Common and Rare Variant Prediction and Penetrance of IBD in a Large, Multi-ethnic, Health System-based Biobank Cohort

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UK IBD Genetics Consortium , Natl Inst Diabet Digestive Kidney , Gettler , K , Levantovsky , R , Moscati , A , Daly , M J & Cho , J H 2021 , ' Common and Rare Variant Prediction and Penetrance of IBD in a Large, Multi-ethnic, Health System-based Biobank Cohort ' , Gastroenterology , vol. 160 , no. 5 , pp. 1546-1557 . https://doi.org/10.1053/j.gastro.2020.12.034

Title: Common and Rare Variant Prediction and Penetrance of IBD in a Large, Multi-ethnic, Health System-based Biobank Cohort
Author: UK IBD Genetics Consortium; Natl Inst Diabet Digestive Kidney; Gettler, Kyle; Levantovsky, Rachel; Moscati, Arden; Daly, Mark J.; Cho, Judy H.
Contributor organization: Institute for Molecular Medicine Finland
University of Helsinki
Date: 2021-03
Language: eng
Number of pages: 12
Belongs to series: Gastroenterology
ISSN: 0016-5085
DOI: https://doi.org/10.1053/j.gastro.2020.12.034
URI: http://hdl.handle.net/10138/341386
Abstract: BACKGROUND AND AIMS: Polygenic risk scores (PRS) may soon be used to predict inflammatory bowel disease (IBD) risk in prevention efforts. We leveraged exome-sequence and single nucleotide polymorphism (SNP) array data from 29,358 individuals in the multiethnic, randomly ascertained health system-based BioMe biobank to define effects of common and rare IBD variants on disease prediction and pathophysiology. METHODS: PRS were calculated from European, African American, and Ashkenazi Jewish (AJ) reference case-control studies, and a meta-GWAS run using all three association datasets. PRS were then combined using regression to assess which combination of scores best predicted IBD status in European, AJ, Hispanic, and African American cohorts in BioMe. Additionally, rare variants were assessed in genes associated with very early-onset IBD (VEO-IBD), by estimating genetic penetrance in each BioMe population. RESULTS: Combining risk scores based on association data from distinct ancestral populations improved IBD prediction for every population in BioMe and significantly improved prediction among European ancestry UK Biobank individuals. Lower predictive power for non-Europeans was observed, reflecting in part substantially lower African IBD case-control reference sizes. We replicated associations for two VEO-IBD genes, ADAM17 and LRBA, with high dominant model penetrance in BioMe. Autosomal recessive LRBA risk alleles are associated with severe, early-onset autoimmunity; we show that heterozygous carriage of an African-predominant LRBA protein-altering allele is associated with significantly decreased LRBA and CTLA-4 expression with T-cell activation. CONCLUSIONS: Greater genetic diversity in African populations improves prediction across populations, and generalizes some VEO-IBD genes. Increasing African American IBD case-collections should be prioritized to reduce health disparities and enhance pathophysiological insight.
Subject: IBD
PRS
VEO-IBD
INFLAMMATORY-BOWEL-DISEASE
PRIMARY IMMUNODEFICIENCY DISEASES
GENETIC ARCHITECTURE
RISK
ASSOCIATION
CHLOROQUINE
LOCI
LRBA
3121 General medicine, internal medicine and other clinical medicine
Peer reviewed: Yes
Rights: cc_by_nc_nd
Usage restriction: openAccess
Self-archived version: draft


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