Abstract
Celiac disease (CD) is a gluten-induced enteropathy, which results from the interplay between environmental and genetic factors. There is a strong human leukocyte antigen (HLA) association with the disease, and HLA-DQ alleles represent a major genetic risk factor. In addition to HLA-DQ, non-HLA genes appear to be crucial for CD development. Chromosomal region 5q31–33 has demonstrated linkage with CD in several genome-wide studies, including in our Swedish/Norwegian cohort. In a European meta-analysis 5q31–33 was the only region that reached a genome-wide level of significance except for the HLA region. To identify the genetic variant(s) responsible for this linkage signal, we performed a comprehensive single nucleotide polymorphism (SNP) association screen in 97 Swedish/Norwegian multiplex families who demonstrate linkage to the region. We selected tag SNPs from a 16 Mb region representing the 95% confidence interval of the linkage peak. A total of 1404 SNPs were used for the association analysis. We identified several regions with SNPs demonstrating moderate single- or multipoint associations. However, the isolated association signals appeared insufficient to account for the linkage signal seen in our cohort. Collective effects of multiple risk genes within the region, incomplete genetic coverage or effects related to copy number variation are possible explanations for our findings.
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References
Sollid LM : Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol 2002; 2: 647–655.
Greco L, Romino R, Coto I et al: The first large population based twin study of coeliac disease. Gut 2002; 50: 624–628.
Greco L, Corazza G, Babron MC et al: Genome search in celiac disease. Am J Hum Genet 1998; 62: 669–675.
Greco L, Babron MC, Corazza GR et al: Existence of a genetic risk factor on chromosome 5q in Italian coeliac disease families. Ann Hum Genet 2001; 65: 35–41.
Liu J, Juo SH, Holopainen P et al: Genomewide linkage analysis of celiac disease in Finnish families. Am J Hum Genet 2002; 70: 51–59.
Naluai AT, Nilsson S, Gudjonsdottir AH et al: Genome-wide linkage analysis of Scandinavian affected sib-pairs supports presence of susceptibility loci for celiac disease on chromosomes 5 and 11. Eur J Hum Genet 2001; 9: 938–944.
Zhong F, McCombs CC, Olson JM et al: An autosomal screen for genes that predispose to celiac disease in the Western counties of Ireland. Nat Genet 1996; 14: 329–333.
Babron MC, Nilsson S, Adamovic S et al: Meta and pooled analysis of European coeliac disease data. Eur J Hum Genet 2003; 11: 828–834.
Lander E, Kruglyak L : Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11: 241–247.
Gudjonsdottir AH, Nilsson S, Ek J, Kristiansson B, Ascher H : The risk of celiac disease in 107 families with at least two affected siblings. J Pediatr Gastroenterol Nutr 2004; 38: 338–342.
Gudbjartsson DF, Thorvaldsson T, Kong A, Gunnarsson G, Ingolfsdottir A : Allegro version 2. Nat Genet 2005; 37: 1015–1016.
Walker-Smith J, Guandalini S, Schmitz J, Schmerling D, Visakorpi J : Report of working group of European Society of Paediatric Gastroenterology and Nutrition: revised criteria for diagnosis of coeliac disease. Arch Dis Child 1990; 65: 909–911.
Barrett JC, Fry B, Maller J, Daly MJ : Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.
Carlson CS, Eberle MA, Rieder MJ, Yi Q, Kruglyak L, Nickerson DA : Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 2004; 74: 106–120.
O'Connell JR, Weeks DE : PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998; 63: 259–266.
Markianos K, Daly MJ, Kruglyak L : Efficient multipoint linkage analysis through reduction of inheritance space. Am J Hum Genet 2001; 68: 963–977.
Horvath S, Xu X, Laird NM : The family based association test method: strategies for studying general genotype–phenotype associations. Eur J Hum Genet 2001; 9: 301–306.
Li J, Zhou Y, Elston RC : Haplotype-based quantitative trait mapping using a clustering algorithm. BMC Bioinformatics 2006; 7: 258.
Li J, Jiang T : Haplotype-based linkage disequilibrium mapping via direct data mining. Bioinformatics 2005; 21: 4384–4393.
Montpetit A, Nelis M, Laflamme P et al: An evaluation of the performance of tag SNPs derived from HapMap in a Caucasian population. PLoS Genet 2006; 2: e27.
Zeggini E, Rayner W, Morris AP et al: An evaluation of HapMap sample size and tagging SNP performance in large-scale empirical and simulated data sets. Nat Genet 2005; 37: 1320–1322.
Ke X, Durrant C, Morris AP et al: Efficiency and consistency of haplotype tagging of dense SNP maps in multiple samples. Hum Mol Genet 2004; 13: 2557–2565.
International HapMap Consortium: A haplotype map of the human genome. Nature 2005; 437: 1299–1320.
Redon R, Ishikawa S, Fitch KR et al: Global variation in copy number in the human genome. Nature 2006; 444: 444–454.
Kehrer-Sawatzki H : What a difference copy number variation makes. Bioessays 2007; 29: 311–313.
Fredman D, White SJ, Potter S, Eichler EE, Den Dunnen JT, Brookes AJ : Complex SNP-related sequence variation in segmental genome duplications. Nat Genet 2004; 36: 861–866.
Shephard N, John S, Cardon L, McCarthy MI, Zeggini E : Will the real disease gene please stand up? BMC Genet 2005; 6 (Suppl 1): S66.
Acknowledgements
This work was supported by grants from the Research Council of Norway, the Swedish Medical Research Council and the Swedish Research Council. We thank all the families participating in the study as well as Britt-Marie Käck and The Celiac Society in Sweden for help with collecting families and blood samples. We also thank Ann-Christine Syvänen and the Wallenberg Consortium North (WCN) SNP Technology Platform at Uppsala University, Sweden and the Swegene Genomics and Bioinformatics Core Facilities in Göteborg, Sweden.
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Amundsen, S., Adamovic, S., Hellqvist, Å. et al. A comprehensive screen for SNP associations on chromosome region 5q31–33 in Swedish/Norwegian celiac disease families. Eur J Hum Genet 15, 980–987 (2007). https://doi.org/10.1038/sj.ejhg.5201870
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DOI: https://doi.org/10.1038/sj.ejhg.5201870
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