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. 1999 Nov;45(5):668–671. doi: 10.1136/gut.45.5.668

Relative power of linkage and transmission disequilibrium test strategies to detect non-HLA linked coeliac disease susceptibility genes

S Bevan 1, S Popat 1, R Houlston 1
PMCID: PMC1727705  PMID: 10517901

Abstract

BACKGROUND—Susceptibility to coeliac disease is genetically determined by possession of specific HLA DQ alleles, acting in concert with one or more non-HLA linked genes. The pattern of familial risk is most parsimonious with a multiplicative model for the interaction between these two classes of genes. Haplotype sharing probabilities across the HLA region in affected sibling pairs suggest that genes within the MHC complex contribute no more than 40% of the sibling familial risk of coeliac disease, making the non-HLA linked gene (or genes) the stronger determinant of coeliac disease susceptibility. Attempts to localise these non-HLA linked genes have been carried out using both linkage and association tests.
AIMS—To review the evidence for the involvement of non-HLA linked genes in coeliac disease, and to compare the relative merits of linkage and transmission disequilibrium tests (TDT) to detect the non-HLA linked gene (or genes) contributing to the development of coeliac disease.
METHODS—Under a range of genetic models the number of affected sibling pairs needed to detect linkage was compared with the number of families required to show a relation between marker and disease, adopting the TDT strategy.
RESULTS AND CONCLUSIONS—Power calculations show that, if there is a single major non-HLA linked susceptibility locus, a non-parametric linkage approach may well prove effective. However, if there are a number of non-HLA susceptibility genes, each with small effect, the sample size necessary for linkage studies will be prohibitive and a systematic search for allelic association should be a more effective strategy.


Keywords: coeliac disease; non-HLA linked genes; linkage; TDT test

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Figure 1  .

