Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Genetic colocalization atlas points to common regulatory sites and genes for hematopoietic traits and hematopoietic contributions to disease phenotypes

View ORCID ProfileCS Thom, View ORCID ProfileBF Voight
doi: https://doi.org/10.1101/787333
CS Thom
1Division of Neonatology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
2Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
3Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
4Institute of Translational Medicine and Therapeutics, University of Pennsylvania, PA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for CS Thom
BF Voight
2Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
3Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
4Institute of Translational Medicine and Therapeutics, University of Pennsylvania, PA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for BF Voight
  • For correspondence: bvoight@pennmedicine.upenn.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Background Genetic associations link hematopoietic traits and disease end-points, but most causal variants and genes underlying these relationships are unknown. Here, we used genetic colocalization to nominate loci and genes related to shared genetic signal for hematopoietic, cardiovascular, autoimmune, neuropsychiatric and cancer phenotypes.

Results Our findings recapitulate developmental hematopoietic lineage relationships, identify loci associating traits with causal genetic relationships, and reveal novel associations. Out of 2706 loci with genome-wide significant signal for at least 1 blood trait, we identified 1779 unique sites (66%) with shared genetic signal for 2+ hematologic traits at a false discovery rate <5%. We could assign some sites to specific developmental cell types during hematopoiesis based on affected traits, including those likely to impact hematopoietic progenitor cells and/or megakaryocyte-erythroid progenitor cells. Through an expanded analysis of 70 human traits, we define 2+ colocalizing traits at 2007 loci from an analysis of 9852 sites (20%) containing genome-wide significant signal for at least 1 GWAS trait. In addition to variants and genes underlying shared genetic signal between blood traits and disease phenotypes that had been previously related through mendelian randomization studies, we define loci and related genes underlying shared signal between eosinophil count and eczema. We also identified colocalizing signals in a number of clinically relevant coding mutations, including in sites linking PTPN22 with Crohns disease, NIPA with coronary artery disease and platelet trait variation, and the hemochromatosis gene HFE with altered lipid levels. Finally, we anticipate potential off-target effects on blood traits related novel therapeutic targets, including TRAIL.

Conclusions Our findings provide a road map for gene validation experiments and novel therapeutics related to hematopoietic development, and offer a rationale for pleiotropic interactions between hematopoietic loci and disease end-points.

Copyright 
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.
Back to top
PreviousNext
Posted February 28, 2020.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Genetic colocalization atlas points to common regulatory sites and genes for hematopoietic traits and hematopoietic contributions to disease phenotypes
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Genetic colocalization atlas points to common regulatory sites and genes for hematopoietic traits and hematopoietic contributions to disease phenotypes
CS Thom, BF Voight
bioRxiv 787333; doi: https://doi.org/10.1101/787333
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Genetic colocalization atlas points to common regulatory sites and genes for hematopoietic traits and hematopoietic contributions to disease phenotypes
CS Thom, BF Voight
bioRxiv 787333; doi: https://doi.org/10.1101/787333

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Genetics
Subject Areas
All Articles
  • Animal Behavior and Cognition (4095)
  • Biochemistry (8786)
  • Bioengineering (6493)
  • Bioinformatics (23386)
  • Biophysics (11766)
  • Cancer Biology (9167)
  • Cell Biology (13290)
  • Clinical Trials (138)
  • Developmental Biology (7422)
  • Ecology (11386)
  • Epidemiology (2066)
  • Evolutionary Biology (15119)
  • Genetics (10413)
  • Genomics (14024)
  • Immunology (9145)
  • Microbiology (22108)
  • Molecular Biology (8793)
  • Neuroscience (47445)
  • Paleontology (350)
  • Pathology (1423)
  • Pharmacology and Toxicology (2483)
  • Physiology (3711)
  • Plant Biology (8063)
  • Scientific Communication and Education (1433)
  • Synthetic Biology (2215)
  • Systems Biology (6021)
  • Zoology (1251)