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.

Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control

“…Using clinical phenotype data available in Asthma BRIDGE and in CAMP, we developed two composite scores summarizing self-reported asthma control in the preceding 6 months (chronic, [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and 7 days (acute, 0-28), respectively, each modeled on the ACT questionnaire (11), where higher scores indicate worse asthma control. Based on the medians of the corresponding phenotypic distributions, optimal chronic asthma control was defined as a score less than or equal to six in BRIDGE WB and moderately suboptimal asthma control was defined as a score less than or equal to 11 in BRIDGE CD4 ( Figure 2).…”

“…Subjects were typed on either the HumanHT-12 v4 Expression or HumanRef8 v2 BeadChip platforms (Illumina, Inc., San Diego, CA) (9,18). Log 2 -transformed and quantile-normalized data that passed stringent and commonly used quality control metrics were available for 10,456 gene expression probes found across BRIDGE WB, BRIDGE CD4, and CAMP WB and for a further subset of 6,555 probes in CAMP CD4.…”

Genome-Wide Association Identifies Regulatory Loci Associated with Distinct Local Histogram Emphysema Patterns

“…Most GWAS loci for complex diseases influence gene regulation (35)(36)(37)(38). To determine the overlap of the seven genomewide significant LHE loci found in this study with epigenetic marks and DNase I hypersensitive regions in cell lines from the ENCODE and the Epigenomics Roadmap Projects, we queried the Haploreg database for the seven lead GWAS SNPs, including SNPs in LD at an r 2 threshold of 0.8 (32).…”

“…Previous studies have implicated genetic control of gene expression as a key functional mechanism for most GWAS associations, and publicly available data from the ENCODE and Roadmap Epigenomics projects provide an unprecedented opportunity to link genetic variation with experimental regulatory data from a wide array of cell lines (32,35,37,48,49). Integration of LHE GWAS results with ENCODE and Roadmap regulatory data confirms strong enrichment of enhancer regions among our top LHE GWAS loci and points to a role for multiple cell types in the pathogenesis of emphysema, particularly lung fibroblasts.…”

DNA methylation in lung cells is associated with asthma endotypes and genetic risk

“…5). Asthma-associated SNPs at this locus span an approximately 200-kb block of linkage disequilibrium (LD) and are eQTLs for two coregulated genes, ORMDL3 and GSDMB, in blood cells (19,23,24) and whole lung tissue (19,25). As a result of the extensive LD in this region and the coregulatory effects of associated SNPs on the expression of these two genes, it has been difficult to localize the causal SNP(s) and disentangle the relative roles of ORMDL3 and GSDMB in asthma risk.…”