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

被引：30

作者：

Somineni, Hari K. ^{[1
,2
,3
]}

Nagpal, Sini ^{[4
]}

Venkateswaran, Suresh ^{[2
,3
]}

Cutler, David J. ^{[5
]}

Okou, David T. ^{[2
,3
]}

Haritunians, Talin ^{[6
]}

Simpson, Claire L. ^{[7
]}

Begum, Ferdouse ^{[8
]}

Datta, Lisa W. ^{[8
]}

Quiros, Antonio J. ^{[9
]}

Seminerio, Jenifer ^{[10
]}

Mengesha, Emebet ^{[6
]}

Alexander, Jonathan S. ^{[11
]}

Baldassano, Robert N. ^{[12
]}

Dudley-Brown, Sharon ^{[13
]}

Cross, Raymond K. ^{[14
]}

Dassopoulos, Themistocles ^{[15
]}

Denson, Lee A. ^{[16
]}

Dhere, Tanvi A. ^{[17
]}

Iskandar, Heba ^{[17
]}

Dryden, Gerald W. ^{[18
]}

Hou, Jason K. ^{[19
]}

Hussain, Sunny Z. ^{[20
]}

Hyams, Jeffrey S. ^{[21
]}

Isaacs, Kim L. ^{[22
]}

Kader, Howard ^{[23
]}

Kappelman, Michael D. ^{[24
]}

Katz, Jeffry ^{[25
]}

Kellermayer, Richard ^{[26
]}

Kuemmerle, John F. ^{[27
]}

Lazarev, Mark ^{[28
]}

Li, Ellen ^{[29
]}

Mannon, Peter ^{[30
]}

Moulton, Dedrick E. ^{[31
]}

Newberry, Rodney D. ^{[32
]}

Patel, Ashish S. ^{[33
]}

Pekow, Joel ^{[34
]}

Saeed, Shehzad A. ^{[35
]}

Valentine, John F. ^{[36
]}

Wang, Ming-Hsi ^{[37
]}

McCauley, Jacob L. ^{[38
,39
]}

Abreu, Maria T. ^{[40
,41
]}

Jester, Traci ^{[42
]}

Molle-Rios, Zarela ^{[43
]}

Palle, Sirish ^{[44
]}

Scherl, Ellen J. ^{[45
]}

Kwon, John ^{[46
]}

Rioux, John D. ^{[47
,48
]}

Duerr, Richard H. ^{[49
]}

Silverberg, Mark S. ^{[50
]}

机构：

[1] Emory Univ, Genet & Mol Biol Program, Atlanta, GA 30322 USA

[2] Emory Univ, Sch Med, Dept Pediat, Div Pediat Gastroenterol, Atlanta, GA 30322 USA

[3] Childrens Healthcare Atlanta, Atlanta, GA 30322 USA

[4] Georgia Inst Technol, Ctr Integrat Genom, Atlanta, GA 30332 USA

[5] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA

[6] Cedars Sinai Med Ctr, F Widjaja Fdn Inflammatory Bowel & Immunobiol Res, Los Angeles, CA 90048 USA

[7] Univ Tennessee, Hlth Sci Ctr, Dept Genet Genom & Informat, Memphis, TN 38163 USA

[8] Johns Hopkins Univ, Meyerhoff Inflammatory Bowel Dis Ctr, Dept Med, Sch Med, Baltimore, MD 21205 USA

[9] Med Univ South Carolina, Pediat Ctr Inflammatory Bowel Disorders, Dept Pediat, Summerville, SC 29485 USA

[10] Med Univ South Carolina, Digest Dis Ctr, Dept Gastroenterol, Charleston, SC 29425 USA

[11] Louisiana State Univ, Hlth Sci Ctr, Dept Mol & Cellular Physiol, Shreveport, LA 71103 USA

