Evidence map›Paper›PMID 33887194›Full record

ArticleAmerican journal of human genetics2021

Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program.

Yao Hu, Adrienne M Stilp, Caitlin P McHugh, Shuquan Rao, Deepti Jain, Xiuwen Zheng, John Lane, Sébastian Méric de Bellefon, Laura M Raffield, Ming-Huei Chen and 70 more

Erratum issuedOpen access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 30 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
30citing papers in PubMed, 1 pooled it
4.6field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

30 citing papers in PubMed, 1 synthesis or guideline pooled it, 49 citations in OpenAlex.

  1. Pooled it
  2. Article
  3. PIEZO1-mediated mechanosensation links aging to bladder dysfunction.bioRxiv : the preprint server for biology · 2026
    Article
  4. Article
  5. Article
  6. Article
  7. Article
  8. Open biology · 2025
    Review
  9. Article
  10. Article
  11. Article
  12. Article
  13. Article
  14. Article
  15. Article
  16. Article
  17. Article
  18. Article
  19. Review
  20. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

80 authors at 20 institutions in 3 countries.

Yao HuPublic Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98105, USA.
Adrienne M StilpDepartment of Biostatistics, University of Washington, Seattle, WA 98105, USA.
Caitlin P McHughDepartment of Biostatistics, University of Washington, Seattle, WA 98105, USA.
Shuquan RaoDivision 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.
Deepti JainDepartment of Biostatistics, University of Washington, Seattle, WA 98105, USA.
Xiuwen ZhengDepartment of Biostatistics, University of Washington, Seattle, WA 98105, USA.
John LaneDepartment of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Sébastian Méric de BellefonMontreal Heart Institute, Montréal, QC H1T 1C8, Canada.
Laura M RaffieldDepartment of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
Ming-Huei ChenPopulation 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.
Lisa R YanekDivision of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Marsha WheelerDepartment of Genome Sciences, University of Washington, Seattle, WA 98105, USA.
Yao YaoDivision 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.
Chunyan RenDivision 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.
Jai BroomeDepartment of Biostatistics, University of Washington, Seattle, WA 98105, USA.
Jee-Young MoonDepartment of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Paul S de VriesHuman 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.
Brian D HobbsChanning 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.
Quan SunDepartment of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Praveen SurendranBritish 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.
Jennifer A BrodyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98105, USA.
Thomas W BlackwellTOPMed Informatics Research Center, University of Michigan, Department of Biostatistics, Ann Arbor, MI 48109, USA.
Hélène ChoquetDivision of Research, Kaiser Permanente Northern California, Oakland, CA 94601, USA.
Kathleen RyanDepartment of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Ravindranath DuggiralaDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78539, USA.
Nancy Heard-CostaDepartment 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.
Zhe WangThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Nathalie ChamiThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Michael H PreussThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Nancy MinDepartment of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Lynette EkunweDepartment of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Leslie A LangeDivision of Biomedical Informatics and Personalized Medicine, School of Medicine University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
Mary CushmanDepartment of Medicine, Larner College of Medicine at the University of Vermont, Burlington, VT 05405, USA.
Nauder FaradayDepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Joanne E CurranDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78539, USA.
Laura AlmasyDepartment 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.
Kousik KunduDepartment of Human Genetics, Wellcome Sanger Institute, Hinxton CB10 1SA, UK; Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK.
Albert V SmithTOPMed Informatics Research Center, University of Michigan, Department of Biostatistics, Ann Arbor, MI 48109, USA.
Stacey GabrielBroad Institute, Boston, MA 02142, USA.
Jerome I RotterThe 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.
Myriam FornageUniversity of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Donald M Lloyd-JonesNorthwestern University, Chicago, IL 60208, USA.
Ramachandran S VasanNational 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.
Nicholas L SmithDepartment 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.
Kari E NorthDepartment of Epidemiology, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Eric BoerwinkleHuman 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.
Lewis C BeckerDivision of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Joshua P LewisDepartment of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Goncalo R AbecasisTOPMed Informatics Research Center, University of Michigan, Department of Biostatistics, Ann Arbor, MI 48109, USA.
Lifang HouNorthwestern University, Chicago, IL 60208, USA.
Jeffrey R O'ConnellDepartment of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Alanna C MorrisonHuman 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.
Terri H BeatySchool of Public Health, John Hopkins University, Baltimore, MD 21205, USA.
Robert KaplanDepartment of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Adolfo CorreaDepartment of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
John BlangeroDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78539, USA.
Eric JorgensonDivision of Research, Kaiser Permanente Northern California, Oakland, CA 94601, USA.
Bruce M PsatyDepartment 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.
Charles KooperbergPublic Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98105, USA.
Russell T WaltonCenter for Genomic Medicine and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
Benjamin P KleinstiverCenter for Genomic Medicine and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Hua TangDepartment of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Ruth J F LoosThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Nicole SoranzoBritish 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.
Adam S ButterworthBritish 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.
Debbie NickersonDepartment of Genome Sciences, University of Washington, Seattle, WA 98105, USA.
Stephen S RichCenter for Public Health Genomics, Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
Braxton D MitchellDepartment of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Andrew D JohnsonPopulation 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.
Paul L AuerZilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53205, USA.
Yun LiDepartments of Biostatistics, Genetics, Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Rasika A MathiasDivision of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MA 21205, USA.
Guillaume LettreMontreal Heart Institute, Montréal, QC H1T 1C8, Canada; Faculté de Médecine, Université de Montréal, Montréal, QC H1T 1C8, Canada.
Nathan PankratzDepartment of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Cathy C LaurieDepartment of Biostatistics, University of Washington, Seattle, WA 98105, USA.
Cecelia A LaurieDepartment of Biostatistics, University of Washington, Seattle, WA 98105, USA.
Daniel E BauerDivision 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.
Matthew P ConomosDepartment of Biostatistics, University of Washington, Seattle, WA 98105, USA.
Alexander P ReinerDepartment of Epidemiology, University of Washington, Seattle, WA 98105, USA. Electronic address: apreiner@uw.edu.
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
University of Washington · USBroad Institute · USJohns Hopkins University · USIcahn School of Medicine at Mount Sinai · USThe University of Texas Health Science Center at Houston · USUniversity of Cambridge · GBUniversity of Maryland, Baltimore · USUniversity of North Carolina at Chapel Hill · USThe University of Texas Rio Grande Valley · USUniversity of Michigan · USUniversity of Mississippi Medical Center · USAlbert Einstein College of Medicine · USBoston University · USFred Hutch Cancer Center · USKaiser Permanente · USKaiser Permanente Washington Health Research Institute · USMontreal Heart Institute · CANational Heart Lung and Blood Institute · USNorthwestern University · USUniversity of Minnesota Medical Center · US

