Common and Rare Variant Prediction and Penetrance of IBD in a Large, Multi-ethnic, Health System-based Biobank Cohort
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| Názov: | Common and Rare Variant Prediction and Penetrance of IBD in a Large, Multi-ethnic, Health System-based Biobank Cohort |
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| Autori: | Kyle Gettler, Rachel Levantovsky, Arden Moscati, Mamta Giri, Yiming Wu, Nai-Yun Hsu, Ling-Shiang Chuang, Aleksejs Sazonovs, Suresh Venkateswaran, Ujunwa Korie, Colleen Chasteau, Richard H. Duerr, Mark S. Silverberg, Scott B. Snapper, Mark J. Daly, Dermot P. McGovern, Steven R. Brant, John D. Rioux, Subra Kugathasan, Carl A. Anderson, Yuval Itan, Judy H. Cho |
| Zdroj: | UK IBD Genetics Consortium, National Institute of Diabetes, Digestive and Kidney Diseases Inflammatory Bowel Disease Genetics Consortium 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 |
| Informácie o vydavateľovi: | Elsevier BV, 2021. |
| Rok vydania: | 2021 |
| Predmety: | Multifactorial Inheritance, Network Meta-Analysis, Penetrance, Crohn Disease/diagnosis, Polymorphism, Single Nucleotide, Risk Assessment, Colitis, Ulcerative/diagnosis, Europe/epidemiology, Jews/genetics, Crohn Disease, Risk Factors, Prevalence, Humans, Black or African American/genetics, Genetic Predisposition to Disease, Age of Onset, Hispanic or Latino/genetics, Hispanic or Latino, United States/epidemiology, United States, Race Factors, 3. Good health, Black or African American, Europe, Phenotype, Case-Control Studies, Jews, Colitis, Ulcerative, White People/genetics, Genome-Wide Association Study |
| Popis: | 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.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.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.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. |
| Druh dokumentu: | Article |
| Jazyk: | English |
| ISSN: | 0016-5085 |
| DOI: | 10.1053/j.gastro.2020.12.034 |
| Prístupová URL adresa: | http://www.gastrojournal.org/article/S001650852035575X/pdf https://pubmed.ncbi.nlm.nih.gov/33359885 https://www.gastrojournal.org/article/S001650852035575X/pdf https://www.gastrojournal.org/article/S0016-5085(20)35575-X/fulltext https://www.ncbi.nlm.nih.gov/pubmed/33359885 https://researchportal.helsinki.fi/en/publications/common-and-rare-variant-prediction-and-penetrance-of-ibd-in-a-lar https://pubmed.ncbi.nlm.nih.gov/33359885/ https://www.sciencedirect.com/science/article/abs/pii/S001650852035575X https://vbn.aau.dk/da/publications/ea3123d0-61d4-4a99-941c-329d0a9e2cd7 https://doi.org/10.1053/j.gastro.2020.12.034 |
| Rights: | Elsevier TDM |
| Prístupové číslo: | edsair.doi.dedup.....213264cdec1328e94a6dc3ae3292fc47 |
| Databáza: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | 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.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.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.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. |
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| ISSN: | 00165085 |
| DOI: | 10.1053/j.gastro.2020.12.034 |