Segregation analysis incorporating linkage markers. I. Single-locus models with an application to type I diabetes.
A method is described for segregation analysis that incorporates linkage markers. The model allows for segregation (penetrance), linkage (recombination fraction), and association (linkage disequilibrium) parameters. A single-locus-multiple-allele model underlying the trait phenotype is assumed. When families have been ascertained in a systematic fashion, a joint (markers, phenotypes) likelihood with ascertainment is advocated. When ascertainment correction is not feasible, a conditional (markers given phenotypes) approach is recommended, which is also valid in the presence of reduced fertility and assortative mating. This approach, oriented toward determining mode of inheritance, differs from conventional linkage analysis, which is oriented toward detection of linkage. Therefore, it is more appropriately considered an extension of the affected sib-pair method to arbitrary pedigrees, including association information and allowing for multiple alleles. Incorporation of coupling parameters allows for discrimination between pleiotropy and linkage disequilibrium. The method is demonstrated through a reanalysis of four recently published family studies on type 1 diabetes and HLA. Recessive inheritance is rejected in all four data sets. For three of them, dominant inheritance is not rejected, while in the fourth, all two-allele models are rejected in favor of three alleles. Although association with the DR3 and DR4 alleles is quite strong, pleiotropy with regard to these alleles is unlikely. The results also suggest an additional familial factor(s) (e.g., locus).
D000328:Adult; D000483:Alleles; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005799:Genes, Dominant; D005808:Genes, Recessive; D008040:Genetic Linkage; D005819:Genetic Markers; D006680:HLA Antigens / Q000235:genetics*; D015803:HLA-DR3 Antigen; D015804:HLA-DR4 Antigen; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D008957:Models, Genetic; D011336:Probability
D005819:Genetic Markers; D006680:HLA Antigens; D015803:HLA-DR3 Antigen; D015804:HLA-DR4 Antigen; D000949:Histocompatibility Antigens Class II