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 K Ganesh; Misa Graff; Namrata Gupta; Jiang He; Susan R Heckbert; Bertha Hidalgo; Chani J Hodonsky; Marguerite R Irvin; Andrew D Johnson; Eric Jorgenson; Robert Kaplan; Sharon L R 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 E North; Paul L Auer; Laura M Raffield; Alexander P Reiner; Yun Li; TOPMed Hematology & Hemostasis Working Group

doi:10.1371/journal.pgen.1008500

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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

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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, …

PLoS genetics, Vol.15(12), pp.e1008500-e1008500

12/2019

DOI: https://doi.org/10.1371/journal.pgen.1008500

PMCID: PMC6953885

PMID: 31869403

Abstract

Adult

African Americans - genetics

Aged

Aged, 80 and over

beta-Globins - genetics

Computational Biology - methods

Databases, Genetic

Female

Gene Frequency

Genetic Predisposition to Disease

Genetics, Population

Genome-Wide Association Study

Genotyping Techniques

Hispanic Americans - genetics

Humans

Linkage Disequilibrium

Male

Middle Aged

Precision Medicine - methods

Whole Genome Sequencing - methods

United States

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.

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Title: 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
Creators: Madeline H Kowalski - Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, United States of America
Huijun Qian - Department of Statistics and Operation Research, University of North Carolina, Chapel Hill, North Carolina, United States of America
Ziyi Hou - Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, United States of America
Jonathan D Rosen - Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, United States of America
Amanda L Tapia - Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, United States of America
Yue Shan - Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, United States of America
Deepti Jain - Department of Biostatistics, University of Washington, Seattle, Washington, United States of America
Maria Argos - Division of Epidemiology and Biostatistics, University of Illinois at Chicago, Chicago, Illinois, United States of America
Donna K Arnett - College of Public Health, University of Kentucky, Lexington, Kentucky, United States of America
Christy Avery - Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, United States of America
Kathleen C Barnes - Department of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado, United States of America
Lewis C Becker - GeneSTAR Research Program, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
Stephanie A Bien - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
Joshua C Bis - Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America
John Blangero - Department of Human Genetics and South Texas Diabetes Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas, United States of America
Eric Boerwinkle - Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America
Donald W Bowden - Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America
Steve Buyske - Department of Statistics, Rutgers University, Piscataway, New Jersey, United States of America
Jianwen Cai - Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, United States of America
Michael H Cho - Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
Seung Hoan Choi - Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
Hélène Choquet - Division of Research, Kaiser Permanente Northern California, Oakland, California, United States of America
L Adrienne Cupples - Framingham Heart Study, Framingham, Massachusetts, United States of America
Mary Cushman - Departments of Medicine & Pathology, Larner College of Medicine, University of Vermont, Colchester, Vermont, United States of America
Michelle Daya - Department of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado, United States of America
Paul S de Vries - Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America
Patrick T Ellinor - Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, United States of America
Nauder Faraday - GeneSTAR Research Program, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
Myriam Fornage - School of Public Health, The University of Texas Health Science Center, Houston, Texas, United States of America
Stacey Gabriel - Genomics Platform, Broad Institute, Cambridge, Massachusetts, United States of America
