SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function

Area of Science:

• Genetics and Genomics
• Nephrology
• Developmental Biology

Background:

• Genome-wide association studies (GWAS) have identified over 50 common variants associated with kidney function, yet they do not fully explain the variation in estimated glomerular filtration rate (eGFR).
• Further investigation is needed to uncover additional genetic factors influencing kidney function and development.

Purpose of the Study:

• To perform a large-scale meta-analysis using exome array data to identify novel genetic loci associated with eGFR.
• To investigate the role of rare functional variants in kidney function.
• To explore the developmental impact of identified genes in a model organism.

Main Methods:

• Two-stage meta-analysis of genotype data from the Illumina exome array and eGFRcrea in participants of European ancestry (N=111,666 for Stage 1, N=48,343 for Stage 2).
• Single-variant and gene-based association analyses.
• Experimental follow-up using zebrafish (Danio rerio) embryos to assess the functional impact of candidate genes (acp1 and sos2) on kidney development.

Main Results:

• Identified single nucleotide polymorphisms at seven novel loci (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, ATXN2L) associated with eGFRcrea (P<3.7×10^-7).
• Discovered associations of functional rare variants in three genes with eGFRcrea, including a novel association with SOS2 (P=5.4×10^-8).
• Knockdown of acp1 and sos2 in zebrafish embryos resulted in altered glomerular gene expression, renal tubule morphology, impaired blood clearance, and increased edema.

Conclusions:

• This study significantly expands the number of known genetic loci associated with kidney function.
• Identified SOS2 as a novel gene potentially involved in kidney development.
• Findings highlight the importance of both common and rare variants in kidney function and provide insights into the genetic basis of kidney formation.