[12] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA

[13] Johns Hopkins Univ, Dept Med, Sch Med & Nursing, Baltimore, MD 21205 USA

[14] Univ Maryland, Dept Med, Sch Med, Baltimore, MD 21201 USA

[15] Texas A&M Univ, Baylor Scott & White Ctr Inflammatory Bowel Dis, Dallas, TX 75202 USA

[16] Cincinnati Childrens Hosp Med Ctr, Div Gastroenterol Hepatol & Nutr, Cincinnati, OH 45229 USA

[17] Emory Univ, Dept Med, Sch Med, Atlanta, GA 30322 USA

[18] Univ Louisville, Dept Med, Louisville, KY 40202 USA

[19] Baylor Coll Med, Dept Med, Houston, TX 77030 USA

[20] Willis Knighton Phys Network, Dept Pediat, Shreveport, LA 71101 USA

[21] Connecticut Childrens Med Ctr, Hartford, CT 06106 USA

[22] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA

[23] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA

[24] Univ N Carolina, Dept Pediat, Chapel Hill, NC 27514 USA

[25] Case Western Reserve Univ, Cleveland, OH 44106 USA

[26] Texas Childrens Hosp, Baylor Coll Med, Sect Pediat Gastroenterol, Houston, TX 77030 USA

[27] Virginia Commonwealth Univ, Div Gastroenterol Hepatol & Nutr, Med Coll Virginia Campus, Richmond, VA 23284 USA

[28] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA

[29] SUNY Stony Brook, Sch Med, Dept Med, Stony Brook, NY 11794 USA

[30] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35233 USA

[31] Vanderbilt Childrens Hosp, Nashville, TN 37232 USA

[32] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA

[33] Univ Texas Southwestern Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA

[34] Univ Chicago, Comer Childrens Hosp, Dept Pediat, Chicago, IL 60637 USA

[35] Dayton Childrens Hosp, Dayton, OH 45404 USA

[36] Univ Utah, Hlth Sci, Salt Lake City, UT 84132 USA

[37] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN 55905 USA

[38] Univ Miami, Leonard M Miller Sch Med, John P Hussman Inst Human Genom, Miami, FL 33136 USA

[39] Univ Miami, Dr John T Macdonald Fdn Dept Human Genet, Leonard M Miller Sch Med, Miami, FL 33136 USA

[40] Univ Miami, Leonard M Miller Sch Med, Dept Med, Div Gastroenterol, Miami, FL 33136 USA

[41] Univ Miami, Leonard M Miller Sch Med, Dept Microbiol & Immunol, Miami, FL 33136 USA

[42] UAB Med, Dept Pediat, Birmingham, AL 35233 USA

[43] Nemours DuPont Hosp Children, Pediat Gastroenterol & Nutr, Wilmington, DE 19803 USA

[44] Oklahoma Univ, Dept Pediat, Sch Med, Oklahoma City, OK 73104 USA

[45] Weill Cornell Med, Jill Roberts Ctr IBD, Gastroenterol & Hepatol, New York, NY 10065 USA

[46] UT Southwestern Dept Internal Med, Dallas, TX 75390 USA

[47] Univ Montreal, Dept Med, Montreal, PQ H1Y 3N1, Canada

[48] Montreal Heart Inst Res Ctr, Montreal, PQ H1Y 3N1, Canada

[49] Human Genet & Clin & Translat Sci, Pittsburgh, PA 15213 USA

[50] Univ Toronto, Mt Sinai Hosp, Zane Cohen Ctr Digest Dis, Dept Med, Toronto, ON M5T 3L9, Canada

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2021年 / 108卷 / 03期

基金：

美国国家卫生研究院;

关键词：

POLYGENIC RISK SCORES; WIDE ASSOCIATION; GENOTYPE IMPUTATION; SUSCEPTIBILITY LOCI; METAANALYSIS; COMPONENTS;

D O I：

10.1016/j.ajhg.2021.02.001

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：431 / 445

页数：15

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