ABSTRACT
This chapter will focus on the genetic dissection of complex traits, specifically the non-Mendelian forms of amyotrophic lateral sclerosis (ALS). In contrast to the methods that have successfully been applied to discover the genes responsible for Mendelian (monogenic) ALS (chap. 6), the analysis of the more common form of the disorder is complicated by several factors. For example, instead of a single causal gene such as SOD1, the more common forms of ALS are likely due to one or more susceptibility genes, each conferring a relatively small risk increase (‘‘predisposition’’), as well as to interactions between these genes and between genes and environmental exposures. Even patients with non-Mendelian forms of ALSmay present with a family history (e.g., they may have an affected first-degree relative), but no specific inheritance pattern is apparent in their families. Different individuals within the same family do not necessarily share the same genetic factors. For example, in one individual, gene A could contribute more to the disease than gene B, while in another individual, due to different allelic variations in interacting genes or different environmental challenges, gene B could be the major determinant of disease. Because of these complexities, the probability (penetrance) of expressing a particular phenotype given genotypes at one or more disease-associated loci will depend on many factors typically unknown to the investigator. Many statistical analysis methods for mapping complex disease genes have been specifically developed to accommodate this greater uncertainty in genotype-phenotype relationships.
