Complex nature of SNP genotype effects on gene expression in primary human leucocytes.
- Authors
- Heap, Graham A; Trynka, Gosia; Jansen, Ritsert C; Bruinenberg, Marcel; Swertz, Morris A; Dinesen, Lotte C; Hunt, Karen A; Wijmenga, Cisca; Vanheel, David A; Franke, Lude
- Year
- 2009
- Journal
- BMC medical genomics
- PMID
- 19128478
- DOI
- 10.1186/1755-8794-2-1
- PMCID
- PMC2628677
BACKGROUND: Genome wide association studies have been hugely successful in identifying disease risk variants, yet most variants do not lead to coding changes and how variants influence biological function is usually unknown. METHODS: We correlated gene expression and genetic variation in untouched primary leucocytes (n = 110) from individuals with celiac disease - a common condition with multiple risk variants identified. We compared our observations with an EBV-transformed HapMap B cell line dataset (n = 90), and performed a meta-analysis to increase power to detect non-tissue specific effects. RESULTS: In celiac peripheral blood, 2,315 SNP variants influenced gene expression at 765 different transcripts (< 250 kb from SNP, at FDR = 0.05, cis expression quantitative trait loci, eQTLs). 135 of the detected SNP-probe effects (reflecting 51 unique probes) were also detected in a HapMap B cell line published dataset, all with effects in the same allelic direction. Overall gene expression differences within the two datasets predominantly explain the limited overlap in observed cis-eQTLs. Celiac associated risk variants from two regions, containing genes IL18RAP and CCR3, showed significant cis genotype-expression correlations in the peripheral blood but not in the B cell line datasets. We identified 14 genes where a SNP affected the expression of different probes within the same gene, but in opposite allelic directions. By incorporating genetic variation in co-expression analyses, functional relationships between genes can be more significantly detected. CONCLUSION: In conclusion, the complex nature of genotypic effects in human populations makes the use of a relevant tissue, large datasets, and analysis of different exons essential to enable the identification of the function for many genetic risk variants in common diseases.
Cumulative genomic distance distribution between SNP and probe midpoint for significant cis-eQTLs (FDR = 0.01, SNP-probe midpoint distance < 500 kb) in celiac peripheral blood samples.
Summary of meta-analysis of 4,681 identical probes between the celiac peripheral blood and HapMap B cell line data sets (at an FDR = 0.05, SNP-probe midpoint distance < 250 kb).
Differential Gene Expression between tissue types results in differential cis-eQTL detection Differential gene expression between the celiac dataset and the HapMap dataset is represented as a histogram of log fold change. a) Density plot of log fold change for cis-eQTLs detected in celiac dataset but not in HapMap samples (FDR = 0.01, SNP-probe midpoint distance < 250 kb). b) Density plot of log fold change for cis-eQTLs detected in HapMap dataset but not in the celiac dataset, c) Density plot of log fold change for cis-eQTLs detected in both data sets. P values derived from a Wilcoxon Signed-Ranks Test.
Cis-effects obscure detection of co-expression with other genes a) Co-expression for significant cis-eQTLs was determined; resulting in the identification of co-expression pairs with generally low absolute correlation coefficients b) Through removal of the genotypic effect on the cis-eQTL probe, for some cis-eQTLs strong co-expression can be more easily detected. c) An example for UBA52 indicates that a conditioned co-expression analysis can help to identify meaningful biological relationships: Within the conditioned co-expression distribution (indicated in dark blue) there are more strongly co-expressed genes, opposed to an unconditioned analysis (indicated in red). This is supported by an analysis of 156 known interacting genes for UBA52: In the conditioned co-expression analysis (indicated in light blue) co-expression is generally much stronger than in the unconditioned analysis (indicated in yellow).
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