Genome-wide linkage analysis for celiac disease in North American families

Celiac disease (CD) is an autoimmune disease caused by sensitivity to the dietary protein gluten. It has a prevalence of 1 in 250 in the United States. Multiple-case families are common with a risk to siblings from 10-12%. Previous linkage studies have found no significant evidence for linkage other than to HLA. In this study, we performed a genome-wide search on 62 families with at least two cases of CD to identify non-HLA loci for CD. Two-point and multipoint parametric and nonparametric analyses were performed on the entire set of families and on sets stratified by the HLA genotype. Accounting for multiple testing, we found genome-wide intermediate linkage evidence at 18q (heterogeneity LOD (HLOD) = 3.6) and at 3p (HLOD = 3.2) and suggestive evidence at 5p (HLOD = 2.7). Good consensus between two-point and multipoint evidence was not found, and after genotyping with new markers in these regions, our results were inconclusive. The 18q region had intermediate two-point evidence, but weak multipoint evidence. At 3p and 5p, the addition of follow-up markers added flanking support, yet multipoint evidence was still lacking. Our results indicate that multipoint analyses may be hindered by the complexity of CD. Multipoint analyses are not robust to model misspecification, and further development of models is needed. Additional study of these and other families is necessary to validate or rule out the regions implicated in this study.