15% of adults globally, posing a significant health challenge.
• Estimated glomerular filtration rate (eGFR) is a key indicator for diagnosing and monitoring kidney function.
• Previous genetic studies have identified some, but not all, genetic factors influencing eGFR.

Purpose of the Study:

• To conduct a large-scale genome-wide association study (GWAS) meta-analysis to identify more genetic loci associated with eGFR.
• To investigate sex-specific genetic effects on eGFR.
• To assess the utility of identified genetic variants in predicting CKD risk.

Main Methods:

• Meta-analysis of GWAS data from the Nord-Trøndelag Health Study and Michigan Genomics Initiative, combined with public summary statistics.
• Identification of genetic loci associated with eGFR.
• Sex-stratified analysis to detect sex-specific genetic associations.
• Construction and evaluation of genetic risk scores for CKD prediction.

Main Results:

• Identification of 147 loci associated with eGFR, with 53 being novel discoveries.
• Genes implicated in transcriptional regulation, kidney development, cellular signaling, metabolism, and solute transport were identified.
• One locus showed a significant sex-specific effect, more pronounced in women.
• Genetic risk scores demonstrated general predictability of CKD, with modest improvements over existing clinical factors.

Conclusions:

• This comprehensive GWAS meta-analysis significantly expands the number of known genetic loci influencing eGFR.
• The findings provide deeper insights into the complex genetic architecture of kidney function and CKD.
• While genetic factors are important, their predictive power for CKD is currently modest compared to established clinical risk factors.