Gastroenterology 2021 Apr;160(5):1546-1557. doi: 10.1053/j.gastro.2020.12.034.Epub 2020 Dec 24.

Kyle Gettler ¹, Rachel Levantovsky ¹, Arden Moscati ², Mamta Giri ¹, Yiming Wu ², Nai-Yun Hsu ¹, Ling-Shiang Chuang ¹, Aleksejs Sazonovs ³, Suresh Venkateswaran ⁴, Ujunwa Korie ², Colleen Chasteau ², UK IBD Genetics Consortium, National Institute of Diabetes, Digestive and Kidney Diseases Inflammatory Bowel Disease Genetics Consortium; Richard H Duerr ⁵, Mark S Silverberg ⁶, Scott B Snapper ⁷, Mark J Daly ⁸, Dermot P McGovern ⁹, Steven R Brant ¹⁰, John D Rioux ¹¹, Subra Kugathasan ¹², Carl A Anderson ³, Yuval Itan ², Judy H Cho ¹³

Author information

• ¹Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
• ²The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
• ³Human Genetics, Wellcome Sanger Institute, Hinxton, Cambridgeshire, United Kingdom.
• ⁴Division of Pediatric Gastroenterology, Hepatology & Nutrition, Emory University School of Medicine, Atlanta, Georgia.
• ⁵Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
• ⁶Division of Gastroenterology, Mount Sinai Hospital Inflammatory Bowel Disease Centre, Toronto, Ontario, Canada.
• ⁷Division of Gastroenterology, Hepatology & Nutrition, Boston Children's Hospital, Boston, Massachusetts.
• ⁸Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
• ⁹Medicine and Biomedical Sciences, Cedars-Sinai, Los Angeles, California.
• ¹⁰Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, and Department of Genetics and The Human Genetics Institute of New Jersey, Rutgers University, New Brunswick, New Jersey; Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
• ¹¹Montreal Heart Institute, University of Montreal, Montreal, Canada.
• ¹²Division of Pediatric Gastroenterology, Hepatology & Nutrition, Emory University School of Medicine, Atlanta, Georgia; Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia.
• ¹³Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: judy.cho@mssm.edu.

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.