Santhi K Ganesh - Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States of America
Misa Graff - Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, United States of America
Namrata Gupta - Genomics Platform, Broad Institute, Cambridge, Massachusetts, United States of America
Jiang He - Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Los Angeles, United States of America
Susan R Heckbert - Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, Washington, United States of America
Bertha Hidalgo - Department of Epidemiology, Ryals School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
Chani J Hodonsky - Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, United States of America
Marguerite R Irvin - Department of Epidemiology, Ryals School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
Andrew D Johnson - Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, Massachusetts, United States of America
Eric Jorgenson - Division of Research, Kaiser Permanente Northern California, Oakland, California, United States of America
Robert Kaplan - Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, New York, United States of America
Sharon L R Kardia - Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America
Tanika N Kelly - Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Los Angeles, United States of America
Charles Kooperberg - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
Jessica A Lasky-Su - Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
Ruth J F Loos - The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
Steven A Lubitz - Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, United States of America
Rasika A Mathias - GeneSTAR Research Program, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
Caitlin P McHugh - Department of Biostatistics, University of Washington, Seattle, Washington, United States of America
Courtney Montgomery - Department of Genes and Human Disease, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
Jee-Young Moon - Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, New York, United States of America
Alanna C Morrison - Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America
Nicholette D Palmer - Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America
Nathan Pankratz - Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, United States of America
George J Papanicolaou - National Heart, Lung, and Blood Institute, Division of Cardiovascular Sciences, PPSP/EB, NIH, Bethesda, Maryland, United States of America
Juan M Peralta - Department of Human Genetics and South Texas Diabetes Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas, United States of America
Patricia A Peyser - Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America
Stephen S Rich - Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, United States of America
Jerome I Rotter - The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America
Edwin K Silverman - Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
Jennifer A Smith - Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America
Nicholas L Smith - Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, Washington, United States of America
Kent D Taylor - The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America
Timothy A Thornton - Department of Biostatistics, University of Washington, Seattle, Washington, United States of America
Hemant K Tiwari - Department of Biostatistics, Ryals School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
Russell P Tracy - Departments of Pathology & Laboratory Medicine and Biochemistry, Larrner College of Medicine, University of Vermont, Colchester, Vermont, United States of America
Tao Wang - Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, United States of America
Scott T Weiss - Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
Lu-Chen Weng - Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
Kerri L Wiggins - Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America
James G Wilson - Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, United States of America
Lisa R Yanek - GeneSTAR Research Program, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
Sebastian Zöllner - Department of Psychiatry, University of Michigan, Ann Arbor, Michigan, United States of America
Kari E North - Carolina Center of Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
