Parametric and nonparametric multipoint linkage analysis with imprinting and two-locus-trait models: Application to mite sensitization

We present two extensions to linkage analysis for genetically complex trait s. The first extension allows investigators to perform parametric (LOD-scor e) analysis of traits caused by imprinted genes-that is, of traits showing a parent-of-origin effect. By specification of two heterozygote penetrance parameters, paternal and maternal origin of the mutation can be treated dif ferently in terms of probability of expression of the trait. Therefore, a s ingle-disease-locus-imprinting model includes four penetrances instead of o nly three. In the second extension, parametric and nonparametric linkage an alysis with two trait loci is formulated for a multimarker setting, optiona lly taking imprinting into account. We have implemented both methods into t he program GENEHUNTER. The new tools, GENEHUNTER-IMPRINTING and GENEHUNTER- TWOLOCUS, were applied to human family data for sensitization to mite aller gens. The data set comprises pedigrees from England, Germany, Italy, and Po rtugal. With single-disease-locus-imprinting MOD-score analysis, we find se veral regions that show at least suggestive evidence for linkage. Most prom inently, a maximum LOD score of 4.76 is obtained near D8S511, for the Engli sh population, when a model that implies complete maternal imprinting is us ed. Parametric two-trait-iocus analysis yields a maximum LOD score of 6.09 for the German population, occurring exactly at D45430 and D18S452. The het erogeneity model specified for analysis alludes to complete maternal imprin ting at both disease loci. Altogether, our results suggest that the two nov el formulations of linkage analysis provide valuable tools for genetic mapp ing of multifactorial traits.