The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia

While genetic influences in schizophrenia are substantial, the disorder's m olecular genetic basis remains elusive. Progress has been hindered by lack of means to detect nonpenetrant carriers of the predisposing genes and by u ncertainties concerning the extent of locus heterogeneity. One approach to solving this complexity is to examine the inheritance of pathophysiological processes mediating between genotype and disease phenotype. Here we evalua te whether deficits in neurocognitive functioning covary with degree of gen etic relationship with a proband in the unaffected MZ and DZ co-twins of pa tients with schizophrenia. Twin pairs discordant for schizophrenia were rec ruited from a total population cohort and were compared with a demographica lly balanced sample of control twin pairs, on a comprehensive neuropsycholo gical test battery. The following four neuropsychological functions contrib uted uniquely to the discrimination of degree of genetic loading for schizo phrenia and, when combined, were more highly correlated within MZ pairs tha n within DZ pairs, in both discordant and control twins: spatial working me mory (i.e., remembering a sequence of spatial locations over a brief delay) , divided attention (i.e., simultaneous performance of a counting and visua l-search task), intrusions during recall of a word list (i.e., "remembering " nonlist items), and choice reaction time to visual targets. Together with evidence from human and animal studies of mediation of these functions by partially distinct brain systems, our findings suggest that there are multi ple independently inherited dimensions of neural deficit in schizophrenia a nd encourage a search for genes contributing to quantitative variation in d iscrete aspects of disease liability. On tests of verbal and visual episodi c memory, but not on the liability-related measures, patients were more imp aired than their own MZ co-twins, suggesting a preferential impact of nonge netic influences on long-term memory systems.