Mapping determinants of human gene expression by regional and genome-wide association.
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.
Cheung
Vivian G
VG
Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. vcheung@mail.med.upenn.edu
Spielman
Richard S
RS
Ewens
Kathryn G
KG
Weber
Teresa M
TM
Morley
Michael
M
Burdick
Joshua T
JT
D000483:Alleles; D047369:Chromatin Immunoprecipitation; D005786:Gene Expression Regulation / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D015894:Genome, Human; D006239:Haplotypes; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012319:RNA Polymerase II / Q000276:immunology / Q000378:metabolism
D005819:Genetic Markers; D012319:RNA Polymerase II