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    Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.

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    Author
    Somineni, Hari K
    Nagpal, 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
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    Date
    2021-02-17
    Journal
    American Journal of Human Genetics
    Publisher
    Elsevier Inc.
    Type
    Article
    
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    Show full item record
    See at
    https://doi.org/10.1016/j.ajhg.2021.02.001
    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 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
    CALB2
    PTGER4
    differential genetic architecture
    polygenic risk scores
    rare variants
    trans-ethnic comparative analysis
    understudied populations
    whole-genome sequencing of African Americans
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/14925
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.ajhg.2021.02.001
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