Whole genome sequencing association analysis of quantitative red blood cell phenotypes: the NHLBI TOPMed program
Whole genome sequencing association analysis of quantitative red blood cell phenotypes: the NHLBI TOPMed program
Abstract Whole genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these newly discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3bp indel p.Lys2169del (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis [OMIM 194380], associated with higher MCHC. Stepwise conditional analysis identified 12 independent red cell trait-associated variants in the chromosome 11 region spanning the beta-globin genes. In gene-based rare variant aggregated association analysis, seven genes (HBA1/HBA2, HBB, TMPRSS6, G6PD, CD36, TFRC and SLC12A7) were associated with RBC traits, independently of known single variants. Several of the variants in HBB, HBA1, TMPRSS6, and G6PD represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Together, these results demonstrate the utility of WGS in ethnically-diverse population-based samples for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.
Loos Ruth J.F.、Hobbs Brian D.、Nickerson Debbie、Conomos Matthew P.、Bauer Daniel E.、Laurie Cathy C.、the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium、Soranzo Nicole、Choquet H¨|l¨¨ne、Wang Zhe、Ekunwe Lynette、Lange Leslie A.、Cushman Mary、Almasy Laura、Gabriel Stacey、Fornage Myriam、Lloyd-Jones Donald M.、Smith Nicholas L.、Morrison Alanna C.、Blangero John、Kooperberg Charles、Preuss Michael H.、Stilp Adrienne M.、Rao Shuquan、de Bellefon S¨|bastian M¨|ric、Yanek Lisa R.、de Vries Paul S.、Duggirala Ravindranath、Jorgenson Eric、Abecasis Goncalo R.、Moon Jee-Young、Boerwinkle Eric、Lane John、Laurie Cecelia A.、Tang Hua、Correa Adolfo、Heard-Costa Nancy、O?ˉConnell Jeffrey R.、Jain Deepti、Mitchell Braxton D.、Surendran Praveen、Rich Stephen S.、Curran Joanne E.、Ryan Kathleen、McHugh Caitlin P.、Vasan Ramachandran S.、Rotter Jerome I.、Kaplan Robert、Psaty Bruce M.、Butterworth Adam S.、Lewis Joshua P.、Smith Albert V.、Reiner Alexander P.、Hou Lifang、Lettre Guillaume、Beaty Terri H.、Sun Quan、Faraday Nauder、Chen Ming-Huei、Hu Yao、Li Yun、Raffield Laura M.、Blackwell Thomas W.、Min Nancy、Broome Jai、North Kari E.、Mathias Rasika A.、Johnson Andrew D.、Chami Nathalie、Kundu Kousik、Brody Jennifer A.、Pankratz Nathan、Wheeler Marsha、Zheng Xiuwen、Becker Lewis C.、Auer Paul L.
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount SinaiChanning Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women?ˉs Hospital and Harvard Medical SchoolDepartment of Genome Sciences, University of WashingtonDepartment of Biostatistics, University of WashingtonDivision of Hematology/Oncology, Boston Children?ˉs Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical SchoolDepartment of Biostatistics, University of WashingtonBritish Heart Foundation Centre of Research Excellence, University of Cambridge||Department of Human Genetics, Wellcome Sanger Institute||Department of Haematology, University of Cambridge||National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of CambridgeDivision of Research, Kaiser Permanente Northern CaliforniaThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount SinaiDepartment of Medicine, University of Mississippi Medical CenterDivision of Biomedical Informatics and Personalized Medicine, School of Medicine University of Colorado, Anschutz Medical CampusDepartment of Medicine, Larner College of Medicine at the University of VermontDepartment of Biomedical and Health Informatics, Children?ˉs Hospital of Philadelphia and Department of Genetics University of Pennsylvania Perelman School of MedicineBroad InstituteUniversity of Texas Health Science Center at HoustonNorthwestern UniversityDepartment of Epidemiology, University of Washington||Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington||Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and DevelopmentHuman Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at HoustonDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of MedicinePublic Health Sciences Division, Fred Hutchinson Cancer Research CenterThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount SinaiDepartment of Biostatistics, University of WashingtonDivision of Hematology/Oncology, Boston Children?ˉs Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical SchoolMontreal Heart InstituteDivision of General Internal Medicine, Department of Medicine, Johns Hopkins University School of MedicineHuman Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at HoustonDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of MedicineDivision of Research, Kaiser Permanente Northern CaliforniaTOPMed Informatics Research Center, University of Michigan, Department of BiostatisticsDepartment of Epidemiology and Population Health, Albert Einstein College of MedicineHuman Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at HoustonDepartment of Laboratory Medicine and Pathology, University of Minnesota Medical SchoolDepartment of Biostatistics, University of WashingtonDepartment of Genetics, Stanford University School of MedicineDepartment of Medicine, University of Mississippi Medical CenterDepartment of Genetics, University of North Carolina||National Heart Lung and Blood Institute?ˉs and Boston University?