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Epigenomic and transcriptomic analyses define core cell types, genes and targetable mechanisms for kidney disease

ABSTRACT: More than 800 million people suffer from kidney disease, yet the mechanism of kidney dysfunction is poorly understood. Here we comprehensively characterize genetic associations for kidney function (n = 1,508,659 individuals), DNA methylation (n = 443 individuals) and gene expression (n = 686 individuals). We identify 878 (126 novel) kidney function associated GWAS loci and prioritize target genes for 87% of these loci using a multi-stage prioritization strategy. Heritability analysis reveal that methylation variation explains a larger fraction of GWAS heritability than gene expression. Integration of GWAS and single cell open chromatin (n = 57,229 cells) highlights the key role of proximal tubules and metabolism in kidney function regulation. Further, the causal role of SLC47A1 in kidney disease is defined in mice with genetic loss of Slc47a1 and in human individuals carrying loss-of-function variants. Our findings emphasize the key role of bulk and single-cell epigenomic information in translating genome-wide association studies into identifying causal genes, cellular origins and mechanisms of complex traits.

ORGANISM(S): Homo sapiens

PROVIDER: GSE200547 | GEO | 2022/06/16

REPOSITORIES: GEO

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Project description:Recent genome-wide association studies (GWAS) have identified a number of novel genetic associations with complex human diseases. In spite of these successes, results from GWAS generally explain only a small proportion of disease heritability, an observation termed the M-bM-^@M-^\missing heritability problem.M-bM-^@M-^] Several sources for the missing heritability have been proposed, including the contribution of many common variants with small individual effect sizes, which cannot be reliably found using the standard GWAS approach. The goal of our study was to explore a complementary approach, which combines GWAS results with functional data in order to identify novel genetic associations with small effect sizes. To do so, we conducted a GWAS for lymphocyte count, a physiologic quantitative trait associated with asthma, in 462 Hutterites. In parallel, we performed a genome-wide gene expression study in lymphoblastoid cell lines (LCLs) from 96 Hutterites. We found significant support for genetic associations using the GWAS data when we considered variants near the 193 genes whose expression levels across individuals were most correlated with lymphocyte counts. Interestingly, these variants are also enriched with signatures of an association with asthma susceptibility, an observation we were able to replicate. The associated loci include genes previously implicated in asthma susceptibility, as well as novel candidate genes enriched for functions related to T cell receptor signaling and ATP synthesis. Our results, therefore, establish a new set of asthma susceptibility candidate genes. More generally, our observations support the notion that many loci of small effects influence variation in lymphocyte count and asthma susceptibility. 96 RNA samples were collected (1 subsequently excluded) from lymphoblastoid cell lines derived from Hutterite subjects chosen to represent the extremes of absolute lymphocyte count. The high and low absolute lymphocyte count groups were balanced with respect to age, gender, and relatedness.

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Epigenomic and transcriptomic analyses define core cell types, genes and targetable mechanisms for kidney disease

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