Funding

Cardiovascular Genomics and Bioinformatics projectsZIAHL006170 · NHLBI · NATIONAL HEART, LUNG, AND BLOOD INSTITUTE · PI JOHNSON, ANDREW · 2013 to 2025
$25.3M
PROJECT 4: Somatic evolution of the hematopoietic system in cardiovascular diseaseP01HL142494 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI Charles P. Lin · 2019 to 2026
$19.5M
Next generation functional genomics of hematology traitsR01HL146500 · NHLBI · UNIVERSITY OF WASHINGTON · PI ALEXANDER P REINER · 2020 to 2026
$5.7M
Whole Genome Sequence Analysis of Ischemic Stroke in the Women's Health InitiativeR01HL136574 · NHLBI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI KOOPERBERG, CHARLES L, REINER, ALEXANDER P · 2017 to 2020
$3.1M
Sequence analysis of hemotological traits in African AmericansR01HL130733 · NHLBI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI LANGE, ETHAN MATHER, REINER, ALEXANDER P · 2016 to 2019
$2.7M
High-throughput discovery of essential noncoding sequences for erythropoiesisDP2HL137300 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI BAUER, DANIEL EVAN · 2016 to 2016
$2.7M
Multi-omic Subtyping of Chronic Obstructive Pulmonary DiseaseK08HL136928 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI HOBBS, BRIAN DANIEL · 2017 to 2021
$864k
6 · The paper itself

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, 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.

Indexed as

Genome-Wide Association StudyPhenotypeAdultAgedChromosomes, Human, Pair 16Datasets as TopicErythrocytesFemaleGene EditingGenetic VariationHEK293 CellsHumansMaleMiddle AgedNational Heart, Lung, and Blood Institute (U.S.)Quality Controlbase editingred blood cell traitswhole-genome sequencing

Identifiers

PMID33887194
PMCPMC8206199
OpenAlexW3155035513

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.