Allelic heterogeneity and more detailed analyses of known loci explain additional phenotypic variation and reveal complex patterns of association

Andrew R. Wood, Dena G. Hernandez, Michael A. Nalls, Hanieh Yaghootkar, J. Raphael Gibbs, Lorna W. Harries, Sean Chong, Matthew Moore, Michael N. Weedon, Jack M. Guralnik, Stefania Bandinelli, Anna Murray, Luigi Ferrucci, Andrew B. Singleton, David Melzer, Timothy M. Frayling

Research output: Contribution to journalArticlepeer-review

Abstract

The identification ofmultiple signals at individual loci could explain additional phenotypic variance ('missing heritability') of common traits, and help identify causal genes. We examined gene expression levels as a model trait becauseof the largenumberof stronggenetic effects actingincis.Usingexpressionprofiles from613 individuals, we performed genome-wide single nucleotide polymorphism(SNP) analyses to identify cis-expression quantitative trait loci (eQTLs), and conditional analysis to identify second signals. We examined patterns of association when accounting for multiple SNPs at a locus and when including additional SNPs from the 1000 Genomes Project. We identified 1298 cis-eQTLs at an approximate false discovery rate 0.01, of which 118 (9%) showed evidence of a second independent signal. For this subset of 118 traits, accounting for two signals resulted in an average 31%increase in phenotypic variance explained (Wilcoxon P <0.0001). The association of SNPs with cis gene expression could increase, stay similar or decrease in significance when accounting for linkage disequilibrium with second signals at the same locus. Pairs of SNPs increasing in significance tended to have gene expression increasing alleles on opposite haplotypes, whereas pairs ofSNPs decreasing in significance tended to have gene expression increasing alleles on the same haplotypes. Adding data fromthe 1000 Genomes Project showed that apparently independent signals could be potentially explained by a single association signal. Our results show that accounting for multiple variants at a locus will increase the variance explained in a substantial fraction of loci, but that allelic heterogeneity will be difficult to define without resequencing loci and functional work.

Original languageEnglish (US)
Article numberddr328
Pages (from-to)4082-4092
Number of pages11
JournalHuman Molecular Genetics
Volume20
Issue number20
DOIs
StatePublished - Oct 2011
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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