Open Access Highly Accessed Research article

Complex nature of SNP genotype effects on gene expression in primary human leucocytes

Graham A Heap1, Gosia Trynka23, Ritsert C Jansen24, Marcel Bruinenberg2, Morris A Swertz2, Lotte C Dinesen5, Karen A Hunt1, Cisca Wijmenga23, David A vanHeel1 and Lude Franke123*

Author Affiliations

1 Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, E1 2AT, UK

2 Genetics Department, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, the Netherlands

3 Complex Genetics Section, DBG-Department of Medical Genetics, University Medical Centre Utrecht, 3584 CG Utrecht, the Netherlands

4 Groningen Bioinformatics Centre, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Kerklaan 30, NL-9751 NN Haren, the Netherlands

5 Gastroenterology Unit, University of Oxford, Oxford OX3 7BN, UK

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BMC Medical Genomics 2009, 2:1  doi:10.1186/1755-8794-2-1

Published: 7 January 2009



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.


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.


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.


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.