Mapping of numerous disease-associated expression polymorphisms in primary peripheral blood CD4+ lymphocytes.
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.
Murphy
Amy
A
Channing Laboratory, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA.
Chu
Jen-Hwa
JH
Xu
Mousheng
M
Carey
Vincent J
VJ
Lazarus
Ross
R
Liu
Andy
A
Szefler
Stanley J
SJ
Strunk
Robert
R
Demuth
Karen
K
Castro
Mario
M
Hansel
Nadia N
NN
Diette
Gregory B
GB
Vonakis
Becky M
BM
Adkinson
N Franklin
NF
Klanderman
Barbara J
BJ
Senter-Sylvia
Jody
J
Ziniti
John
J
Lange
Christoph
C
Pastinen
Tomi
T
Raby
Benjamin A
BA
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
D005819:Genetic Markers; D012333:RNA, Messenger