The search for susceptibility genes is further complicated when the aetiology of a complex neurodevelopmental disorder can not be explained by a single genetic variant with a relatively large effect but is rather caused by an interplay of a number of genes with small (additive) effects. For schizophrenia pathogenesis, the essential parameters for single- and multiple-locus models have been calculated and an interaction of about three different genes together with the environment was predicted to underly this disorder [205]. Not surprisingly, in general the greater the number of genes involved the more difficult their identification will be and larger (or additional) cohorts will be necessary to reach significant association. In addition, besides the possibility that multiple susceptibility genes are involved, individuals may be affected by the absence of protective alleles, while epistasis may also play a role.
