How to model a complex trait. 1. General considerations and suggestions

Usually, when complex traits are at issue, not only are the loci of the responsible genes a priori unknown; the same also holds for the mode of inheritance of the trait, and sometimes even for the phenotype definition. The term mode of inheritance relates to both the genetic mechanism, i.e., the number of loci implicated in the etiology of the disease, and the genotype-phenotype relation, which describes the influence of these loci on the trait. Having an idea of the genetic model can crucially facilitate the mapping process. This holds especially in the context of linkage analysis, where an appropriate parametric model or a suitable nonparametric allele sharing statistic may accordingly be selected. Here, we review the difficulties with parametric and nonparametric linkage analysis when applied to multifactorial diseases. We address the question why it is necessary to adequately model a genetically complex trait in a linkage study, and elucidate the steps to do so. Furthermore, we discuss the value of including unaffected individuals into the analysis, as well as of looking at larger pedigrees, both with parametric and nonparametric methods. Our considerations and suggestions aim at guiding researchers to genotyping individuals at a trait locus as accurately as possible.