Paul L Auer - Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, United States of America
Laura M Raffield - Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, United States of America
Alexander P Reiner - Department of Epidemiology, University of Washington, Seattle, Washington, United States of America
Yun Li - Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina, United States of America
TOPMed Hematology & Hemostasis Working Group
Publication Details: PLoS genetics, Vol.15(12), pp.e1008500-e1008500
Date published: 12/2019
Grant note: N01HC95169 / NHLBI NIH HHS N01HC65235 / NHLBI NIH HHS R01 HL121007 / NHLBI NIH HHS HHSN268201500014C / NHLBI NIH HHS R01 HL067348 / NHLBI NIH HHS R01 HL139731 / NHLBI NIH HHS HHSN268201100037C / NHLBI NIH HHS R01 HL119443 / NHLBI NIH HHS R01 HL071251 / NHLBI NIH HHS R01 HL128914 / NHLBI NIH HHS R56 HG010297 / NHGRI NIH HHS N01HC95163 / NHLBI NIH HHS HHSN268201200008I / NHLBI NIH HHS N01HC95166 / NHLBI NIH HHS HHSN268201700003I / NHLBI NIH HHS R01 HL117626 / NHLBI NIH HHS HHSN268201200008C / NHLBI NIH HHS HHSN268201300025C / NHLBI NIH HHS R01 HL141826 / NHLBI NIH HHS R01 DK101855 / NIDDK NIH HHS HHSN268201500001I / NHLBI NIH HHS HHSN268201500003C / NHLBI NIH HHS R01 HL090682 / NHLBI NIH HHS R01 HL055673 / NHLBI NIH HHS UL1 RR033176 / NCRR NIH HHS F32 HL085989 / NHLBI NIH HHS U01 HG007419 / NHGRI NIH HHS U01 HG007416 / NHGRI NIH HHS M01 RR007122 / NCRR NIH HHS R01 HL092577 / NHLBI NIH HHS HHSN268201500003I / NHLBI NIH HHS UL1 TR000040 / NCATS NIH HHS R01 HL112064 / NHLBI NIH HHS U01 HG007376 / NHGRI NIH HHS HHSN268201700005C / NHLBI NIH HHS P30 DK063491 / NIDDK NIH HHS HHSN271201100004C / NIA NIH HHS R01 HL120393 / NHLBI NIH HHS N01HC95161 / NHLBI NIH HHS R01 HL087698 / NHLBI NIH HHS HHSN268201700005I / NHLBI NIH HHS R01 HL071250 / NHLBI NIH HHS HHSN268201700002I / NHLBI NIH HHS N01HC65237 / NHLBI NIH HHS N01HC95167 / NHLBI NIH HHS R01 DK116738 / NIDDK NIH HHS HHSN268201100003I / NHLBI NIH HHS U01 HL089856 / NHLBI NIH HHS UL1 TR001079 / NCATS NIH HHS HHSN268201700003C / NHLBI NIH HHS R01 HL092301 / NHLBI NIH HHS HHSN268201100002I / NHLBI NIH HHS HHSN268201100001C / WHI NIH HHS T32 HL007284 / NHLBI NIH HHS N01HC95160 / NHLBI NIH HHS R37 HL066289 / NHLBI NIH HHS HHSN268201800012C / NHLBI NIH HHS HHSN268201700002C / NHLBI NIH HHS 18SFRN34110082 / American Heart Association-American Stroke Association HHSN268201100001I / NHLBI NIH HHS R01 NS058700 / NINDS NIH HHS R01 HL104135 / NHLBI NIH HHS HHSN268201700001C / NHLBI NIH HHS HHSN268201700001I / NHLBI NIH HHS HHSN268201800011C / NHLBI NIH HHS HHSN268201300027C / NHLBI NIH HHS HHSN268201100004I / NHLBI NIH HHS HHSN268200900041C / NHLBI NIH HHS UL1 TR001881 / NCATS NIH HHS HHSN268201700004C / NHLBI NIH HHS HHSN268201800014C / NHLBI NIH HHS HHSN268201100004C / WHI NIH HHS HHSN268201100002C / WHI NIH HHS R01 HL129132 / NHLBI NIH HHS R01 HL142302 / NHLBI NIH HHS HHSN268201700004I / NHLBI NIH HHS R21 HL091397 / NHLBI NIH HHS U01 HL072518 / NHLBI NIH HHS HHSN268201100003C / WHI NIH HHS P01 HL132825 / NHLBI NIH HHS T32 HL129982 / NHLBI NIH HHS R01 HL113326 / NHLBI NIH HHS R01 DK071891 / NIDDK NIH HHS R01 HL113323 / NHLBI NIH HHS K01 HL130609 / NHLBI NIH HHS U01 HL072507 / NHLBI NIH HHS HHSN268201100046C / NHLBI NIH HHS N01HC25195 / NHLBI NIH HHS N01HC65233 / NHLBI NIH HHS M01 RR000052 / NCRR NIH HHS T32 ES007018 / NIEHS NIH HHS HHSN268201800015I / NHLBI NIH HHS N01HC65236 / NHLBI NIH HHS N01HC95168 / NHLBI NIH HHS HHSN268201500015C / NHLBI NIH HHS R01 HL071258 / NHLBI NIH HHS RC2 AG036607 / NIA NIH HHS N01HC95165 / NHLBI NIH HHS N01HC95162 / NHLBI NIH HHS UL1 TR001420 / NCATS NIH HHS N01HC95164 / NHLBI NIH HHS HHSN268201500001C / NHLBI NIH HHS R01 HL071051 / NHLBI NIH HHS HHSN268201300026C / NHLBI NIH HHS N01HC95159 / NHLBI NIH HHS R01 HL085571 / NHLBI NIH HHS R01 AR048797 / NIAMS NIH HHS R01 HL087263 / NHLBI NIH HHS K24 HL105780 / NHLBI NIH HHS R01 HL118356 / NHLBI NIH HHS U01 HG007417 / NHGRI NIH HHS U01 HL089897 / NHLBI NIH HHS HHSN268201300029C / NHLBI NIH HHS HHSN268201800013I / NIMHD NIH HHS R01 EY027004 / NEI NIH HHS N01HC65234 / NHLBI NIH HHS R01 HL123915 / NHLBI NIH HHS R01 HG006703 / NHGRI NIH HHS R01 HL071259 / NHLBI NIH HHS U54 HG003067 / NHGRI NIH HHS R01 NS075107 / NINDS NIH HHS U54 HG003273 / NHGRI NIH HHS HHSN268201300028C / NHLBI NIH HHS R01 HL071205 / NHLBI NIH HHS R01 HL104608 / NHLBI NIH HHS
Academic Unit: Statistics (SAS)
Language: English
Resource Type: Journal article
Identifiers: 991031666035104646