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

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.

Keywords: IBD; PRS; VEO-IBD.

Figure 1:. Polygenic risk score calculation.

Polygenic risk scores were generated and evaluated for each individual based on their ability to predict IBD status (25 from each association dataset). Combined models using the most predictive scores from each individual-population dataset were then used to assess improvements to prediction using multi-racial scores.

Figure 2:. Risk score prediction of disease is most accurate when including association data from multiple racial groups.

A. Single-population association risk scores were assessed using logistic regression models, and the significance of the risk score as a predictor of IBD state is shown. B. AUC values calculated using logistic regression models which predicted IBD status using age, sex, and the combination of predictors on the x-axis. Cross-validation was also performed to test for overfitting. Association data used for risk scores: Liu included European individuals, Brant included African American individuals, and Hui included AJ individuals.

Figure 3:. Combination of risk scores improves IBD prediction across BioMe racial populations.

A. BioMe individuals with higher risk scores have a higher rate of IBD regardless of ancestry. Integration of association data from multiple populations also increases IBD prediction in every population, though IBD prediction is more challenging in African Americans. B. Replication in UK Biobank individuals of European ancestry shows similar improvement.

Figure 4:. VEO-IBD missense SNP penetrance.

Penetrance dot colors (within light blue layer) reflect ancestry: blue = European, red = AA, green = Hispanic. AJ individuals are included as European-ancestry. Penetrance points plotted if TotalHet # > 10, HetCases > 1, and penetrance > 1. Max penetrance values for the light blue layer: Eur = 21.43, Afr = 10.53, His = 9.09. White layer = GERP scores > 3 and green layer = CADD scores > 10. Outer ticks represent 100kb in gene region.

Figure 5.. Expression of LRBA and CTLA-4 in heterozygous carriers and controls.

A. Mean intracellular expression of LRBA. B. Mean extracellular expression of CTLA-4, with and without 18-hour chloroquine treatment. All conditions were performed in triplicate. P-values calculated using Welch’s t-test. MFI, mean fluorescence intensity; WT, wild type.

Figure 6:. VEO-IBD gene expression in intestinal single-cell RNA-seq.

Average expression across each cell type cluster is shown, based on sorting using Seurat 3.0. Genes and cell types clustered based on similarity of expression among the VEO-IBD genes plotted.