RT Journal Article
SR Electronic
T1 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
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 683201
DO 10.1101/683201
A1 Madeline H. Kowalski
A1 Huijun Qian
A1 Ziyi Hou
A1 Jonathan D. Rosen
A1 Amanda L. Tapia
A1 Yue Shan
A1 Deepti Jain
A1 Maria Argos
A1 Donna K. Arnett
A1 Christy Avery
A1 Kathleen C. Barnes
A1 Lewis C. Becker
A1 Stephanie A. Bien
A1 Joshua C. Bis
A1 John Blangero
A1 Eric Boerwinkle
A1 Donald W. Bowden
A1 Steve Buyske
A1 Jianwen Cai
A1 Michael H. Cho
A1 Seung Hoan Choi
A1 Hélène Choquet
A1 L Adrienne Cupples
A1 Mary Cushman
A1 Michelle Daya
A1 Paul S. de Vries
A1 Patrick T. Ellinor
A1 Nauder Faraday
A1 Myriam Fornage
A1 Stacey Gabriel
A1 Santhi Ganesh
A1 Misa Graff
A1 Namrata Gupta
A1 Jiang He
A1 Susan R. Heckbert
A1 Bertha Hidalgo
A1 Chani Hodonsky
A1 Marguerite R. Irvin
A1 Andrew D. Johnson
A1 Eric Jorgenson
A1 Robert Kaplan
A1 Sharon LR. Kardia
A1 Tanika N. Kelly
A1 Charles Kooperberg
A1 Jessica A. Lasky-Su
A1 Ruth J.F. Loos
A1 Steven A. Lubitz
A1 Rasika A. Mathias
A1 Caitlin P. McHugh
A1 Courtney Montgomery
A1 Jee-Young Moon
A1 Alanna C. Morrison
A1 Nicholette D. Palmer
A1 Nathan Pankratz
A1 George J. Papanicolaou
A1 Juan M. Peralta
A1 Patricia A. Peyser
A1 Stephen S. Rich
A1 Jerome I. Rotter
A1 Edwin K. Silverman
A1 Jennifer A. Smith
A1 Nicholas L. Smith
A1 Kent D. Taylor
A1 Timothy A. Thornton
A1 Hemant K. Tiwari
A1 Russell P. Tracy
A1 Tao Wang
A1 Scott T. Weiss
A1 Lu Chen Weng
A1 Kerri L. Wiggins
A1 James G. Wilson
A1 Lisa R. Yanek
A1 Sebastian Zöllner
A1 Kari N. North
A1 Paul L. Auer
A1 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
A1 TOPMed Hematology & Hemostasis Working Group
A1 Laura M. Raffield
A1 Alexander P. Reiner
A1 Yun Li
YR 2019
UL http://biorxiv.org/content/early/2019/07/02/683201.abstract
AB 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 still limited. In addition to the limited inclusion of these populations in genetic studies, these populations have more complex linkage disequilibrium structure that may reduce the number of variants associated with a phenotype. 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 commercial genome-wide genotyping array data. We demonstrate that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhances 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, respectively. Impressively, even for extremely rare variants with sample 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 ~20,000 self-identified African descent individuals and ~23,000 self-identified Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC (p=8.1×10−12) in African populations, rs11549407 with lower HGB (p=1.59×10−12) and HCT (p=1.13×10−9) 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 TOPMed imputation reference panel for identification of novel associations between rare variants and complex traits not previously detected in similar sized genome-wide studies of under-represented African and Hispanic/Latino populations.Author summary Admixed African and Hispanic/Latino populations remain understudied in genome-wide association and fine-mapping studies of complex diseases. These populations have more complex linkage disequilibrium (LD) structure that can impair mapping of variants associated with complex diseases and their risk factors. Genotype imputation represents an approach to improve genome coverage, especially for rare or ancestry-specific variation; however, these understudied populations also have smaller relevant imputation reference panels that need to be expanded to represent their more complex LD patterns. In this study, we leveraged >100,000 phased sequences generated from the multi-ethnic NHLBI TOPMed project to impute in admixed cohorts encompassing ~20,000 individuals of African ancestry (AAs) and ~23,000 Hispanics/Latinos. We demonstrated substantially higher imputation quality for low frequency and rare variants in comparison to the state-of-the-art reference panels (1000 Genomes Project and Haplotype Reference Consortium). Association analyses of ~35 million (AAs) and ~27 million (Hispanics/Latinos) variants passing stringent post-imputation filtering with quantitative hematological traits led to the discovery of associations with two rare variants in the HBB gene; one of these variants was replicated in an independent sample, and the other is known to cause anemia in the homozygous state. By comparison, the same HBB variants would not have been genome-wide significant using other state-of-the-art reference panels due to lower imputation quality. Our findings demonstrate the power of the TOPMed whole genome sequencing data for imputation and subsequent association analysis in admixed African and Hispanic/Latino populations.