Segregation and Linkage Analysis of 40 Multiplex Multiple Sclerosis Families

Abstract

40 multiplex multiple sclerosis (MS) families were analyzed for evidence of an MS susceptibility gene linked to the HLA region of the sixth chromosome. We assumed that population associations between specific HLA alleles and MS are due to linkage disequilibrium, so preference was given to hypotheses compatible with tight linkage, and explanations were sought for conflicting evidence. The analyses proceeded in two steps: (1) segregation analysis using the computer program POINTER, and (2) linkage analysis using LINKAS, first assuming linkage equilibrium and then allowing for linkage disequilibrium and etiological heterogeneity. The results of the segregation analyses were indeterminate. The results of the linkage analyses suggest that analyses that do not allow for disequilibrium lose substantial evidence on linkage. Of the models that were investigated under linkage disequilibrium, the best fit is with a model of complete linkage (Θ = 0.0) in 75% of tghe pedigrees and no linkage in the remaining pedigrees. We were unable, however, to statistically reject another model involving loose linkage and no heterogeneity.

Inheritance mode of multiple sclerosis: the effect of HLA class II alleles is stronger than additive

“…Ample investigations have shown that both environmental and genetic factors play a role. There are indications that there is a major locus (Haile et al 1981;Sadovnick et al 1981), although there is no consensus as to the etiological fraction of this locus (Haines et al 1998;Kellar-Wood et al 1995;Oturai et al 1999;Risch 1986). The major locus is most likely situated in the HLA region.…”

“…Using different parametric and nonparametric methods, many studies aimed to investigate the presence of linkage between MS and loci in the HLA region or association with specific alleles (Clerget-Darpoux et al 1984;Eoli et al 1995;Epplen et al 1997;Fogdell et al 1997;Haile et al 1981;Haines et al1998;Ho et al 1982;Kellar-Wood et al 1995;Oturai et al 1999;Payami et al 1986;Risch 1986;Sherman et al 1986;Stewart et al 1981;Thomson 1983;Tienari et al 1994;Tiwari et al 1980). These investigators applied dominant, intermediate and recessive models, based on former studies or theoretical arguments.…”

Case-Control Studies of Multiple Sclerosis

“…This hypoth esis emphasizes the importance of both multiple individually insufficient but collectively necessary exposures and the sequence in which they must occur. In addition, this disease may demonstrate étiologie heterogeneity [12][13][14]. The above model also underscores the complexity of trying to identify these individual factors in a case-control study.…”

“…If genetic sus ceptibility is a necessary but insufficient factor, then it will be more efficient statistically to select controls who are also genetically susceptible. Unfortu nately, genetic susceptibility can only be determined at the present time by matching on chromosome identity within families [11][12][13]20].…”

A linkage analysis of the Gm locus and multiple sclerosis

“…Linkage analysis was 17;21,26,27 ~~1 ,2,17;21,26,27 and Gm3;5,10,11,13,14,26,27 *Data on these pedigrees are available on request 'If epistatic interaction between two loci is the correct model and one gene is dominant while the other gene is recessive, segregation analyses that test for a single major gene effect should tend toward the recessive model (lower segregation ratio), since this IS the more "demanding" model, ie, it requlres two genes instead of one. A recessive model for Gm, therefore, seems somewhat unlikely, since previous segregation analyses of MS pedigrees strongly suggested a dominant model and rejected the recessive model [Haile et al, 1981;Ho et al, 19821. One may hypothesize a recessive model in a subgroup of the data; however, such hypotheses are impossible to disprove.…”