Figure 1  

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Effect of sibling relative risk and recombination on the probability of affected sibling pairs sharing two alleles identical by descent (IBD). Values based on the assumption that the sibling and parent-offspring relative risks are equal.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Camp N. J. Genomewide transmission/disequilibrium testing--consideration of the genotypic relative risks at disease loci. Am J Hum Genet. 1997 Dec;61(6):1424–1430. doi: 10.1086/301648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Catassi C., Fabiani E., Rätsch I. M., Coppa G. V., Giorgi P. L., Pierdomenico R., Alessandrini S., Iwanejko G., Domenici R., Mei E. The coeliac iceberg in Italy. A multicentre antigliadin antibodies screening for coeliac disease in school-age subjects. Acta Paediatr Suppl. 1996 May;412:29–35. doi: 10.1111/j.1651-2227.1996.tb14244.x. [DOI] [PubMed] [Google Scholar]
  3. Catassi C., Rätsch I. M., Fabiani E., Ricci S., Bordicchia F., Pierdomenico R., Giorgi P. L. High prevalence of undiagnosed coeliac disease in 5280 Italian students screened by antigliadin antibodies. Acta Paediatr. 1995 Jun;84(6):672–676. doi: 10.1111/j.1651-2227.1995.tb13725.x. [DOI] [PubMed] [Google Scholar]
  4. Greco L., Corazza G., Babron M. C., Clot F., Fulchignoni-Lataud M. C., Percopo S., Zavattari P., Bouguerra F., Dib C., Tosi R. Genome search in celiac disease. Am J Hum Genet. 1998 Mar;62(3):669–675. doi: 10.1086/301754. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Greco L., Tozzi A. E., Mayer M., Grimaldi M., Silano G., Auricchio S. Unchanging clinical picture of coeliac disease presentation in Campania, Italy. Eur J Pediatr. 1989 Jun;148(7):610–613. doi: 10.1007/BF00441511. [DOI] [PubMed] [Google Scholar]
  6. Greenberg D. A., Hodge S. E., Rotter J. I. Evidence for recessive and against dominant inheritance at the HLA-"linked" locus in coeliac disease. Am J Hum Genet. 1982 Mar;34(2):263–277. [PMC free article] [PubMed] [Google Scholar]
  7. Grodzinsky E. Screening for coeliac disease in apparently healthy blood donors. Acta Paediatr Suppl. 1996 May;412:36–38. doi: 10.1111/j.1651-2227.1996.tb14245.x. [DOI] [PubMed] [Google Scholar]
  8. Hernández J. L., Michalski J. P., McCombs C. C., McCarthy C. F., Stevens F. M., Elston R. C. Evidence for a dominant gene mechanism underlying coeliac disease in the west of Ireland. Genet Epidemiol. 1991;8(1):13–27. doi: 10.1002/gepi.1370080103. [DOI] [PubMed] [Google Scholar]
  9. Houlston R. S., Ford D. Genetics of coeliac disease. QJM. 1996 Oct;89(10):737–743. doi: 10.1093/qjmed/89.10.737. [DOI] [PubMed] [Google Scholar]
  10. Houlston R. S., Tomlinson I. P., Ford D., Seal S., Marossy A. M., Ferguson A., Holmes G. K., Hosie K. B., Howdle P. D., Jewell D. P. Linkage analysis of candidate regions for coeliac disease genes. Hum Mol Genet. 1997 Aug;6(8):1335–1339. doi: 10.1093/hmg/6.8.1335. [DOI] [PubMed] [Google Scholar]
  11. Lander E., Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995 Nov;11(3):241–247. doi: 10.1038/ng1195-241. [DOI] [PubMed] [Google Scholar]
  12. Logan R. F., Rifkind E. A., Busuttil A., Gilmour H. M., Ferguson A. Prevalence and "incidence" of celiac disease in Edinburgh and the Lothian region of Scotland. Gastroenterology. 1986 Feb;90(2):334–342. doi: 10.1016/0016-5085(86)90929-7. [DOI] [PubMed] [Google Scholar]
  13. Logan R. F., Tucker G., Rifkind E. A., Heading R. C., Ferguson A. Changes in clinical features of coeliac disease in adults in Edinburgh and the Lothians 1960-79. Br Med J (Clin Res Ed) 1983 Jan 8;286(6359):95–97. doi: 10.1136/bmj.286.6359.95. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Marsh M. N. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity ('celiac sprue'). Gastroenterology. 1992 Jan;102(1):330–354. [PubMed] [Google Scholar]
  15. Midhagen G., Järnerot G., Kraaz W. Adult coeliac disease within a defined geographic area in Sweden. A study of prevalence and associated diseases. Scand J Gastroenterol. 1988 Oct;23(8):1000–1004. doi: 10.3109/00365528809090160. [DOI] [PubMed] [Google Scholar]
  16. Mylotte M., Egan-Mitchell B., McCarthy C. F., McNicholl B. Incidence of coeliac disease in the West of Ireland. Br Med J. 1973 Mar 24;1(5855):703–705. doi: 10.1136/bmj.1.5855.703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Müller-Myhsok B., Abel L. Genetic analysis of complex diseases. Science. 1997 Feb 28;275(5304):1328–1330. [PubMed] [Google Scholar]
  18. Not T., Horvath K., Hill I. D., Partanen J., Hammed A., Magazzu G., Fasano A. Celiac disease risk in the USA: high prevalence of antiendomysium antibodies in healthy blood donors. Scand J Gastroenterol. 1998 May;33(5):494–498. doi: 10.1080/00365529850172052. [DOI] [PubMed] [Google Scholar]
  19. Petronzelli F., Bonamico M., Ferrante P., Grillo R., Mora B., Mariani P., Apollonio I., Gemme G., Mazzilli M. C. Genetic contribution of the HLA region to the familial clustering of coeliac disease. Ann Hum Genet. 1997 Jul;61(Pt 4):307–317. doi: 10.1046/j.1469-1809.1997.6140307.x. [DOI] [PubMed] [Google Scholar]
  20. Peña A. S., Mann D. L., Hague N. E., Heck J. A., van Leeuwen H. A., van Rood J. J., Strober W. Genetic basis of gluten-sentitive enteropathy. Gastroenterology. 1978 Aug;75(2):230–235. [PubMed] [Google Scholar]
  21. Risch N. Linkage strategies for genetically complex traits. II. The power of affected relative pairs. Am J Hum Genet. 1990 Feb;46(2):229–241. [PMC free article] [PubMed] [Google Scholar]
  22. Risch N., Merikangas K. The future of genetic studies of complex human diseases. Science. 1996 Sep 13;273(5281):1516–1517. doi: 10.1126/science.273.5281.1516. [DOI] [PubMed] [Google Scholar]
  23. Sollid L. M., Thorsby E. HLA susceptibility genes in celiac disease: genetic mapping and role in pathogenesis. Gastroenterology. 1993 Sep;105(3):910–922. doi: 10.1016/0016-5085(93)90912-v. [DOI] [PubMed] [Google Scholar]
  24. Spielman R. S., Ewens W. J. The TDT and other family-based tests for linkage disequilibrium and association. Am J Hum Genet. 1996 Nov;59(5):983–989. [PMC free article] [PubMed] [Google Scholar]
  25. Zhong F., McCombs C. C., Olson J. M., Elston R. C., Stevens F. M., McCarthy C. F., Michalski J. P. An autosomal screen for genes that predispose to celiac disease in the western counties of Ireland. Nat Genet. 1996 Nov;14(3):329–333. doi: 10.1038/ng1196-329. [DOI] [PubMed] [Google Scholar]

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