. 2021 Mar 4;108(3):431-445.

doi: 10.1016/j.ajhg.2021.02.001. Epub 2021 Feb 17.

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

Hari K Somineni¹, Sini Nagpal², Suresh Venkateswaran³, David J Cutler⁴, David T Okou³, Talin Haritunians⁵, Claire L Simpson⁶, Ferdouse Begum⁷, Lisa W Datta⁷, Antonio J Quiros⁸, Jenifer Seminerio⁹, Emebet Mengesha⁵, Jonathan S Alexander¹⁰, Robert N Baldassano¹¹, Sharon Dudley-Brown¹², Raymond K Cross¹³, Themistocles Dassopoulos¹⁴, Lee A Denson¹⁵, Tanvi A Dhere¹⁶, Heba Iskandar¹⁶, Gerald W Dryden¹⁷, Jason K Hou¹⁸, Sunny Z Hussain¹⁹, Jeffrey S Hyams²⁰, Kim L Isaacs²¹, Howard Kader²², Michael D Kappelman²³, Jeffry Katz²⁴, Richard Kellermayer²⁵, John F Kuemmerle²⁶, Mark Lazarev²⁷, Ellen Li²⁸, Peter Mannon²⁹, Dedrick E Moulton³⁰, Rodney D Newberry³¹, Ashish S Patel³², Joel Pekow³³, Shehzad A Saeed³⁴, John F Valentine³⁵, Ming-Hsi Wang³⁶, Jacob L McCauley³⁷, Maria T Abreu³⁸, Traci Jester³⁹, Zarela Molle-Rios⁴⁰, Sirish Palle⁴¹, Ellen J Scherl⁴², John Kwon⁴³, John D Rioux⁴⁴, Richard H Duerr⁴⁵, Mark S Silverberg⁴⁶, Michael E Zwick⁴, Christine Stevens⁴⁷, Mark J Daly⁴⁷, Judy H Cho⁴⁸, Greg Gibson², Dermot P B McGovern⁵, Steven R Brant⁴⁹, Subra Kugathasan⁵⁰

Affiliations

¹ Genetics and Molecular Biology Program, Emory University, Atlanta, GA 30322, USA; Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
² Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, GA 30332, USA.
³ Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
⁴ Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.
⁵ F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁶ Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
⁷ Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁸ Department of Pediatrics, Medical University of South Carolina, Pediatric Center for Inflammatory Bowel Disorders, Summerville, SC 29485, USA.
⁹ Department of Gastroenterology, Medical University of South Carolina Digestive Disease Center, Charleston, SC 29425, USA.
¹⁰ Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA.
¹¹ Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
¹² Department of Medicine, Johns Hopkins University Schools of Medicine & Nursing, Baltimore, MD 21205, USA.
¹³ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
¹⁴ Baylor Scott and White Center for Inflammatory Bowel Diseases, Texas A&M University, Dallas, TX 75202, USA.
¹⁵ Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
¹⁶ Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
¹⁷ Department of Medicine, University of Louisville, Louisville, KY 40202, USA.
¹⁸ Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁹ Department of Pediatrics, Willis-Knighton Physician Network, Shreveport, LA 71101, USA.
²⁰ Connecticut Children's Medical Center, Hartford, CT 06106, USA.
²¹ Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
²² Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
²³ Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
²⁴ Case Western Reserve University, Cleveland, OH 44106, USA.
²⁵ Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.
²⁶ Division of Gastroenterology, Hepatology and Nutrition, Medical College of Virginia Campus of Virginia Commonwealth University, Richmond, VA 23284, USA.
²⁷ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
²⁸ Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA.
²⁹ Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
³⁰ Vanderbilt Children's Hospital, Nashville, TN 37232, USA.
³¹ Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
³² Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
³³ Department of Pediatrics, University of Chicago Comer Children's Hospital, Chicago, IL 60637, USA.
³⁴ Dayton Children's Hospital, Dayton, OH 45404, USA.
³⁵ University of Utah, Health Sciences, Salt Lake City, UT 84132, USA.
³⁶ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA.
³⁷ John P. Hussman Institute for Human Genomics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136 USA; The Dr. John T. Macdonald Foundation Department of Human Genetics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
³⁸ Division of Gastroenterology, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Microbiology and Immunology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
³⁹ Department of Pediatrics, UAB Medicine, Birmingham, AL 35233, USA.
⁴⁰ Pediatric Gastroenterology and Nutrition, Nemours duPont Hospital for Children, DE 19803, USA.
⁴¹ Department of Pediatrics, Oklahoma University School of Medicine, Oklahoma City, OK 73104, USA.
⁴² Gastroenterology and Hepatology, Jill Roberts Center for IBD, Weill Cornell Medicine, New York, NY 10065, USA.
⁴³ UT Southwestern Department of Internal Medicine, Dallas, TX 75390, USA.
⁴⁴ Department of Medicine, Université de Montréal and the Montreal Heart Institute Research Center, Montreal, QC H1Y3N1, Canada.
⁴⁵ Human Genetics, and Clinical and Translational Science, Pittsburgh, PA 15213, USA.
⁴⁶ Department of Medicine, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, ON M5T3L9, Canada.
⁴⁷ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁴⁸ Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁴⁹ The Human Genetics Institute of New Jersey, Rutgers University, New Brunswick and Piscataway, NJ 08854, USA.
⁵⁰ Genetics and Molecular Biology Program, Emory University, Atlanta, GA 30322, USA; Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, Atlanta, GA 30322, USA. Electronic address: skugath@emory.edu.

