Chunk #116 — 5. Implications for understanding gene-brain-behavior relationships in health and disease — 5.1. Intermediate phenotypes, or “endophenotypes”
One of the initial arguments in favor of the focus on intermediate phenotypes was that variability at the neurobiological level is “closer” to immediate gene effects, such as change of a protein function than complex behavior and, due to this proximity to gene products, the effects of single genes on neurophenotypes can be relatively large and therefore readily detectable. However, this turned out not to be the case, as neurophenotypes, at least those that can be measured non-invasively in humans and likely to play a causal role in behavioral differences, are also quite complex and are therefore unlikely to demonstrate simpler genetic architecture (de Geus, 2010; Flint and Munafo, 2007). Various models linking genes, endophenotypes, and clinical phenotypes are discussed by Rommelse et al. (2011). However, this complexity does not diminish the value of neurophenotypes, since with the advent of GWAS and growing number of genetic variants contributing to behavioral variation, there is an increasing need in the investigation of the pathways mediating the effects of these variants on behavior. In fact, functional significance of many of genetic loci being
