62 Thus, one might hypothesize that the shared candidate symptom might be represented by positive symptoms. Brzustowicz et al63 provided the first evidence of the value of using a quantitative dimensional approach in a linkage study in a sample of multiply affected families. Positive linkage with markers on the p arm of chromosome Inhibitors,research,lifescience,medical 6 was obtained only when using scores on positive symptoms as phenotypes among schizophrenic patients and their nonaffected relatives. Negative linkage results were

obtained with negative scores or with a classical nosographical approach. The endophenotype strategy Endophenotypes are traits that are associated with the expression of an illness and are believed to represent the genetic liability of the disorder among nonaffected subjects. Using the endophenotypic strategy, Gamma-secretase inhibition schizophrenia can be conceptualized as an illness caused by the interaction of several elementary neurobiological dysfunctions Inhibitors,research,lifescience,medical – each underlined by a specific defect in a particular candidate gene – with nongenetic Inhibitors,research,lifescience,medical factors. There are several examples of somatic diseases in which “endophenotypic” level helped define the genetic basis of the illness in

molecular terms. For instance, understanding the mode of inheritance of idiopathic hemochromatosis was unclear until serum iron concentration was selected as a biological indicator of intrinsic liability to the disease. Including serum iron in the analysis uncovered a linkage with Inhibitors,research,lifescience,medical the HLA-A locus.64 In order to identify a genetic susceptibility factor in juvenile myoclonic epilepsy, investigators chose a subclinical trait (ie, an abnormal electroencephalogram) as an endophenotype in affected and nonaffected family members, and found linkage to chromosome 6.65 Focusing on families with the highest serum glucose levels as a specific phenotype led to the discovery of a genetic deficit that results in type 2 diabetes.66 In schizophrenia, several neurochemical, electrophysiological, and cognitive abnormalities have been reported among nonaffected relatives of Inhibitors,research,lifescience,medical schizophrenic patients. Two endophenotypes

in particular, eye tracking6 and P50 evoked potential measurements,7 have already been used as phenotypes, and yielded positive linkage results. Neurochemical abnormalities Investigations of neurochemical new abnormalities among unaffected relatives of schizophrenic patients is a convenient method to explore biochemical predisposition to schizophrenia in natural conditions, without any pharmacological challenge and in the absence of confounding factors, such as chronicity of illness or effects of medication. Dopaminergic abnormalities have been explored in nonpsychotic relatives under the hypothesis that negative and positive symptoms are associated with decreased and increased brain dopamine (DA) functions, respectively.