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

Polygenicity of complex traits is explained by negative selection

Luke J. O’Connor, Armin P. Schoech, Farhad Hormozdiari, Steven Gazal, Nick Patterson, Alkes L. Price
doi: https://doi.org/10.1101/420497
Luke J. O’Connor
1Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
2Program in Bioinformatics and Integrative Genomics, Harvard Graduate School of Arts and Sciences, Cambridge, MA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: loconnor@g.harvard.edu aprice@hsph.harvard.edu
Armin P. Schoech
1Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Farhad Hormozdiari
1Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Steven Gazal
1Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nick Patterson
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alkes L. Price
1Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: loconnor@g.harvard.edu aprice@hsph.harvard.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Complex traits and common disease are highly polygenic: thousands of common variants are causal, and their effect sizes are almost always small. Polygenicity could be explained by negative selection, which constrains common-variant effect sizes and may reshape their distribution across the genome. We refer to this phenomenon as flattening, as genetic signal is flattened relative to the underlying biology. We introduce a mathematical definition of polygenicity, the effective number of associated SNPs, and a robust statistical method to estimate it. This definition of polygenicity differs from the number of causal SNPs, a standard definition; it depends strongly on SNPs with large effects. In analyses of 33 complex traits (average N=361k), we determined that common variants are ∼4x more polygenic than low-frequency variants, consistent with pervasive flattening. Moreover, functionally important regions of the genome have increased polygenicity in proportion to their increased heritability, implying that heritability enrichment reflects differences in the number of associations rather than their magnitude (which is constrained by selection). We conclude that negative selection constrains the genetic signal of biologically important regions and genes, reshaping genetic architecture.

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 4.0 International license.
Back to top
PreviousNext
Posted September 18, 2018.
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.
Polygenicity of complex traits is explained by negative selection
(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
Polygenicity of complex traits is explained by negative selection
Luke J. O’Connor, Armin P. Schoech, Farhad Hormozdiari, Steven Gazal, Nick Patterson, Alkes L. Price
bioRxiv 420497; doi: https://doi.org/10.1101/420497
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Polygenicity of complex traits is explained by negative selection
Luke J. O’Connor, Armin P. Schoech, Farhad Hormozdiari, Steven Gazal, Nick Patterson, Alkes L. Price
bioRxiv 420497; doi: https://doi.org/10.1101/420497

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 (3602)
  • Biochemistry (7568)
  • Bioengineering (5523)
  • Bioinformatics (20789)
  • Biophysics (10328)
  • Cancer Biology (7980)
  • Cell Biology (11638)
  • Clinical Trials (138)
  • Developmental Biology (6603)
  • Ecology (10202)
  • Epidemiology (2065)
  • Evolutionary Biology (13617)
  • Genetics (9541)
  • Genomics (12846)
  • Immunology (7920)
  • Microbiology (19541)
  • Molecular Biology (7657)
  • Neuroscience (42095)
  • Paleontology (308)
  • Pathology (1258)
  • Pharmacology and Toxicology (2202)
  • Physiology (3267)
  • Plant Biology (7041)
  • Scientific Communication and Education (1294)
  • Synthetic Biology (1951)
  • Systems Biology (5426)
  • Zoology (1117)