The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia

Abstract

While genetic influences in schizophrenia are substantial, the disorder's molecular genetic basis remains elusive. Progress has been hindered by lack of means to detect nonpenetrant carriers of the predisposing genes and by uncertainties 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 evaluate whether deficits in neurocognitive functioning covary with degree of genetic relationship with a proband in the unaffected MZ and DZ co-twins of patients with schizophrenia. Twin pairs discordant for schizophrenia were recruited from a total population cohort and were compared with a demographically balanced sample of control twin pairs, on a comprehensive neuropsychological test battery. The following four neuropsychological functions contributed uniquely to the discrimination of degree of genetic loading for schizophrenia and, when combined, were more highly correlated within MZ pairs than within DZ pairs, in both discordant and control twins: spatial working memory (i.e., remembering a sequence of spatial locations over a brief delay), divided attention (i.e., simultaneous performance of a counting and visual-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 multiple independently inherited dimensions of neural deficit in schizophrenia and encourage a search for genes contributing to quantitative variation in discrete aspects of disease liability. On tests of verbal and visual episodic memory, but not on the liability-related measures, patients were more impaired than their own MZ co-twins, suggesting a preferential impact of nongenetic influences on long-term memory systems.

Figure 1

Frequency distribution (in %) of MZ co-twin (blackened bars), DZ co-twin (hatched bars), and control twin (unmarked bars) groups, according to their standardized scores on the liability-related canonical neuropsychological variate. The canonical variate represents the linear combination of neuropsychological scores that best discriminates among liability groups; the measures contributing uniquely to the discrimination are (in order of magnitude) divided attention, spatial working memory, recall intrusions, and choice reaction time. For statistical information, see table 3.

Figure 2

Frequency distribution (in %) of the schizophrenia (blackened bars) and control (unblackened bars) groups, according to their standardized scores on the disease-related canonical neuropsychological variate. The canonical variate represents the linear combination of neuropsychological scores that best discriminates among diagnostic groups; the measures contributing uniquely to the discrimination are (in order of magnitude) verbal episodic memory, visual episodic memory, motor speed, spatial working memory, divided attention, and choice reaction time. For statistical information, see table 3.

Figure 3

Mean ± SEM differences between patients and their own MZ co-twins, with regard to the liability- and disease-related measures. Canonical variates are in SD units; all other variables are in original units. *P<.05.