Genome-Wide Association Study of Quantitative Kidney Function in 52,531 Individuals with Diabetes Identifies Five Diabetes-Specific Loci.
basic_science · Level V
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- Record sourced from PubMed, PMID 40323663.
- Also identified by DOI 10.1681/ASN.0000000718 and PMC identifier 12499614.
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Abstract
Comprehensive genome-wide association study of eGFR in diabetes, accounting for diabetes duration, kidney disease, and known modifiers, identified novel genetic effects. Incorporation of various kidney multi-omics data provides supporting evidence for the role of novel genome-wide association study loci in diabetic kidney disease. Diabetic kidney disease (DKD) is a serious diabetes complication caused by both environmental and genetic risk factors. Previous genome-wide association studies (GWAS) have identified several loci associated with kidney function and kidney disease in the general population and, to a lesser extent, in diabetes. To uncover the genetic factors driving diabetes-induced kidney function, we conducted a series of GWAS meta-analyses of eGFR in 17,267 individuals with type 1 diabetes and 35,264 with type 2 diabetes (52,531 total), using multiple well-characterized cohorts of type 1 diabetes DKD and data from the UK Biobank and SUrrogate markers for Micro- and Macrovascular hard end points for Innovative diabetes Tools (SUMMIT) consortium. We further accounted for DKD case/control status, diabetes duration and subtype, body mass index, glycated hemoglobin levels, and the relationship between eGFR and albuminuria. GWAS identified 13 loci associated with eGFR (<i>P</i> < 5×10<sup>−8</sup>), with five loci (candidate genes: <i>HIPK3</i>, <i>TRIM5</i>, <i>RORA</i>, <i>ERBB4</i>, and <i>BCL6</i>/<i>LPP</i>) not associated with or were in opposite directions as compared with eGFR in the general population. Four candidate genes (<i>HIPK3</i>, <i>BCL6, LPP</i>, and <i>RORA</i>) demonstrated evidence of differential expression in kidney compartments and cells among subgroups with DKD or diabetes versus controls. Lead single-nucleotide polymorphisms rs8027829 (<i>RORA</i>) and rs76300256 (<i>BCL6/LPP</i>) were methylation quantitative trait loci in whole blood and kidney tissue, respectively, and rs76300256 and its related CpGs all cluster in a kidney enhancer. Our integrated approach identified candidate genes with diabetes-specific effects on kidney function.