Schizophrenia, V: Risk Markers

Identifying genetic factors that contribute to disease onset and expression has been a major focus in schizophrenia research. Ultimately, we seek to describe the causal pathway(s) from specific genetic variants to CNS protein changes to changes in neuronal functioning to behavioral changes associated with specific functional impairments. Past efforts have been hampered by the apparent heterogeneity of the disease. The clinical diagnosis encompasses a varying combination of several such causal paths and is therefore characterized by a varying collection of phenotypes, each associated with specific neurocognitive deficits reflecting the effects of a small subset of genes. This may explain why traditional genetic approaches that focus on the presence or absence of the disease have generally been less informative than approaches that focus on more specific disease-related phenotypes. Family studies of schizophrenia have identified a number of neurophysiological and neurocognitive measures that differentiate persons with schizophrenia and a proportion of their biological relatives from healthy individuals and may be associated with genetic risk. We have developed a strategy in which we examine these putative risk markers in individuals who, on the basis of their biological relation to individuals diagnosed with schizophrenia and the expression of relevant clinical symptoms, vary in their degree of risk. In order of decreasing likelihood of “genetic carrier” status, we study 1) schizophrenia patients, 2) relatives of schizophrenia patients who exhibit schizophrenia spectrum personality symptoms, 3) relatives of schizophrenia patients who do not exhibit schizophrenia spectrum personality symptoms, 4) persons who exhibit schizophrenia spectrum personality symptoms in the absence of a family history of psychotic illness, and 5) persons who do not exhibit schizophrenia spectrum personality symptoms and do not have a family history of psychotic illness. For these five groups, measures of neurophysiological and cognitive impairment that are most strongly associated with disease risk are likely to show the same decreasing pattern. The results we have obtained suggest that smooth pursuit eye movement abnormalities, antisaccade performance, visual attention, and verbal working memory follow this pattern (the Figure illustrates smooth pursuit eye movement and visual attention findings). We are now examining the interrelations among these risk markers to determine which are likely to represent independent genetic effects and which are related to common underlying genetic changes; we then plan to apply these single and composite phenotypes in molecular genetic studies. It is hoped that this will increase the likelihood of identifying specific genes that confer risk for schizophrenia and help to determine how they interact (e.g., additively or multiplicatively) to cause overt illness.