@article{5a603a76c018487a9e72489f17bbac08,
title = "Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease",
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.",
keywords = "CALB2, PTGER4, differential genetic architecture, polygenic risk scores, rare variants, trans-ethnic comparative analysis, understudied populations, whole-genome sequencing of African Americans",
author = "Somineni, {Hari K.} and Sini Nagpal and Suresh Venkateswaran and Cutler, {David J.} and Okou, {David T.} and Talin Haritunians and Simpson, {Claire L.} and Ferdouse Begum and Datta, {Lisa W.} and Quiros, {Antonio J.} and Jenifer Seminerio and Emebet Mengesha and Alexander, {Jonathan S.} and Baldassano, {Robert N.} and Sharon Dudley-Brown and Cross, {Raymond K.} and Themistocles Dassopoulos and Denson, {Lee A.} and Dhere, {Tanvi A.} and Heba Iskandar and Dryden, {Gerald W.} and Hou, {Jason K.} and Hussain, {Sunny Z.} and Hyams, {Jeffrey S.} and Isaacs, {Kim L.} and Howard Kader and Kappelman, {Michael D.} and Jeffry Katz and Richard Kellermayer and Kuemmerle, {John F.} and Mark Lazarev and Ellen Li and Peter Mannon and Moulton, {Dedrick E.} and Newberry, {Rodney D.} and Patel, {Ashish S.} and Joel Pekow and Saeed, {Shehzad A.} and Valentine, {John F.} and Wang, {Ming Hsi} and McCauley, {Jacob L.} and Abreu, {Maria T.} and Traci Jester and Zarela Molle-Rios and Sirish Palle and Scherl, {Ellen J.} and John Kwon and Rioux, {John D.} and Duerr, {Richard H.} and Silverberg, {Mark S.} and Zwick, {Michael E.} and Christine Stevens and Daly, {Mark J.} and Cho, {Judy H.} and Greg Gibson and McGovern, {Dermot P.B.} and Brant, {Steven R.} and Subra Kugathasan",
note = "Funding Information: The National Institutes of Health (NIH) grants DK062431 (S.R.B.); DK087694 (S.K.); DK062413 (D.P.B.M. and K.T.); DK046763-19 , AI067068 , and U54DE023789-01 (D.P.B.M.); DK062429 (J.H.C. and P.S.); DK062422 (J.H.C.); DK062420 (R.H.D.); DK062432 (J.D.R.); and DK062423 (M.S.S.) supported this study. Sequencing at the Broad Institute was supported by NHGRI grants 5U54HG003067-13 and UM1HG008895 . S.R.B. was also supported in part by funding from Rutgers Crohns and Colitis Center of New Jersey . We acknowledge the clinicians and organizations that contributed to samples used in this study. Finally, we are grateful to the many families whose participation made this study possible. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = mar,
day = "4",
doi = "10.1016/j.ajhg.2021.02.001",
language = "English (US)",
volume = "108",
pages = "431--445",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "3",
}