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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

View ORCID ProfileMadeline H. Kowalski, View ORCID ProfileHuijun Qian, Ziyi Hou, Jonathan D. Rosen, Amanda L. Tapia, Yue Shan, Deepti Jain, Maria Argos, Donna K. Arnett, Christy Avery, Kathleen C. Barnes, Lewis C. Becker, Stephanie A. Bien, Joshua C. Bis, John Blangero, Eric Boerwinkle, Donald W. Bowden, Steve Buyske, Jianwen Cai, Michael H. Cho, Seung Hoan Choi, Hélène Choquet, L Adrienne Cupples, Mary Cushman, Michelle Daya, Paul S. de Vries, Patrick T. Ellinor, Nauder Faraday, Myriam Fornage, Stacey Gabriel, Santhi Ganesh, Misa Graff, Namrata Gupta, Jiang He, Susan R. Heckbert, Bertha Hidalgo, Chani Hodonsky, Marguerite R. Irvin, Andrew D. Johnson, Eric Jorgenson, Robert Kaplan, Sharon LR. Kardia, Tanika N. Kelly, Charles Kooperberg, Jessica A. Lasky-Su, Ruth J.F. Loos, Steven A. Lubitz, Rasika A. Mathias, Caitlin P. McHugh, Courtney Montgomery, Jee-Young Moon, Alanna C. Morrison, Nicholette D. Palmer, Nathan Pankratz, George J. Papanicolaou, Juan M. Peralta, Patricia A. Peyser, Stephen S. Rich, Jerome I. Rotter, Edwin K. Silverman, Jennifer A. Smith, Nicholas L. Smith, Kent D. Taylor, Timothy A. Thornton, Hemant K. Tiwari, Russell P. Tracy, Tao Wang, Scott T. Weiss, Lu Chen Weng, Kerri L. Wiggins, James G. Wilson, Lisa R. Yanek, Sebastian Zöllner, Kari N. North, Paul L. Auer, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology & Hemostasis Working Group, Laura M. Raffield, View ORCID ProfileAlexander P. Reiner, View ORCID ProfileYun Li
doi: https://doi.org/10.1101/683201
Madeline H. Kowalski
1Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA
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  • ORCID record for Madeline H. Kowalski
Huijun Qian
2Department of Statistics and Operation Research, University of North Carolina, Chapel Hill, NC, USA
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  • ORCID record for Huijun Qian
Ziyi Hou
3Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
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Jonathan D. Rosen
1Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA
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Amanda L. Tapia
1Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA
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Yue Shan
1Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA
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Deepti Jain
4Department of Biostatistics, University of Washington, Seattle, WA, USA
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Maria Argos
5Division of Epidemiology and Biostatistics, University of Illinois at Chicago, Chicago, IL, USA
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Donna K. Arnett
6College of Public Health, University of Kentucky, Lexington, KY, USA
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Christy Avery
7Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
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Kathleen C. Barnes
8Department of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA
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Lewis C. Becker
9GeneSTAR Research Program, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
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Stephanie A. Bien
10Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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Joshua C. Bis
11Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
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John Blangero
12Department of Human Genetics and South Texas Diabetes Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA
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Eric Boerwinkle
13Human Genome Sequencing Center, University of Texas Health Science Center at Houston; Baylor College of Medicine, Houston, TX, USA
14Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
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Donald W. Bowden
15Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA
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Steve Buyske
16Department of Statistics, Rutgers University, Piscataway, NJ, USA
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Jianwen Cai
17Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA
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Michael H. Cho
18Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA
19Department of Medicine, Harvard Medical School, Boston, MA, USA
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Seung Hoan Choi
20Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Hélène Choquet
21Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
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L Adrienne Cupples
22Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
23Framingham Heart Study, Framingham, MA, USA
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Mary Cushman
24Departments of Medicine & Pathology, Larner College of Medicine, University of Vermont, Colchester, VT, USA
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Michelle Daya
8Department of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA
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Paul S. de Vries
14Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
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Patrick T. Ellinor
20Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
25Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
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Nauder Faraday
9GeneSTAR Research Program, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
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Myriam Fornage
26School of Public Health, The University of Texas Health Science Center, Houston, TX, USA
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Stacey Gabriel
27Genomics Platform, Broad Institute, Cambridge, MA, USA
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Santhi Ganesh
28Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
29Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
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Misa Graff
7Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
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Namrata Gupta
27Genomics Platform, Broad Institute, Cambridge, MA, USA
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Jiang He
30Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleas, LA, USA
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Susan R. Heckbert
31Department of Epidemiology, University of Washington, Seattle, WA, USA
32Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA, USA
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Bertha Hidalgo
