DMMC Course POPULATION GENETICS & SNP ANALYSIS

Durkan Lecture Theatre, Institute of Molecular Medicine, TCD, St James's Hospital

1500-1540 Wednesday 6June 2007.

Genome wide association study in coeliac disease.
D van Heel, L Franke, K Hunt, R Gwilliam, A Zhernakova, M Inouye, R McManus, R McGinnis, L Cardon, P Deloukas, C Wijmenga. (Queen Mary University of London, Wellcome Trust Centre for Human Genetics, Wellcome Trust Sanger Institute, UK. Trinity College Dublin, Ireland. University Medical Center Utrecht, The Netherlands).

Introduction: Coeliac disease is a common (1% prevalence) chronic inflammatory small bowel disease. An immune response against dietary wheat, rye and barley occurs. HLA-DQ2 (present in 95% of coeliacs) is necessary to present wheat epitopes to CD4+ T cells, but not sufficient for disease (present in 30% of the population). Pairwise concordance rates are 71% MZ twins, 9% DZ twins with the majority of heritability due to non-HLA factors.

Aims: To identify inherited (germline) genetic factors predisposing to coeliac disease.
Methods: 778 UK celiac disease cases and 1422 UK population controls (1958 Birth Cohort) were genotyped by Illumina HumanHap300/550 BeadChips. A novel clustering algorithm was applied. Case-control association tests were performed with 310,605 single nucleotide polymorphisms passing QC criteria (call rate 99.9%).

Results: Strong HLA association was seen, as expected. Outside the HLA, the most significant finding was in a linkage disequilibrium block containing several genes of known immunological function. Association with SNP1 and three other correlated SNPs was confirmed in two independent Dutch and Irish collections. These SNPs were all carried on a single associated haplotype.

Conclusions: We have identified and confirmed, using a genome wide association study and replication approach, a novel susceptibility locus for coeliac disease.