Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.
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Author
Somineni, Hari KNagpal, Sini
Venkateswaran, Suresh
Cutler, David J
Okou, David T
Haritunians, Talin
Simpson, Claire L
Begum, Ferdouse
Datta, Lisa W
Quiros, Antonio J
Seminerio, Jenifer
Mengesha, Emebet
Alexander, Jonathan S
Baldassano, Robert N
Dudley-Brown, Sharon
Cross, Raymond K
Dassopoulos, Themistocles
Denson, Lee A
Dhere, Tanvi A
Iskandar, Heba
Dryden, Gerald W
Hou, Jason K
Hussain, Sunny Z
Hyams, Jeffrey S
Isaacs, Kim L
Kader, Howard
Kappelman, Michael D
Katz, Jeffry
Kellermayer, Richard
Kuemmerle, John F
Lazarev, Mark
Li, Ellen
Mannon, Peter
Moulton, Dedrick E
Newberry, Rodney D
Patel, Ashish S
Pekow, Joel
Saeed, Shehzad A
Valentine, John F
Wang, Ming-Hsi
McCauley, Jacob L
Abreu, Maria T
Jester, Traci
Molle-Rios, Zarela
Palle, Sirish
Scherl, Ellen J
Kwon, John
Rioux, John D
Duerr, Richard H
Silverberg, Mark S
Zwick, Michael E
Stevens, Christine
Daly, Mark J
Cho, Judy H
Gibson, Greg
McGovern, Dermot P B
Brant, Steven R
Kugathasan, Subra
Date
2021-02-17Journal
American Journal of Human GeneticsPublisher
Elsevier Inc.Type
Article
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Show full item recordAbstract
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 Ca2+-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.Rights/Terms
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.Keyword
CALB2PTGER4
differential genetic architecture
polygenic risk scores
rare variants
trans-ethnic comparative analysis
understudied populations
whole-genome sequencing of African Americans
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http://hdl.handle.net/10713/14925ae974a485f413a2113503eed53cd6c53
10.1016/j.ajhg.2021.02.001
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