PMID- 33887194 OWN - NLM STAT- MEDLINE DCOM- 20210630 LR - 20220326 IS - 1537-6605 (Electronic) IS - 0002-9297 (Print) IS - 0002-9297 (Linking) VI - 108 IP - 5 DP - 2021 May 6 TI - Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program. PG - 874-893 LID - S0002-9297(21)00134-8 [pii] LID - 10.1016/j.ajhg.2021.04.003 [doi] AB - 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, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these 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 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders. CI - Copyright (c) 2021 American Society of Human Genetics. All rights reserved. FAU - Hu, Yao AU - Hu Y AD - Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98105, USA. FAU - Stilp, Adrienne M AU - Stilp AM AD - Department of Biostatistics, University of Washington, Seattle, WA 98105, USA. FAU - McHugh, Caitlin P AU - McHugh CP AD - Department of Biostatistics, University of Washington, Seattle, WA 98105, USA. FAU - Rao, Shuquan AU - Rao S AD - Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA. FAU - Jain, Deepti AU - Jain D AD - Department of Biostatistics, University of Washington, Seattle, WA 98105, USA. FAU - Zheng, Xiuwen AU - Zheng X AD - Department of Biostatistics, University of Washington, Seattle, WA 98105, USA. FAU - Lane, John AU - Lane J AD - Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA. FAU - Meric de Bellefon, Sebastian AU - Meric de Bellefon S AD - Montreal Heart Institute, Montreal, QC H1T 1C8, Canada. FAU - Raffield, Laura M AU - Raffield LM AD - Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA. FAU - Chen, Ming-Huei AU - Chen MH AD - Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA; National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01701, USA. FAU - Yanek, Lisa R AU - Yanek LR AD - Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. FAU - Wheeler, Marsha AU - Wheeler M AD - Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA. FAU - Yao, Yao AU - Yao Y AD - Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA. FAU - Ren, Chunyan AU - Ren C AD - Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA. FAU - Broome, Jai AU - Broome J AD - Department of Biostatistics, University of Washington, Seattle, WA 98105, USA. FAU - Moon, Jee-Young AU - Moon JY AD - Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA. FAU - de Vries, Paul S AU - de Vries PS AD - 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, TX 77030, USA. FAU - Hobbs, Brian D AU - Hobbs BD AD - Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. FAU - Sun, Quan AU - Sun Q AD - Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. FAU - Surendran, Praveen AU - Surendran P AD - British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge CB1 8RN, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge CB1 8RN, UK; Rutherford Fund Fellow, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK. FAU - Brody, Jennifer A AU - Brody JA AD - Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98105, USA. FAU - Blackwell, Thomas W AU - Blackwell TW AD - TOPMed Informatics Research Center, University of Michigan, Department of Biostatistics, Ann Arbor, MI 48109, USA. FAU - Choquet, Helene AU - Choquet H AD - Division of Research, Kaiser Permanente Northern California, Oakland, CA 94601, USA. FAU - Ryan, Kathleen AU - Ryan K AD - Department of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA. FAU - Duggirala, Ravindranath AU - Duggirala R AD - Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78539, USA. FAU - Heard-Costa, Nancy AU - Heard-Costa N AD - Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01701, USA; Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA. FAU - Wang, Zhe AU - Wang Z AD - The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. FAU - Chami, Nathalie AU - Chami N AD - The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. FAU - Preuss, Michael H AU - Preuss MH AD - The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. FAU - Min, Nancy AU - Min N AD - Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA. FAU - Ekunwe, Lynette AU - Ekunwe L AD - Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA. FAU - Lange, Leslie A AU - Lange LA