ˉs Framingham Heart Study||Department of Neurology, Boston University School of MedicineDepartment of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland School of MedicineDepartment of Biostatistics, University of WashingtonDepartment of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland School of MedicineBritish Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge||British Heart Foundation Centre of Research Excellence, University of Cambridge||Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge||Rutherford Fund Fellow, Department of Public Health and Primary Care, University of CambridgeCenter for Public Health Genomics, Department of Public Health Sciences, University of Virginia School of MedicineDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of MedicineDepartment of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland School of MedicineDepartment of Biostatistics, University of WashingtonNational Heart Lung and Blood Institute?ˉs and Boston University?ˉs Framingham Heart Study||Departments of Cardiology and Preventive Medicine, Department of Medicine, Boston University School of Medicine||Department of Biostatistics, Boston University School of Public HealthThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterDepartment of Epidemiology and Population Health, Albert Einstein College of MedicineDepartment of Epidemiology, University of Washington||Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington||Department of Medicine, University of WashingtonBritish Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge||British Heart Foundation Centre of Research Excellence, University of Cambridge||Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge||National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge||National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University HospitalsDepartment of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland School of MedicineTOPMed Informatics Research Center, University of Michigan, Department of BiostatisticsDepartment of Epidemiology, University of WashingtonNorthwestern UniversityMontreal Heart Institute||Facult¨| de M¨|decine, Universit¨| de Montr¨|alSchool of Public Health, John Hopkins UniversityDepartment of Biostatistics, University of North Carolina at Chapel HillDepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of MedicinePopulation Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute||National Heart Lung and Blood Institute?ˉs and Boston University?ˉs Framingham Heart StudyPublic Health Sciences Division, Fred Hutchinson Cancer Research CenterDepartments of Biostatistics, Genetics, Computer Science, University of North Carolina at Chapel HillDepartment of Genetics, University of North CarolinaTOPMed Informatics Research Center, University of Michigan, Department of BiostatisticsDepartment of Medicine, University of Mississippi Medical CenterDepartment of Biostatistics, University of WashingtonDepartment of Epidemiology, Gillings School of Public Health, University of North Carolina at Chapel HillDivision of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of MedicinePopulation Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute||National Heart Lung and Blood Institute?ˉs and Boston University?ˉs Framingham Heart StudyThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount SinaiDepartment of Human Genetics, Wellcome Sanger Institute||Department of Haematology, University of CambridgeCardiovascular Health Research Unit, Department of Medicine, University of WashingtonDepartment of Laboratory Medicine and Pathology, University of Minnesota Medical SchoolDepartment of Genome Sciences, University of WashingtonDepartment of Biostatistics, University of WashingtonDivision of Cardiology, Department of Medicine, Johns Hopkins University School of MedicineZilber School of Public Health, University of Wisconsin-Milwaukee
医学研究方法基础医学遗传学
Loos Ruth J.F.,Hobbs Brian D.,Nickerson Debbie,Conomos Matthew P.,Bauer Daniel E.,Laurie Cathy C.,the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium,Soranzo Nicole,Choquet H¨|l¨¨ne,Wang Zhe,Ekunwe Lynette,Lange Leslie A.,Cushman Mary,Almasy Laura,Gabriel Stacey,Fornage Myriam,Lloyd-Jones Donald M.,Smith Nicholas L.,Morrison Alanna C.,Blangero John,Kooperberg Charles,Preuss Michael H.,Stilp Adrienne M.,Rao Shuquan,de Bellefon S¨|bastian M¨|ric,Yanek Lisa R.,de Vries Paul S.,Duggirala Ravindranath,Jorgenson Eric,Abecasis Goncalo R.,Moon Jee-Young,Boerwinkle Eric,Lane John,Laurie Cecelia A.,Tang Hua,Correa Adolfo,Heard-Costa Nancy,O?ˉConnell Jeffrey R.,Jain Deepti,Mitchell Braxton D.,Surendran Praveen,Rich Stephen S.,Curran Joanne E.,Ryan Kathleen,McHugh Caitlin P.,Vasan Ramachandran S.,Rotter Jerome I.,Kaplan Robert,Psaty Bruce M.,Butterworth Adam S.,Lewis Joshua P.,Smith Albert V.,Reiner Alexander P.,Hou Lifang,Lettre Guillaume,Beaty Terri H.,Sun Quan,Faraday Nauder,Chen Ming-Huei,Hu Yao,Li Yun,Raffield Laura M.,Blackwell Thomas W.,Min Nancy,Broome Jai,North Kari E.,Mathias Rasika A.,Johnson Andrew D.,Chami Nathalie,Kundu Kousik,Brody Jennifer A.,Pankratz Nathan,Wheeler Marsha,Zheng Xiuwen,Becker Lewis C.,Auer Paul L..Whole genome sequencing association analysis of quantitative red blood cell phenotypes: the NHLBI TOPMed program[EB/OL].(2025-03-28)[2025-05-02].https://www.medrxiv.org/content/10.1101/2020.12.09.20246736.点此复制
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