Cognition in t(1;11) translocation carriers and patients with psychotic disorders

Deficits in a number of cognitive domains have been associated with core symptoms of schizophrenia, including working memory, attention, motor skills, reaction time, episodic memory and executive function. Bipolar Disorder is also associated with cognitive impairment; however the level of impairment appears to be less severe than that seen in schizophrenia. A translocation (t(1;11)) containing the Disrupted-in-Schizophrenia 1 (DISC1) gene has been found to be highly associated with schizophrenia, bipolar disorder and major depressive disorder. As such, this gene has been the focus of much research and to date DISC1 has been found to be associated with brain development, brain structure and the glutamate system - all key factors in current models of schizophrenia and affective disorders. The aim of this PhD is to identify cognitive domains that are differentially impaired or unimpaired in a large Scottish family, some of whom carry this rare DISC1 variant, a balanced translocation (t (1;11) (q 42; q14.3)), that segregates with schizophrenia and affective disorders, as well as psychiatric patients with schizophrenia and bipolar disorder and healthy control subjects. All participants have undergone standardised cognitive assessments to measure premorbid I.Q. (NART), current I.Q. (WASI) verbal memory, working memory, verbal fluency, processing speed, motor skills, executive function (BACS) and selected CANTAB tasks to assess simple and five-choice reaction time. Polygenic risk profile scores and self-report questionnaire data have also been investigated. Results indicate an impact of the DISC1 t(1;11) translocation on general intelligence and attention and processing speed. Significant differences were also identified between DISC1 t(1;11) carriers and non-carriers on self-report questionnaire data. Mean scores for polygenic risk for bipolar disorder were significantly different between DISC1 t(1;11) carriers and non-carriers and polygenic risk for schizophrenia was significantly associated with symptom severity, as measured by the Positive and Negative Symptom Scale (PANSS). Within the patient groups, a measure of processing speed (the token motor task) was found to be significantly different between those with schizophrenia and bipolar disorder and there was also a trend for attention and processing speed. As expected, I.Q. was significantly different between patients and control participants. Clinical ratings were significantly associated with neuropsychological and self-report measures. Polygenic risk for major depressive disorder was found to be significantly associated with impaired general intelligence (current IQ) and slowed reaction time in patients who were not currently depressed, suggesting there may be genetic risk markers in this population which impact on cognition. This is a novel finding and further suggests the possibility of a biological component related to the genetics of depression. In conclusion, and in line with the literature, psychosis has a negative impact on cognition with reduced performance across several neuropsychological tasks between patient groups, with schizophrenia patients performing worse than patients with bipolar disorder and both patient groups performing worse than healthy control participants. Cognition is markedly more impaired in DISC1 t(1;11) translocation carriers and especially in those with psychosis. The DISC1 t(1;11) translocation and psychosis may therefore confer a “double hit” on cognition - in addition to psychosis itself - which is known to impair cognitive function, significantly increasing the level of cognitive impairment and increasing the risk for psychosis in general