PMID: 33600772
PMCID: PMC8008495
DOI: 10.1016/j.ajhg.2021.02.001

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

Hari K Somineni et al. Am J Hum Genet. 2021.

. 2021 Mar 4;108(3):431-445.

doi: 10.1016/j.ajhg.2021.02.001. Epub 2021 Feb 17.

Authors

Affiliations

¹ Genetics and Molecular Biology Program, Emory University, Atlanta, GA 30322, USA; Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
² Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, GA 30332, USA.
³ Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
⁴ Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.
⁵ F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁶ Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
⁷ Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁸ Department of Pediatrics, Medical University of South Carolina, Pediatric Center for Inflammatory Bowel Disorders, Summerville, SC 29485, USA.
⁹ Department of Gastroenterology, Medical University of South Carolina Digestive Disease Center, Charleston, SC 29425, USA.
¹⁰ Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA.
¹¹ Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
¹² Department of Medicine, Johns Hopkins University Schools of Medicine & Nursing, Baltimore, MD 21205, USA.
¹³ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
¹⁴ Baylor Scott and White Center for Inflammatory Bowel Diseases, Texas A&M University, Dallas, TX 75202, USA.
¹⁵ Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
¹⁶ Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
¹⁷ Department of Medicine, University of Louisville, Louisville, KY 40202, USA.
¹⁸ Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁹ Department of Pediatrics, Willis-Knighton Physician Network, Shreveport, LA 71101, USA.
²⁰ Connecticut Children's Medical Center, Hartford, CT 06106, USA.
²¹ Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
²² Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
²³ Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
²⁴ Case Western Reserve University, Cleveland, OH 44106, USA.
²⁵ Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.
²⁶ Division of Gastroenterology, Hepatology and Nutrition, Medical College of Virginia Campus of Virginia Commonwealth University, Richmond, VA 23284, USA.
²⁷ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
²⁸ Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA.
²⁹ Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
³⁰ Vanderbilt Children's Hospital, Nashville, TN 37232, USA.
³¹ Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
³² Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
³³ Department of Pediatrics, University of Chicago Comer Children's Hospital, Chicago, IL 60637, USA.
³⁴ Dayton Children's Hospital, Dayton, OH 45404, USA.
³⁵ University of Utah, Health Sciences, Salt Lake City, UT 84132, USA.
³⁶ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA.
³⁷ John P. Hussman Institute for Human Genomics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136 USA; The Dr. John T. Macdonald Foundation Department of Human Genetics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
³⁸ Division of Gastroenterology, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Microbiology and Immunology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
³⁹ Department of Pediatrics, UAB Medicine, Birmingham, AL 35233, USA.
⁴⁰ Pediatric Gastroenterology and Nutrition, Nemours duPont Hospital for Children, DE 19803, USA.
⁴¹ Department of Pediatrics, Oklahoma University School of Medicine, Oklahoma City, OK 73104, USA.
⁴² Gastroenterology and Hepatology, Jill Roberts Center for IBD, Weill Cornell Medicine, New York, NY 10065, USA.
⁴³ UT Southwestern Department of Internal Medicine, Dallas, TX 75390, USA.
⁴⁴ Department of Medicine, Université de Montréal and the Montreal Heart Institute Research Center, Montreal, QC H1Y3N1, Canada.
⁴⁵ Human Genetics, and Clinical and Translational Science, Pittsburgh, PA 15213, USA.
⁴⁶ Department of Medicine, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, ON M5T3L9, Canada.
⁴⁷ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁴⁸ Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁴⁹ The Human Genetics Institute of New Jersey, Rutgers University, New Brunswick and Piscataway, NJ 08854, USA.
⁵⁰ Genetics and Molecular Biology Program, Emory University, Atlanta, GA 30322, USA; Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, Atlanta, GA 30322, USA. Electronic address: skugath@emory.edu.

