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

TOPMed Hematology & Hemostasis Working Group, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

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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.

Original languageEnglish (US)
Article numbere1008500
JournalPLoS genetics
Issue number12
StatePublished - 2019

Bibliographical note

Funding Information:
Laura M. Raffield and Chani J. Hodonsky are funded by T32 HL129982. Madeline H Kowalski, Huijun Qian, Alexander P. Reiner, and Yun Li are funded on R01 HL129132. Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116. Eric Jorgenson and Hélène Choquet are funded by R01 EY027004 and R01 DK116738. Ruth J.F. Loos is funded by U01 HG007417 and R56HG010297. Steve Buyske is funded by U01 HG007419. Rasika A. Mathias, Lewis C. Becker, Nauder Faraday, and Lisa R. Yanek are funded by U01 HL72518, R01 HL087698, and R01 HL112064. Russell P Tracy, Stephen S. Rich, Jerome I. Rotter, and Mary Cushman are funded by 3R01HL-117626-02S1, 3R01HL-120393-02S1, HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Edwin K Silverman and Michael H Cho are funded by U01 HL089856. L Adrienne Cupples is funded by NO1-HC-25195, HHSN268201500001I, and R01 HL092577-06S1. Hemant K. Tiwari and Marguerite R. Irvin are funded by R01 HL055673. Jiang He is funded by U01HL072507, R01HL087263, and R01HL090682. Juan M. Peralta and John Blangero are funded by R01 HL113323. Sharon L.R. Kardia and Jennifer A. Smith are funded by R01 HL119443 and R01 HL085571. Scott T. Weiss and Jessica A. Lasky-Su are funded by P01 HL132825. Kathleen C Barnes and Michelle Daya are funded by R01HL104608. Patrick T Ellinor is funded by NIH 1RO1HL092577, R01HL128914, K24HL105780, AHA 18SFRN34110082, and Fondation Leducq 14CVD01. Donna K Arnett is funded by R01 R01HL091397. Bertha Hidalgo is funded by K01 HL130609 01. Courtney Montgomery is funded by R01 HL113326. Nicholette D Palmer and Donald W Bowden are funded by R01 HL92301, R01 HL67348, R01 NS058700, R01 NS075107, R01 AR48797, R01 DK071891, M01 RR07122, F32 HL085989, P60 AG10484. Steven A. Lubitz is funded by NIH 1R01HL139731 and American Heart Association 18SFRN34250007. Kent D. Taylor is funded by 3R01HL-117626-02S1, 3R01HL-120393-02S1, R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071258, R01HL071259, UL1RR033176, and UL1TR001881. Patricia A. Peyser is funded by R01 HL119443 and R01 HL085571. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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