According to the neuroimaging genetics paradigm, to simply demonstrate that a susceptibility gene for schizophrenia impacts brain function is a necessary but not sufficient biological proof of a mechanism of susceptibility. This is because many, if not most, genes expressed in the brain, are apt to have a brain effect of some sort. A sine qua non of this proof is to show that the physiological

intermediate phenotype associated with a susceptibilitygene for schizophrenia is itself linked to illness risk. To make this link, it is necessary to demonstrate that the physiological intermediate Inhibitors,research,lifescience,medical phenotype is a characteristic of individuals who are at AUY-922 molecular weight increased genetic risk but do Inhibitors,research,lifescience,medical not manifest the clinical syndrome. The ideal samples in which to demonstrate this are unaffected relatives, eg, cotwins, siblings. This has been done for a number of brain-associated intermediate

phenotypes related to increased risk for schizophrenia, including cognitive dysfunctions and neuroimaging phenotypes.9-14 Thus, the study of healthy relatives as a target population is critical for establishing the link between genetic association with clinical risk, and genetic association with biological Inhibitors,research,lifescience,medical risk. Having identified a neuroimaging phenotype related to increased genetic Inhibitors,research,lifescience,medical risk for illness, investigators can ask the question of whether genetic variation in a gene of interest maps onto the specific phenotype, as an indication of its putative neural mechanism of risk. The question arises of which population to choose to conduct this test. Neuroimaging studies of only affected subjects is confounded by illness-associated

Inhibitors,research,lifescience,medical epiphenomena that are difficult to control, including smoking history, medical comorbidities, chronic illness burden, or prolonged neuroleptic exposure. This makes results in patient samples difficult to interpret, as the associations may reflect an interaction of the gene with any of these epiphenomena. Instead, the imaging genetics paradigm to test a specific gene-association hypothesis, le, the association of variation in Rutecarpine a putative susceptibility gene and brain function linked to increased genetic risk, is best performed in healthy subjects. Healthy individuals possess common at-risk genotypes, but are not themselves symptomatic or clinically ill, thereby reducing the effect of confounding variables. This approach isolates the simple biologic effect of the genetic variation on brain function(Figure 1). Figure 1. The brain imaging intermediate phenotype concept.