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

Abstract

This article has an accompanying continuing medical education activity, also eligible for MOC credit, on page e21. Learning Objective: Upon completion of this CME activity, successful learners will be able to interpret the clinical impact of rare genetic variants in diverse populations on the prediction of inflammatory bowel disease risk and monogenic contribution to pathogenesis. 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.

Genome-wide risk prediction of common diseases across ancestries in one million people

“…Most importantly, we need better representation of different ancestries in GWASs. 18 , 44 , 45 , 46 , 47 , 48 Of the four GWASs used for generating our genome-wide PRSs, the proportion of individuals of other than European ancestry was highest for CAD (23%), the majority of whom were of South or East Asian ancestry. In breast cancer, the proportion of individuals of East Asian ancestry was 11%, whereas the T2D and prostate cancer GWASs were limited to individuals of European ancestry.…”

Stability of polygenic scores across discovery genome-wide association studies

“…One goal is to utilize PGS in clinical settings to facilitate the diagnosis and treatment of a wide range of heritable diseases, 6 such as inflammatory bowel disease, 7 diabetes, 8 cardiovascular disease, 9 , 10 cancer, 11 Alzheimer disease, 12 attention-deficit/hyperactivity disorder, 13 major depressive disorder, 14 bipolar disorder, 15 and schizophrenia. 16 While progress has been made toward reaching this goal, 17 , 18 , 19 , 20 numerous challenges remain to be solved.…”

Stability of Polygenic Scores Across Discovery Genome-Wide Association Studies

“…Numerous methods have been developed for computing PGS for a target population using summary statistics from a discovery genome-wide association study (GWAS) run for an independent population, with newer Bayesian-based techniques such as LDpred, 1 SBayesR, 2 and PRS-CS 3 generally yielding more predictive PGS than those produced using older methodologies that rely on a combination of linkage disequilibrium (LD) clumping and P-value thresholding. 4 One goal is to utilize PGS in clinical settings to facilitate the diagnosis and treatment of a wide range of heritable diseases, 5 such as inflammatory bowel disease, 6 diabetes, 7 cardiovascular disease, 8; 9 cancer, 10 Alzheimer's disease, 11 attention-deficit/hyperactivity disorder, 12 major depressive disorder, 13 bipolar disorder, 14 and schizophrenia. 15 While progress has been made towards reaching this goal, [16][17][18][19] numerous challenges remain to be solved.…”