33Department of Epidemiology, Ryals School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA
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Chani Hodonsky
7Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
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Marguerite R. Irvin
33Department of Epidemiology, Ryals School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA
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Andrew D. Johnson
34Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, MA, USA
23Framingham Heart Study, Framingham, MA, USA
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Eric Jorgenson
21Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
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Robert Kaplan
35Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
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Sharon LR. Kardia
36Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
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Tanika N. Kelly
30Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleas, LA, USA
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Charles Kooperberg
10Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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Jessica A. Lasky-Su
18Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA
19Department of Medicine, Harvard Medical School, Boston, MA, USA
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Ruth J.F. Loos
37The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
38The Mindich Child Health and Develoment Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Steven A. Lubitz
20Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
25Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
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Rasika A. Mathias
9GeneSTAR Research Program, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
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Caitlin P. McHugh
4Department of Biostatistics, University of Washington, Seattle, WA, USA
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Courtney Montgomery
39Department of Genes and Human Disease, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
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Jee-Young Moon
35Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
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Alanna C. Morrison
14Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
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Nicholette D. Palmer
15Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA
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Nathan Pankratz
40Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
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George J. Papanicolaou
41National Heart, Lung, and Blood Institute, Division of Cardiovascular Sciences, PPSP/EB, NIH, Bethesda, MD, USA
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Juan M. Peralta
12Department of Human Genetics and South Texas Diabetes Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA
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Patricia A. Peyser
36Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
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Stephen S. Rich
42Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
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Jerome I. Rotter
43The Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
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Edwin K. Silverman
18Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA
19Department of Medicine, Harvard Medical School, Boston, MA, USA
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Jennifer A. Smith
44Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
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Nicholas L. Smith
31Department of Epidemiology, University of Washington, Seattle, WA, USA
32Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA, USA
45Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA, USA
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Kent D. Taylor
46The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
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Timothy A. Thornton
4Department of Biostatistics, University of Washington, Seattle, WA, USA
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Hemant K. Tiwari
47Department of Biostatistics, Ryals School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA
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Russell P. Tracy
48Departments of Pathology & Laboratory Medicine and Biochemistry, Larrner College of Medicine, University of Vermont, Colchester, VT, USA
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Tao Wang
49Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
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Scott T. Weiss
18Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA
19Department of Medicine, Harvard Medical School, Boston, MA, USA
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Lu Chen Weng
20Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Kerri L. Wiggins
11Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
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James G. Wilson
50Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA
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Lisa R. Yanek
9GeneSTAR Research Program, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
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Sebastian Zöllner
51Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
52Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA
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Kari N. North
7Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
53Carolina Center of Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Paul L. Auer
54Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA
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Laura M. Raffield
55Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
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Alexander P. Reiner
31Department of Epidemiology, University of Washington, Seattle, WA, USA
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Yun Li
55Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
1Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA
56Department of Computer Science, University of North Carolina, Chapel Hill, NC, USA
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  • For correspondence: yunli@med.unc.edu
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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 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.