AD - Division of Biomedical Informatics and Personalized Medicine, School of Medicine University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. FAU - Cushman, Mary AU - Cushman M AD - Department of Medicine, Larner College of Medicine at the University of Vermont, Burlington, VT 05405, USA. FAU - Faraday, Nauder AU - Faraday N AD - Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. FAU - Curran, Joanne E AU - Curran JE AD - Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78539, USA. FAU - Almasy, Laura AU - Almasy L AD - Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia and Department of Genetics University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. FAU - Kundu, Kousik AU - Kundu K AD - Department of Human Genetics, Wellcome Sanger Institute, Hinxton CB10 1SA, UK; Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK. FAU - Smith, Albert V AU - Smith AV AD - TOPMed Informatics Research Center, University of Michigan, Department of Biostatistics, Ann Arbor, MI 48109, USA. FAU - Gabriel, Stacey AU - Gabriel S AD - Broad Institute, Boston, MA 02142, USA. FAU - Rotter, Jerome I AU - Rotter JI AD - The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA. FAU - Fornage, Myriam AU - Fornage M AD - University of Texas Health Science Center at Houston, Houston, TX 77030, USA. FAU - Lloyd-Jones, Donald M AU - Lloyd-Jones DM AD - Northwestern University, Chicago, IL 60208, USA. FAU - Vasan, Ramachandran S AU - Vasan RS AD - National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01701, USA; Departments of Cardiology and Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA. FAU - Smith, Nicholas L AU - Smith NL AD - Department of Epidemiology, University of Washington, Seattle, WA 98105, USA; Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA 98105, USA; Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA 98105, USA. FAU - North, Kari E AU - North KE AD - Department of Epidemiology, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. FAU - Boerwinkle, Eric AU - Boerwinkle E AD - 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, TX 77030, USA. FAU - Becker, Lewis C AU - Becker LC AD - Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. FAU - Lewis, Joshua P AU - Lewis JP AD - Department of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA. FAU - Abecasis, Goncalo R AU - Abecasis GR AD - TOPMed Informatics Research Center, University of Michigan, Department of Biostatistics, Ann Arbor, MI 48109, USA. FAU - Hou, Lifang AU - Hou L AD - Northwestern University, Chicago, IL 60208, USA. FAU - O'Connell, Jeffrey R AU - O'Connell JR AD - Department of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA. FAU - Morrison, Alanna C AU - Morrison AC AD - 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, TX 77030, USA. FAU - Beaty, Terri H AU - Beaty TH AD - School of Public Health, John Hopkins University, Baltimore, MD 21205, USA. FAU - Kaplan, Robert AU - Kaplan R AD - Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA. FAU - Correa, Adolfo AU - Correa A AD - Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA. FAU - Blangero, John AU - Blangero J AD - Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78539, USA. FAU - Jorgenson, Eric AU - Jorgenson E AD - Division of Research, Kaiser Permanente Northern California, Oakland, CA 94601, USA. FAU - Psaty, Bruce M AU - Psaty BM AD - Department of Epidemiology, University of Washington, Seattle, WA 98105, USA; Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA 98105, USA; Department of Medicine, University of Washington, Seattle, WA 98105, USA. FAU - Kooperberg, Charles AU - Kooperberg C AD - Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98105, USA. FAU - Walton, Russell T AU - Walton RT AD - Center for Genomic Medicine and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. FAU - Kleinstiver, Benjamin P AU - Kleinstiver BP AD - Center for Genomic Medicine and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA. FAU - Tang, Hua AU - Tang H AD - Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. FAU - Loos, Ruth J F AU - Loos RJF AD - The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. FAU - Soranzo, Nicole AU - Soranzo N AD - British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge CB1 8RN, UK; Department of Human Genetics, Wellcome Sanger Institute, Hinxton CB10 1SA, UK; Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK; National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge CB1 8RN, UK. FAU - Butterworth, Adam S AU - Butterworth AS AD - British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge CB1 8RN, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge CB1 8RN, UK; National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge CB1 8RN, UK; National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge CB1 8RN, UK. FAU - Nickerson, Debbie AU - Nickerson D AD - Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA. FAU - Rich, Stephen S AU - Rich SS AD - Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA 22903, USA. FAU - Mitchell, Braxton D AU - Mitchell BD AD - Department of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA. FAU - Johnson, Andrew D AU - Johnson AD AD - Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA; National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01701, USA. FAU - Auer, Paul L AU - Auer PL AD - Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53205, USA. FAU - Li, Yun AU - Li Y AD - Departments of Biostatistics, Genetics, Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. FAU - Mathias, Rasika A AU - Mathias RA AD - Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MA 21205, USA. FAU - Lettre, Guillaume AU - Lettre G AD - Montreal Heart Institute, Montreal, QC H1T 1C8, Canada; Faculte de Medecine, Universite de Montreal, Montreal, QC H1T 1C8, Canada. FAU - Pankratz, Nathan AU - Pankratz N AD - Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA. FAU - Laurie, Cathy C AU - Laurie CC AD - Department of Biostatistics, University of Washington, Seattle, WA 98105, USA. FAU - Laurie, Cecelia A AU - Laurie CA AD - Department of Biostatistics, University of Washington, Seattle, WA 98105, USA. FAU - Bauer, Daniel E AU - Bauer DE AD - Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA. FAU - Conomos, Matthew P AU - Conomos MP AD - Department of Biostatistics, University of Washington, Seattle, WA 98105, USA. FAU - Reiner, Alexander P AU - Reiner AP AD - Department of Epidemiology, University of Washington, Seattle, WA 98105, USA. Electronic address: apreiner@uw.edu. CN - NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium LA - eng GR - R01 HL130733/HL/NHLBI NIH HHS/United States GR - DP2 HL137300/HL/NHLBI NIH HHS/United States GR - R01 HL148565/HL/NHLBI NIH HHS/United States GR - P01 HL142494/HL/NHLBI NIH HHS/United States GR - R01 HL136574/HL/NHLBI NIH HHS/United States GR - K08 HL136928/HL/NHLBI NIH HHS/United States GR - R01 HL146500/HL/NHLBI NIH HHS/United States PT - Journal Article DEP - 20210421 PL - United States TA - Am J Hum Genet JT - American journal of human genetics JID - 0370475 SB - IM EIN - Am J Hum Genet. 2021 Jun 3;108(6):1165. PMID: 34087167 MH - Adult MH - Aged MH - Chromosomes, Human, Pair 16/genetics MH - Datasets as Topic MH - Erythrocytes/*metabolism/*pathology MH - Female MH - Gene Editing MH - Genetic Variation/genetics MH - *Genome-Wide Association Study MH - HEK293 Cells MH - Humans MH - Male MH - Middle Aged MH - National Heart, Lung, and Blood Institute (U.S.)/*organization & administration MH - *Phenotype MH - Quality Control MH - Reproducibility of Results MH - United States PMC - PMC8206199 OTO - NOTNLM OT - base editing OT - red blood cell traits OT - whole-genome sequencing COIS- B.P.K. is an inventor on patent applications filed by Mass General Brigham that describe genome engineering technologies, is an advisor to Acrigen Biosciences, and consults for Avectas Inc. and ElevateBio. EDAT- 2021/04/23 06:00 MHDA- 2021/07/01 06:00 PMCR- 2021/11/06 CRDT- 2021/04/22 20:11 PHST- 2020/12/19 00:00 [received] PHST- 2021/03/30 00:00 [accepted] PHST- 2021/04/23 06:00 [pubmed] PHST- 2021/07/01 06:00 [medline] PHST- 2021/04/22 20:11 [entrez] PHST- 2021/11/06 00:00 [pmc-release] AID - S0002-9297(21)00134-8 [pii] AID - 10.1016/j.ajhg.2021.04.003 [doi] PST - ppublish SO - Am J Hum Genet. 2021 May 6;108(5):874-893. doi: 10.1016/j.ajhg.2021.04.003. Epub 2021 Apr 21.