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

Abstract

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.

Genome-wide linkage analysis of 160 North American families with celiac disease

“…29 Of the 160 families included in this analysis, 44 had been studied in a previous parametric linkage analysis of 62 families. 15 In the previous analysis, there were 128 CD cases in the 62 families, whereas in this study, there were 562 CD cases in 160 families. The families that we enrolled since the previous study are larger and with more affected individuals.…”

“…[14][15][16][17][18][19][20][21][22][23][24] Based on previous heritability studies, segregation Because of the close association of CD and the HLA DQ genotypes, it is difficult to identify if there are other genes in the region accounting for susceptibility to CD risk. There have been several studies attempting to investigate other genes.…”

“…There have been multiple genomewide studies to identify loci for CD. [14][15][16][17][18][19][20][21][22][23][24] All studies have identified significant linkage evidence to the HLA region, but there have been few significant linkages outside the HLA region and little to no confirmation of suggestive linkages. For complex diseases, difficulty in finding significant evidence for linkage and non-replication of linkage results are common, and may be due to the low power of studies to detect genes of relatively small effect and/or to a high degree of genetic heterogeneity among families.…”

Genetic association of coeliac disease susceptibility to polymorphisms in the ICOS gene on chromosome 2q33

“…The HLA locus has been estimated to account for B30% of the whole familial risk of CD leaving a definitive role for other genetic, as well as environmental factors in disease susceptibility. [17][18][19][20] Eight whole genome screenings [21][22][23][24][25][26][27][28] for the additional risk loci have been reported so far with inconsistent results between populations. In addition to systematic screening, many candidate gene approaches have been carried out.…”

Celiac Disease and HLA in a Bedouin Kindred

“…Box 6511, Aurora, Colorado 80045, The fact that HLA-specific relative risk to siblings is 2.3-5.5 [1] compared to the overall relative risk to siblings of 30-60 suggests that non-HLA genes play a large role in the etiology of CD. Several linkage studies, either of candidate genes or whole genome screens, to find non-HLA genes have been performed (e.g., [2,[8][9][10][11][12][13][14][15][16][17][18]), but few regions have been replicated, and replication has occurred only in studies of European or European-derived populations. The exceptions are the HLA region, which consistently shows extremely strong evidence of linkage to CD, and three regions, 2q33, 11p11 and 5q31-33.…”