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Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.
Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.
- Source :
-
American journal of human genetics [Am J Hum Genet] 2021 Mar 04; Vol. 108 (3), pp. 431-445. Date of Electronic Publication: 2021 Feb 17. - Publication Year :
- 2021
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Abstract
- Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca <superscript>2+</superscript> -binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.<br /> (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Black or African American genetics
Aged
Aged, 80 and over
Colitis, Ulcerative genetics
Colitis, Ulcerative pathology
Crohn Disease genetics
Crohn Disease pathology
Female
Gene Frequency
Genome-Wide Association Study
Humans
Inflammatory Bowel Diseases pathology
Male
Multifactorial Inheritance genetics
Polymorphism, Single Nucleotide genetics
White People genetics
Whole Genome Sequencing
Calbindin 2 genetics
Genetic Predisposition to Disease
Inflammatory Bowel Diseases genetics
Receptors, Prostaglandin E, EP4 Subtype genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1537-6605
- Volume :
- 108
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- American journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 33600772
- Full Text :
- https://doi.org/10.1016/j.ajhg.2021.02.001