Footnotes

  • ^ Membership in Trans-Omics for Precision Medicine Consortium and the Hematology & Hemostasis Working Group are listed in supplemental files.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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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
Madeline H. Kowalski, Huijun Qian, Ziyi Hou, Jonathan D. Rosen, Amanda L. Tapia, Yue Shan, Deepti Jain, Maria Argos, Donna K. Arnett, Christy Avery, Kathleen C. Barnes, Lewis C. Becker, Stephanie A. Bien, Joshua C. Bis, John Blangero, Eric Boerwinkle, Donald W. Bowden, Steve Buyske, Jianwen Cai, Michael H. Cho, Seung Hoan Choi, Hélène Choquet, L Adrienne Cupples, Mary Cushman, Michelle Daya, Paul S. de Vries, Patrick T. Ellinor, Nauder Faraday, Myriam Fornage, Stacey Gabriel, Santhi Ganesh, Misa Graff, Namrata Gupta, Jiang He, Susan R. Heckbert, Bertha Hidalgo, Chani Hodonsky, Marguerite R. Irvin, Andrew D. Johnson, Eric Jorgenson, Robert Kaplan, Sharon LR. Kardia, Tanika N. Kelly, Charles Kooperberg, Jessica A. Lasky-Su, Ruth J.F. Loos, Steven A. Lubitz, Rasika A. Mathias, Caitlin P. McHugh, Courtney Montgomery, Jee-Young Moon, Alanna C. Morrison, Nicholette D. Palmer, Nathan Pankratz, George J. Papanicolaou, Juan M. Peralta, Patricia A. Peyser, Stephen S. Rich, Jerome I. Rotter, Edwin K. Silverman, Jennifer A. Smith, Nicholas L. Smith, Kent D. Taylor, Timothy A. Thornton, Hemant K. Tiwari, Russell P. Tracy, Tao Wang, Scott T. Weiss, Lu Chen Weng, Kerri L. Wiggins, James G. Wilson, Lisa R. Yanek, Sebastian Zöllner, Kari N. North, Paul L. Auer, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology & Hemostasis Working Group, Laura M. Raffield, Alexander P. Reiner, Yun Li
bioRxiv 683201; doi: https://doi.org/10.1101/683201
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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
Madeline H. Kowalski, Huijun Qian, Ziyi Hou, Jonathan D. Rosen, Amanda L. Tapia, Yue Shan, Deepti Jain, Maria Argos, Donna K. Arnett, Christy Avery, Kathleen C. Barnes, Lewis C. Becker, Stephanie A. Bien, Joshua C. Bis, John Blangero, Eric Boerwinkle, Donald W. Bowden, Steve Buyske, Jianwen Cai, Michael H. Cho, Seung Hoan Choi, Hélène Choquet, L Adrienne Cupples, Mary Cushman, Michelle Daya, Paul S. de Vries, Patrick T. Ellinor, Nauder Faraday, Myriam Fornage, Stacey Gabriel, Santhi Ganesh, Misa Graff, Namrata Gupta, Jiang He, Susan R. Heckbert, Bertha Hidalgo, Chani Hodonsky, Marguerite R. Irvin, Andrew D. Johnson, Eric Jorgenson, Robert Kaplan, Sharon LR. Kardia, Tanika N. Kelly, Charles Kooperberg, Jessica A. Lasky-Su, Ruth J.F. Loos, Steven A. Lubitz, Rasika A. Mathias, Caitlin P. McHugh, Courtney Montgomery, Jee-Young Moon, Alanna C. Morrison, Nicholette D. Palmer, Nathan Pankratz, George J. Papanicolaou, Juan M. Peralta, Patricia A. Peyser, Stephen S. Rich, Jerome I. Rotter, Edwin K. Silverman, Jennifer A. Smith, Nicholas L. Smith, Kent D. Taylor, Timothy A. Thornton, Hemant K. Tiwari, Russell P. Tracy, Tao Wang, Scott T. Weiss, Lu Chen Weng, Kerri L. Wiggins, James G. Wilson, Lisa R. Yanek, Sebastian Zöllner, Kari N. North, Paul L. Auer, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology & Hemostasis Working Group, Laura M. Raffield, Alexander P. Reiner, Yun Li
bioRxiv 683201; doi: https://doi.org/10.1101/683201

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