Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations

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  • Kowalski, M.H.
    • Affiliation: Gillings School of Global Public Health, Department of Biostatistics
  • Qian, H.
    • Other Affiliation: Department of Statistics and Operation Research
  • Hou, Z.
    • Other Affiliation: Harvard Medical School
  • Rosen, J.D.
    • Affiliation: Gillings School of Global Public Health, Department of Biostatistics
  • Tapia, A.L.
    • Affiliation: Gillings School of Global Public Health, Department of Biostatistics
  • Shan, Y.
    • Affiliation: Gillings School of Global Public Health, Department of Biostatistics
  • Jain, D.
    • Other Affiliation: University of Washington
  • Argos, M.
    • Other Affiliation: University of Illinois at Chicago
  • Arnett, D.K.
    • Other Affiliation: University of Kentucky
  • Avery, C.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Barnes, K.C.
    • Other Affiliation: University of Colorado Denver
  • Becker, L.C.
    • Other Affiliation: Johns Hopkins School of Medicine
  • Bien, S.A.
    • Other Affiliation: Fred Hutchinson Cancer Research Center
  • Bis, J.C.
    • Other Affiliation: University of Washington
  • Blangero, J.
    • Other Affiliation: University of Texas Rio Grande Valley
  • Boerwinkle, E.
    • Other Affiliation: Baylor College of Medicine
  • Bowden, D.W.
    • Other Affiliation: Wake Forest School of Medicine
  • Buyske, S.
    • Other Affiliation: Rutgers University
  • Cai, J.
    • Affiliation: Gillings School of Global Public Health, Department of Biostatistics
  • Cho, M.H.
    • Other Affiliation: Harvard Medical School
  • Choi, S.H.
    • Other Affiliation: Broad Institute of MIT and Harvard
  • Choquet, H.
    • Other Affiliation: Kaiser Permanente Northern California
  • Cupples, L. A.
    • Other Affiliation: Boston University School of Public Health
  • Cushman, M.,
    • Other Affiliation: University of Vermont
  • Daya, M.
    • Other Affiliation: University of Colorado Denver
  • de Vries, P.S.
    • Other Affiliation: University of Texas Health Science Center at Houston
  • Ellinor, P.T.
    • Other Affiliation: Massachusetts General Hospital
  • Faraday, N.
    • Other Affiliation: Johns Hopkins School of Medicine
  • Fornage, M.
    • Other Affiliation: University of Texas Health Science Center
  • Gabriel, S.
    • Other Affiliation: Broad Institute
  • Ganesh, S.K.
    • Other Affiliation: University of Michigan
  • Graff, M.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Gupta, N.
    • Other Affiliation: Broad Institute
  • He, J.
    • Other Affiliation: Tulane University School of Public Health and Tropical Medicine
  • Heckbert, S.R.
    • Other Affiliation: Kaiser Permanente Washington Health Research Institute
  • Hidalgo, B.
    • Other Affiliation: University of Alabama at Birmingham
  • Hodonsky, C.J.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Irvin, M.R.
    • Other Affiliation: University of Alabama at Birmingham
  • Johnson, A.D.
    • Other Affiliation: National Heart, Lung and Blood Institute
  • Jorgenson, E.
    • Other Affiliation: Kaiser Permanente Northern California
  • Kaplan, R.
    • Other Affiliation: Albert Einstein College of Medicine
  • Kardia, S.L.R.
    • Other Affiliation: University of Michigan
  • Kelly, T.N.
    • Other Affiliation: Tulane University School of Public Health and Tropical Medicine
  • Kooperberg, C.
    • Other Affiliation: Fred Hutchinson Cancer Research Center
  • Lasky-Su, J.A.
    • Other Affiliation: Harvard Medical School
  • Loos, R.J.F.
    • Other Affiliation: Icahn School of Medicine at Mount Sinai
  • Lubitz, S.A.
    • Other Affiliation: Massachusetts General Hospital
  • Mathias, R.A.
    • Other Affiliation: Johns Hopkins School of Medicine
  • McHugh, C.P.
    • Other Affiliation: University of Washington
  • Montgomery, C.
    • Other Affiliation: Oklahoma Medical Research Foundation
  • Moon, J.-Y.
    • Other Affiliation: Albert Einstein College of Medicine
  • Morrison, A.C.
    • Other Affiliation: University of Texas Health Science Center at Houston
  • Palmer, N.D.
    • Other Affiliation: Wake Forest School of Medicine
  • Pankratz, N.
    • Other Affiliation: University of Minnesota
  • Papanicolaou, G.J.
    • Other Affiliation: NIH
  • Peralta, J.M.
    • Other Affiliation: University of Texas Rio Grande Valley
  • Peyser, P.A.
    • Other Affiliation: University of Michigan
  • Rich, S.S.
    • Other Affiliation: University of Virginia
  • Rotter, J.I.
    • Other Affiliation: Harbor-UCLA Medical Center
  • Silverman, E.K.
    • Other Affiliation: Harvard Medical School
  • Smith, J.A.
    • Other Affiliation: University of Michigan
  • Smith, N.L.
    • Other Affiliation: Seattle Epidemiologic Research and Information Center
  • Taylor, K.D.
    • Other Affiliation: Harbor-UCLA Medical Center
  • Thornton, T.A.
    • Other Affiliation: University of Washington
  • Tiwari, H.K.
    • Other Affiliation: University of Alabama at Birmingham
  • Tracy, R.P.
    • Other Affiliation: University of Vermont
  • Wang, T.
    • Other Affiliation: Albert Einstein College of Medicine
  • Weiss, S.T.
    • Other Affiliation: Harvard Medical School
  • Weng, L.-C.
    • Other Affiliation: Broad Institute of MIT and Harvard
  • Wiggins, K.L.
    • Other Affiliation: University of Washington
  • Wilson, J.G.
    • Other Affiliation: University of Mississippi Medical Center
  • Yanek, L.R.
    • Other Affiliation: Johns Hopkins School of Medicine
  • Zöllner, S.
    • Other Affiliation: University of Michigan
  • North, K.E.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Auer, P.L.
    • Other Affiliation: University of Wisconsin-Milwaukee
  • NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
  • TOPMed Hematology & Hemostasis Working Group
  • Raffield, L.M.
    • Affiliation: School of Medicine, Department of Genetics
  • Reiner, A.P.
    • Other Affiliation: University of Washington
  • Li, Y.
    • Affiliation: Gillings School of Global Public Health, Department of Biostatistics
Abstract
  • Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.
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  • Article
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  • In Copyright
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  • Public Domain Mark 1.0
Journal title
  • PLoS Genetics
Journal volume
  • 15
Journal issue
  • 12
Language
  • English
ISSN
  • 1553-7390
Publisher
  • Public Library of Science

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