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<p>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 <i>TBX5</i>, thereby influencing <i>TBX2</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月14日

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  • Jiyun Jang,
  • Jaeyong Choi,
  • Sungji Moon,
  • Jeong Mi Kim,
  • Jong-Il Kim,
  • Sun-Wha Im

摘要

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.