Mapping determinants of human gene expression by regional and genome-wide association

Nature. 2005 Oct 27;437(7063):1365-9. doi: 10.1038/nature04244.


To study the genetic basis of natural variation in gene expression, we previously carried out genome-wide linkage analysis and mapped the determinants of approximately 1,000 expression phenotypes. In the present study, we carried out association analysis with dense sets of single-nucleotide polymorphism (SNP) markers from the International HapMap Project. For 374 phenotypes, the association study was performed with markers only from regions with strong linkage evidence; these regions all mapped close to the expressed gene. For a subset of 27 phenotypes, analysis of genome-wide association was performed with >770,000 markers. The association analysis with markers under the linkage peaks confirmed the linkage results and narrowed the candidate regulatory regions for many phenotypes with strong linkage evidence. The genome-wide association analysis yielded highly significant results that point to the same locations as the genome scans for about 50% of the phenotypes. For one candidate determinant, we carried out functional analyses and confirmed the variation in cis-acting regulatory activity. Our findings suggest that association studies with dense SNP maps will identify susceptibility loci or other determinants for some complex traits or diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Chromatin Immunoprecipitation
  • Gene Expression Regulation / genetics*
  • Genetic Markers / genetics
  • Genetic Predisposition to Disease / genetics
  • Genome, Human*
  • Haplotypes
  • Humans
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics*
  • RNA Polymerase II / immunology
  • RNA Polymerase II / metabolism


  • Genetic Markers
  • RNA Polymerase II