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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.

TitleUse 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.
Publication TypeJournal Article
Year of Publication2019
AuthorsKowalski MH, Qian H, Hou Z, Rosen JD, Tapia AL, Shan Y, Jain D, Argos M, Arnett DK, Avery C, Barnes KC, Becker LC, Bien SA, Bis JC, Blangero J, Boerwinkle E, Bowden DW, Buyske S, Cai J, Cho MH, Choi SHoan, Choquet H, L Cupples A, Cushman M, Daya M, de Vries PS, Ellinor PT, Faraday N, Fornage M, Gabriel S, Ganesh SK, Graff M, Gupta N, He J, Heckbert SR, Hidalgo B, Hodonsky CJ, Irvin MR, Johnson AD, Jorgenson E, Kaplan R, Kardia SLR, Kelly TN, Kooperberg C, Lasky-Su JA, Loos RJF, Lubitz SA, Mathias RA, McHugh CP, Montgomery C, Moon J-Y, Morrison AC, Palmer ND, Pankratz N, Papanicolaou GJ, Peralta JM, Peyser PA, Rich SS, Rotter JI, Silverman EK, Smith JA, Smith NL, Taylor KD, Thornton TA, Tiwari HK, Tracy RP, Wang T, Weiss ST, Weng L-C, Wiggins KL, Wilson JG, Yanek LR, Zöllner S, North KE, Auer PL, Raffield LM, Reiner AP
Secondary AuthorsLi Y
Corporate AuthorsNHLBI Trans-Omics for Precision Medicine(TOPMed) Consortium, TOPMed Hematology & Hemostasis Working Group
JournalPLoS Genet
Volume15
Issue12
Paginatione1008500
Date Published2019 12
ISSN1553-7404
KeywordsAdult, African Americans, Aged, Aged, 80 and over, beta-Globins, Computational Biology, Databases, Genetic, Female, Gene Frequency, Genetic Predisposition to Disease, Genetics, Population, Genome-Wide Association Study, Genotyping Techniques, Hispanic Americans, Humans, Linkage Disequilibrium, Male, Middle Aged, Precision Medicine, United States, Whole Genome Sequencing
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) 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.

DOI10.1371/journal.pgen.1008500
Alternate JournalPLoS Genet
PubMed ID31869403
PubMed Central IDPMC6953885
Grant ListR01 HL113326 / HL / NHLBI NIH HHS / United States
HHSN268201500014C / HL / NHLBI NIH HHS / United States
N01HC95167 / HL / NHLBI NIH HHS / United States
R01 HL071205 / HL / NHLBI NIH HHS / United States
R01 HL118356 / HL / NHLBI NIH HHS / United States
UL1 RR033176 / RR / NCRR NIH HHS / United States
R01 HL112064 / HL / NHLBI NIH HHS / United States
HHSN268201100037C / HL / NHLBI NIH HHS / United States
U01 HG007417 / HG / NHGRI NIH HHS / United States
HHSN268201100001I / HL / NHLBI NIH HHS / United States
HHSN268201500003C / HL / NHLBI NIH HHS / United States
R01 DK116738 / DK / NIDDK NIH HHS / United States
R01 HL113323 / HL / NHLBI NIH HHS / United States
R01 HL139731 / HL / NHLBI NIH HHS / United States
HHSN268201300026C / HL / NHLBI NIH HHS / United States
RC2 AG036607 / AG / NIA NIH HHS / United States
U01 HG007419 / HG / NHGRI NIH HHS / United States
K01 HL130609 / HL / NHLBI NIH HHS / United States
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K24 HL105780 / HL / NHLBI NIH HHS / United States
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