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.

Pubmed ID: 31869403

Pubmed Central ID: PMC6953885

Journal: PLoS genetics

Publication Date: Dec. 23, 2019

Affiliation: Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina, United States of America.

MeSH Terms: Humans, Male, Adult, Female, Aged, Aged, 80 and over, United States, Gene Frequency, Genetic Predisposition to Disease, Middle Aged, Genome-Wide Association Study, Databases, Genetic, Computational Biology, Precision Medicine, Linkage Disequilibrium, Hispanic or Latino, Genetics, Population, Whole Genome Sequencing, Genotyping Techniques, beta-Globins, Black or African American

Grants: N01HC25195, UL1 TR001079, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN268201100046C, HHSN271201100004C, P30 DK063491, U54 HG003273, R01 HL120393, HHSN268201300029C, HHSN268201300025C, HHSN268201300028C, HHSN268201300026C, HHSN268200900041C, HHSN268201300027C, R01 HL104135, UL1 RR033176, N01HC95163, N01HC95161, N01HC95167, R01 HL071251, R01 HL071259, N01HC95159, R01 HL071250, N01HC95162, N01HC95166, R01 HL119443, R01 HL071051, N01HC95169, N01HC95165, N01HC95164, R01 HL071205, N01HC95160, UL1 TR000040, N01HC95168, R01 HL071258, R01 HL055673, HHSN268201100001I, HHSN268201100002I, HHSN268201100004I, R01 HL092577, HHSN268201700004I, U01 HG007417, U01 HG007419, U01 HG007416, U01 HG007376, R01 HL117626, M01 RR000052, UL1 TR001881, UL1 TR001420, R01 HL113326, HHSN268201500001I, HHSN268201500001C, HHSN268201100003I, HHSN268201800014C, HHSN268201800013I, HHSN268201800011C, HHSN268201800015I, HHSN268201800012C, HHSN268201500003I, HHSN268201700001I, HHSN268201700003I, HHSN268201700005I, HHSN268201700002I, R01 HL139731, R01 HL141826, R01 HL123915, R01 HL118356, R01 HL112064, HHSN268201100037C, HHSN268201500003C, R01 HL113323, RC2 AG036607, R01 HL087698, K24 HL105780, U54 HG003067, R01 HL121007, R01 HG006703, T32 ES007018, R01 AR048797, R21 HL091397, U01 HL089897, R01 HL129132, R01 HL142302, N01HC65236, R01 EY027004, N01HC65235, R01 NS058700, F32 HL085989, R01 HL128914, N01HC65234, HHSN268201200008C, R37 HL066289, U01 HL089856, T32 HL129982, R01 HL067348, N01HC65233, HHSN268201700002C, R01 DK101855, N01HC65237, 18SFRN34110082, HHSN268201500015C, R56 HG010297, R01 DK116738, R01 HL104608, U01 HL072518, HHSN268201500014C, M01 RR007122, R01 NS075107, R01 HL087263, HHSN268201700005C, HHSN268201700001C, U01 HL072507, HHSN268201700003C, R01 DK071891, K01 HL130609, R01 HL085571, HHSN268201700004C, T32 HL007284, R01 HL090682, P01 HL132825, HHSN268201200008I, R01 HL092301

Authors: Tracy RP, Cushman M, Li Y, He J, Smith NL, Reiner AP, Rich SS, Ganesh SK, Heckbert SR, Boerwinkle E, Gupta N, Weng LC, Johnson AD, Taylor KD, Lubitz SA, Rotter JI, Wilson JG, Morrison AC, Cupples LA, North KE, Bis JC, Fornage M, Auer PL, Pankratz N, Kooperberg C, de Vries PS, Avery C, Cai J, Graff M, Arnett DK, Irvin MR, Hidalgo B, Tiwari HK, Smith JA, Jain D, Wang T, Buyske S, Blangero J, Loos RJF, Palmer ND, Wiggins KL, Peyser PA, Cho MH, Raffield LM, Choi SH, Ellinor PT, Barnes KC, Daya M, Weiss ST, Mathias RA, Yanek LR, Becker LC, Peralta JM, Montgomery C, Kardia SLR, Kelly TN, Bowden DW, Kaplan R, Thornton TA, Gabriel S, Silverman EK, Papanicolaou GJ, Zöllner S, Kowalski MH, Qian H, Hou Z, Rosen JD, Tapia AL, Shan Y, Argos M, Bien SA, Choquet H, Faraday N, Hodonsky CJ, Jorgenson E, Lasky-Su JA, McHugh CP, Moon JY

Cite As: Kowalski 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 SH, Choquet H, Cupples LA, 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 JY, 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 LC, Wiggins KL, Wilson JG, Yanek LR, Zöllner S, North KE, Auer PL, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology & Hemostasis Working Group, Raffield LM, Reiner AP, Li Y. 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. PLoS Genet 2019 Dec 23;15(12):e1008500. doi: 10.1371/journal.pgen.1008500. eCollection 2019 Dec.

Studies:

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.