Rare variant optimized GWAS with functional validation identifies causal architecture of kidney function in East Asian population

초록

Chronic kidney disease is a growing burden, yet the genetic architecture of kidney function requires further investigation. We performed a genome-wide association study of estimated glomerular filtration rate in 72,298 Korean individuals using a population-specific Korean Biobank Array and genetic imputation with a population matching imputation panel enabling high-resolution variant detection. We identified 30 independent signals including an East Asian-specific rare variant rs535291258. Through fine-mapping and functional annotation using epigenomic data, rs9895661 was predicted to modulate the binding affinity of the transcription factor TBX5, thereby influencing TBX2 expression. We also experimentally validated the allele-specific enhancer activity of this variant. Our results reveal both common and rare variants underlying kidney function in an East Asian population, highlight the value of population-specific approaches and illustrate how integrating epigenomic profiling and experimental approaches with GWAS results can connect genetic associations with molecular mechanisms of kidney function.

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