Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients.
Yiming WuKyle GettlerMeltem Ece KarsMamta GiriDalin LiCigdem Sevim BayrakPeng ZhangAayushee JainPatrick MaffucciKsenija SabicTielman T Van VleckGirish Nitin NadkarniLee A DensonHarry OstrerAdam P LevineElena R SchiffAnthony Walter SegalSubra KugathasanPeter D StensonDavid N CooperL Philip SchummScott B SnapperMark J DalyTalin HarituniansRichard H DuerrMark S SilverbergJohn D RiouxSteven R BrantDermot P B McGovernJudy H ChoYuval ItanPublished in: Nature communications (2023)
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.
Keyphrases
- genome wide
- ulcerative colitis
- early onset
- single cell
- copy number
- dna methylation
- end stage renal disease
- ejection fraction
- oxidative stress
- rna seq
- bioinformatics analysis
- chronic kidney disease
- late onset
- inflammatory response
- newly diagnosed
- dendritic cells
- peritoneal dialysis
- patient reported outcomes
- genome wide analysis