Chunk #112 — 5. Implications for understanding gene-brain-behavior relationships in health and disease — 5.1. Intermediate phenotypes, or “endophenotypes”
genes and pathways involved in common diseases and other complex traits (Visscher et al., 2012). However, most of these recent successes concerned “somatic” phenotypes such as auto-immune or metabolic diseases, while the progress in the identification of loci associated with behavioral phenotypes such as psychiatric disorders was relatively modest, with a few exceptions (e.g. Rietveld et al., 2013; Smoller et al., 2013). The root of the problem lies in the complexity, variability, and possible etiological heterogeneity of the diagnostic phenotypes, as well as the large “distance” between the predisposing genes and their phenotypic expression. Genetic influences on complex behavioral phenotypes are mediated by numerous pathways and mechanisms that interact in a highly non-linear fashion and are strongly modulated by environmental influences. The second source of the lies in the large number of genes and their small effect sizes. At the early stages of behavioral and psychiatric genetics there was a hope that substantial portion of variance of complex phenotypes can be explained by “oligogenes”, i.e. a few genes with relatively large effects. However, this assumption has been largely refuted by recent GWAS studies, as it became clear that many genes with very small effects are likely to be involved in
