The genetics of cognition in schizophrenia

Abstract

This conceptual review focuses on recent insights into the nature of the relationship between genetic predisposition and cognitive impairment as risk factors for schizophrenia, and the factors that influence the degree of cognitive impairment in those with the disorder. There is clear evidence that premorbid cognitive impairment is frequently present in those who develop schizophrenia, and, across the range of abilities, poorer premorbid cognition is associated with higher liability to the disorder. Evidence from genetic and population studies strongly supports the hypothesis that premorbid cognitive impairment is a marker for underlying neurodevelopmental risk factors for the disorder, rather than a prodromal manifestation. The premorbid cognitive deficit seems to be largely explained by non-familial factors rather than by familial factors that jointly influence liability to schizophrenia and cognitive ability, and these non-familial risk factors appear act to sensitize individuals to familial risk. There is also evidence that neurodevelopmental risk may be better indexed by the degree to which premorbid cognitive ability deviates from familial expectations than by cognitive ability per se. Premorbid cognitive impairment thus does not itself lie on the causal pathway to schizophrenia, rather it is a marker of a neurodevelopmental abnormality that is substantially non-familial, and which increases risk for schizophrenia. Genetic risk factors, including both common and rare alleles, that influence IQ in the general population also contribute both to liability for schizophrenia and to the degree of cognitive impairment in those with the disorder. There is also evidence for further decline in cognitive function after diagnosis in some individuals as well as an increased risk of dementia. This does not appear to reflect substantial shared heritability with neurodegenerative disorders, but the causes of postonset cognitive decline and its relationship to schizophrenia pathophysiology remain uncertain.