Widespread Allelic Heterogeneity in Complex Traits

Farhad Hormozdiari, Anthony Zhu, Gleb Kichaev, Chelsea J.T. Ju, Ayellet V. Segrè, Jong Wha J. Joo, Hyejung Won, Sriram Sankararaman, Bogdan Pasaniuc, Sagiv Shifman*, Eleazar Eskin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Recent successes in genome-wide association studies (GWASs) make it possible to address important questions about the genetic architecture of complex traits, such as allele frequency and effect size. One lesser-known aspect of complex traits is the extent of allelic heterogeneity (AH) arising from multiple causal variants at a locus. We developed a computational method to infer the probability of AH and applied it to three GWASs and four expression quantitative trait loci (eQTL) datasets. We identified a total of 4,152 loci with strong evidence of AH. The proportion of all loci with identified AH is 4%–23% in eQTLs, 35% in GWASs of high-density lipoprotein (HDL), and 23% in GWASs of schizophrenia. For eQTLs, we observed a strong correlation between sample size and the proportion of loci with AH (R2 = 0.85, p = 2.2 × 10−16), indicating that statistical power prevents identification of AH in other loci. Understanding the extent of AH may guide the development of new methods for fine mapping and association mapping of complex traits.

Original languageAmerican English
Pages (from-to)789-802
Number of pages14
JournalAmerican Journal of Human Genetics
Volume100
Issue number5
DOIs
StatePublished - 4 May 2017

Bibliographical note

Publisher Copyright:
© 2017

Keywords

  • allelic heterogeneity
  • causal variants
  • complex traits
  • eQTL
  • gene expression

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