PMID: 33600772
PMCID: PMC8008495
DOI: 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.

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

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

**Figure 1**
Regional plots of the *PTGER4* region in the discovery whole-genome sequence data Crohn disease (top); ulcerative colitis (middle); inflammatory bowel disease (bottom). Dashed red lines indicate genome-wide significance (p = 5 × 10⁻⁸). Variants are color coded to show linkage disequilibrium structure relative to a variant, rs6896969, that showed the strongest association with Crohn disease in African Americans in our previous GWAS.

**Figure 2**
QQ plot of rare-variant gene-level association analysis of ulcerative colitis Observed negative log p values are from the SKAT-O test.

**Figure 3**
Comparison of effect sizes across populations (A) Statistical power of the discovery whole-genome sequencing dataset to replicate previously known variants at p < 0.05. The known variants that showed an association (p < 0.05) with Crohn disease, ulcerative colitis, or inflammatory bowel disease in African Americans are colored to denote their p value of association. (B–D) Comparison of effect sizes at known variants in African Americans and Europeans. Each variant is colored to denote the p value of association for Crohn disease (B), ulcerative colitis (C), or inflammatory bowel disease (D) in African Americans from the discovery whole-genome sequencing cohort. The red line shows the linear regression fit to indicate the general trend. Significance and goodness-of-fit are shown. *ADCY7* was not included while computing goodness-of-fit in (C) (see subjects and methods).

**Figure 4**
Median proportion of variance explained by inflammatory bowel disease loci in African Americans and Europeans via effects estimated from the two populations (A and B) Median proportion of variance explained (PVE) by the known loci (n = 215 SNPs) assessed via allele frequencies and effect sizes estimated in African American pseudo-controls and UK Biobank datasets measured on lnOR and liability scales across five discovery sets. PVE is computed as 2p.q.ln(OR)² on lnOR scale (A); 2.p.alpha₁² + 2.q.alpha₂², where alpha1 and alpha2 are liability estimates on liability scale (B).

**Figure 5**
Comparison of proportion of variance explained (PVE) per locus in African Americans and Europeans at known loci (n = 215 SNPs) via effects estimated on the lnOR and liability scales (A) PVE is computed as 2p.q.ln(OR)². (B) PVE is computed as 2.p.alpha1² + 2.q.alpha2², where *alpha1* and *alpha2* are liability scale estimates.

**Figure 6**
Polygenic risk scores (PRSs) in African Americans and Europeans as a function of different discovery ancestry groups PRSs in African Americans and UK Biobank individuals derived via 215 of the known disease SNPs and liability scale effects estimated from the African American discovery cohort (AA_liability, red) or the UK Biobank discovery cohort (UKBB_liability, green). (A and B) Prevalence of IBD (%) versus percentile of PRS in each cohort. (C and D) Mean proportion of variance explained (PVE) by each PRS. Standard error bars are from five test sets.

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

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

Authors

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Abstract

Conflict of interest statement

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