Conditional likelihood score functions for mixed models in linkage analysis.

In this paper, we develop a general strategy for linkage analysis, applicable for arbitrary pedigree structures and genetic models with one major gene, polygenes and shared environmental effects. Extending work of Whittemore (1996), McPeek (1999) and Hossjer (2003d), the efficient score statistic is computed from a conditional likelihood of marker data given phenotypes. The resulting semiparametric linkage analysis is very similar to nonparametric linkage based on affected individuals. The efficient score S depends not only on identical-by-descent sharing and phenotypes, but also on a few parameters chosen by the user. We focus on (1) weak penetrance models, where the major gene has a small effect and (2) rare disease models, where the major gene has a possibly strong effect but the disease causing allele is rare. We illustrate our results for a large class of genetic models with a multivariate Gaussian liability. This class incorporates one major gene, polygenes and shared environmental effects in the liability, and allows e.g. binary, Gaussian, Poisson distributed and life-length phenotypes. A detailed simulation study is conducted for Gaussian phenotypes. The performance of the two optimal score functions S(wpairs) and S(normdom) are investigated. The conclusion is that (i) inclusion of polygenic effects into the score function increases overall performance for a wide range of genetic models and (ii) score functions based on the rare disease assumption are slightly more powerful.