Back to Search Start Over

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.

Authors :
Somineni HK
Nagpal S
Venkateswaran S
Cutler DJ
Okou DT
Haritunians T
Simpson CL
Begum F
Datta LW
Quiros AJ
Seminerio J
Mengesha E
Alexander JS
Baldassano RN
Dudley-Brown S
Cross RK
Dassopoulos T
Denson LA
Dhere TA
Iskandar H
Dryden GW
Hou JK
Hussain SZ
Hyams JS
Isaacs KL
Kader H
Kappelman MD
Katz J
Kellermayer R
Kuemmerle JF
Lazarev M
Li E
Mannon P
Moulton DE
Newberry RD
Patel AS
Pekow J
Saeed SA
Valentine JF
Wang MH
McCauley JL
Abreu MT
Jester T
Molle-Rios Z
Palle S
Scherl EJ
Kwon J
Rioux JD
Duerr RH
Silverberg MS
Zwick ME
Stevens C
Daly MJ
Cho JH
Gibson G
McGovern DPB
Brant SR
Kugathasan S
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

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.)

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