title: Mapping of numerous disease-associated expression polymorphisms in primary peripheral blood CD4+ lymphocytes.
abstract: Genome-wide association studies of human gene expression promise to identify functional regulatory genetic variation that contributes to phenotypic diversity. However, it is unclear how useful this approach will be for the identification of disease-susceptibility variants. We generated gene expression profiles for 22 184 mRNA transcripts using RNA derived from peripheral blood CD4+ lymphocytes, and genome-wide genotype data for 516 512 autosomal markers in 200 subjects. We screened for cis-acting variants by testing variants mapping within 50 kb of expressed transcripts for association with transcript abundance using generalized linear models. Significant associations were identified for 1585 genes at a false discovery rate of 0.05 (corresponding to P-values ranging from 1 × 10(-91) to 7 × 10(-4)). Importantly, we identified evidence of regulatory variation for 119 previously mapped disease genes, including 24 examples where the variant with the strongest evidence of disease-association demonstrates strong association with specific transcript abundance. The prevalence of cis-acting variants among disease-associated genes was 63% higher than the genome-wide rate in our data set (P = 6.41 × 10(-6)), and although many of the implicated loci were associated with immune-related diseases (including asthma, connective tissue disorders and inflammatory bowel disease), associations with genes implicated in non-immune-related diseases including lipid profiles, anthropomorphic measurements, cancer and neurologic disease were also observed. Genetic variants that confer inter-individual differences in gene expression represent an important subset of variants that contribute to disease susceptibility. Population-based integrative genetic approaches can help identify such variation and enhance our understanding of the genetic basis of complex traits.
authors.affiliation: Channing Laboratory, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Murphy
authors.forename: Jen-Hwa
authors.initials: JH
authors.lastname: Chu
authors.forename: Mousheng
authors.initials: M
authors.lastname: Xu
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Carey
authors.forename: Ross
authors.initials: R
authors.lastname: Lazarus
authors.forename: Andy
authors.initials: A
authors.lastname: Liu
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Szefler
authors.forename: Robert
authors.initials: R
authors.lastname: Strunk
authors.forename: Karen
authors.initials: K
authors.lastname: Demuth
authors.forename: Mario
authors.initials: M
authors.lastname: Castro
authors.forename: Nadia N
authors.initials: NN
authors.lastname: Hansel
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Diette
authors.forename: Becky M
authors.initials: BM
authors.lastname: Vonakis
authors.forename: N Franklin
authors.initials: NF
authors.lastname: Adkinson
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Klanderman
authors.forename: Jody
authors.initials: J
authors.lastname: Senter-Sylvia
authors.forename: John
authors.initials: J
authors.lastname: Ziniti
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
mesh_terms: D001249:Asthma / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes; D015870:Gene Expression; D020869:Gene Expression Profiling; D005816:Genetic Complementation Test; D030342:Genetic Diseases, Inborn; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D005819:Genetic Markers; D012333:RNA, Messenger