4.8 Article

Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients

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NATURE COMMUNICATIONS
卷 14, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41467-023-37849-3

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In this study, novel IBD-associated variants and genes are identified by sequencing the genomes of 4453 Ashkenazi Jewish IBD cases and controls. The physiological relevance of these genes to IBD is demonstrated through biological pathway analyses and RNA sequencing. The study also reveals the genetic overlap between adult IBD in Ashkenazi Jews and early-onset IBD, as well as the pleiotropic effects of IBD genes on other immune responses. Lastly, it is shown that polygenic risk score analyses based on high impact variants have high predictive power for IBD susceptibility.
Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility. Inflammatory bowel disease (IBD) is highly prevalent among the Ashkenazi Jewish population. Here, the authors identify novel IBD-associated variants and genes, validated by transcriptomic and phenome-wide associations.

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