Abstract
It has been shown that genetic factors within the HLA region are involved in the etiology of several diseases. For some of these, the existence of another genetic factor has been suggested, although not proven. A possible way to give evidence for another locus (G) is to show that the disease and an unlinked HLA-marker locus (M) do not segregate independently. The usual lod-score method, which assumes monogenic inheritance, is inappropriate for this test. We propose a correction of this method for performing a linkage analysis between the G and M loci, taking into account the role of HLA. A very simple way of using the HLA information is by modifying, for each individual of a pedigree, the penetrance values at the G locus according to the number of HLA haplotypes shared with the index case. These penetrance values are inferred from the observed IBD (identity-by-descent) distribution of HLA haplotypes in a sample of affected sib-pairs. The advantage of using this empirical distribution is that it is not based on any assumptions concerning the mode of inheritance at the HLA-linked locus. This correction method was established using a two-locus model with restrictive assumptions. Its value is discussed for various sets of parameters in more general and realistic two-locus models using simulations.
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Selected References
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- Clerget-Darpoux F., Bonaïti-Pellié C., Deschamps I., Hors J., Feingold N. Juvenile insulin-dependent diabetes: a possible susceptibility gene in interaction with HLA. Ann Hum Genet. 1981 May;45(Pt 2):199–206. doi: 10.1111/j.1469-1809.1981.tb00321.x. [DOI] [PubMed] [Google Scholar]
- Greenberg D. A., Rotter J. I. Two locus models for gluten sensitive enteropathy: population genetic considerations. Am J Med Genet. 1981;8(2):205–214. doi: 10.1002/ajmg.1320080211. [DOI] [PubMed] [Google Scholar]
- Hodge S. E., Anderson C. E., Neiswanger K., Field L. L., Spence M. A., Sparkes R. S., Sparkes M. C., Crist M., Terasaki P. I., Rimoin D. L. Close genetic linkage between diabetes mellitus and kidd blood group. Lancet. 1981 Oct 24;2(8252):893–895. doi: 10.1016/s0140-6736(81)91391-x. [DOI] [PubMed] [Google Scholar]
- MORTON N. E. Sequential tests for the detection of linkage. Am J Hum Genet. 1955 Sep;7(3):277–318. [PMC free article] [PubMed] [Google Scholar]
- Ott J. Estimation of the recombination fraction in human pedigrees: efficient computation of the likelihood for human linkage studies. Am J Hum Genet. 1974 Sep;26(5):588–597. [PMC free article] [PubMed] [Google Scholar]
- 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]
- Suarez B., Hodge S. E., Reich T. Is juvenile diabetes determined by a single gene closely linked to HLA? Diabetes. 1979 Jun;28(6):527–532. doi: 10.2337/diab.28.6.527. [DOI] [PubMed] [Google Scholar]
- Thomson G. A two locus model for juvenile diabetes. Ann Hum Genet. 1980 May;43(4):383–398. doi: 10.1111/j.1469-1809.1980.tb01572.x. [DOI] [PubMed] [Google Scholar]
- Uno H., Sasazuki T., Tamai H., Matsumoto H. Two major genes, linked to HLA and Gm, control susceptibility to Graves' disease. Nature. 1981 Aug 20;292(5825):768–770. doi: 10.1038/292768a0. [DOI] [PubMed] [Google Scholar]
- Whittingham S., Mathews J. D., Schanfield M. S., Matthews J. V., Tait B. D., Morris P. J., Mackay I. R. Interactive effect of Gm allotypes and HLA-B locus antigens on the human antibody response to a bacterial antigen. Clin Exp Immunol. 1980 Apr;40(1):8–15. [PMC free article] [PubMed] [Google Scholar]
- Whittingham S., Mathews J. D., Schanfield M. S., Tait B. D., Mackay I. R. Interaction of HLA and Gm in autoimmune chronic active hepatitis. Clin Exp Immunol. 1981 Jan;43(1):80–86. [PMC free article] [PubMed] [Google Scholar]