Figure 4.

Intermediate phenotypes as tools for gene discovery versus neural mechanism characterization. Examples of two alternative approaches to the identification of genetic variants linked to psychiatric disorders are illustrated, with the relevant genes, neural systems and behavioral phenotypes highlighted in red, and arrows indicating the direction of research inference. a. the gene discovery approach, behavioral or neural systems phenotypes are used to reduce genetic complexity and increase penetrance to identify genes implicated in psychiatric disorders. For example, deficiencies in the electrophysiological response to auditory stimulation were used to identify an association of schizophrenia with the α7 nicotinic receptor ¹⁰¹. In the figure, prefrontal cortex dysfunction has been linked to catechol-O-methyltransferase (COMT) and GRM3 genetic variations ¹⁰², ¹⁰³, and emotional regulation has been linked to variation in COMT, MAOA and 5-HTT ², ¹⁰⁴, ¹⁰⁵, and so could have been hypothetically employed as a phenotype to identify these genes. b. in the neural mechanism approach, genes known to be associated with psychiatric disorders or behavioral traits are used to discover neural mechanisms mediating their complex emergent phenotype associations, implicating these mechanisms in the psychiatric disorders to which they have been linked. Examples include the use of the COMT Val158Met polymorphism to characterize prefrontal function and prefrontal-midbrain interactions linked to risk for schizophrenia ¹⁰², ¹⁰⁶, and the delineation of cingulate circuitry regulating amygdala function mediating risk for anxiety and depression through an investigation of the MAOA VNTR ¹⁰⁵, ¹⁰⁷. BA 25, Broadman’s area 25; HF, Hippocampal formation; MB, midbrain; OFC, orbitofrontal cortex. Reproduced with permission from Nat. Rev. Neuroscience REF 2 (2006) © Macmillan Publishers Ltd. A color version of this figure can be viewed online.