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

Hari K. Somineni, Sini Nagpal, Suresh Venkateswaran, David J. Cutler, David T. Okou, Talin Haritunians, Claire L. Simpson, Ferdouse Begum, Lisa W. Datta, Antonio J. Quiros, Jenifer Seminerio, Emebet Mengesha, Jonathan S. Alexander, Robert N. Baldassano, Sharon Dudley-Brown, Raymond K. Cross, Themistocles Dassopoulos, Lee A. Denson, Tanvi A. Dhere, Heba IskandarGerald W. Dryden, Jason K. Hou, Sunny Z. Hussain, Jeffrey S. Hyams, Kim L. Isaacs, Howard Kader, Michael D. Kappelman, Jeffry Katz, Richard Kellermayer, John F. Kuemmerle, Mark Lazarev, Ellen Li, Peter Mannon, Dedrick E. Moulton, Rodney D. Newberry, Ashish S. Patel, Joel Pekow, Shehzad A. Saeed, John F. Valentine, Ming Hsi Wang, Jacob L. McCauley, Maria T. Abreu, Traci Jester, Zarela Molle-Rios, Sirish Palle, Ellen J. Scherl, John Kwon, John D. Rioux, Richard H. Duerr, Mark S. Silverberg, Michael E. Zwick, Christine Stevens, Mark J. Daly, Judy H. Cho, Greg Gibson, Dermot P.B. McGovern, Steven R. Brant, Subra Kugathasan

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)431-445
Number of pages15
JournalAmerican journal of human genetics
Volume108
Issue number3
DOIs
StatePublished - Mar 4 2021

Keywords

  • CALB2
  • differential genetic architecture
  • polygenic risk scores
  • PTGER4
  • rare variants
  • trans-ethnic comparative analysis
  • understudied populations
  • whole-genome sequencing of African Americans

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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