Cognitive Deficits in Unaffected First-Degree Relatives of Schizophrenia Patients: A Meta-analytic Review of Putative Endophenotypes

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Abstract
Cognitive deficits may index genetic liability for schizophrenia and are candidate endophenotypes for the illness. In order to compare the degree of sensitivity among cognitive tasks to group differences between healthy relatives and controls and the influence of moderator variables, this review reports mean effect sizes for 43 cognitive test scores from 58 studies of cognitive performance in the unaffected adult relatives of schizophrenia patients. Results indicate reliable relative-control differences, in the small to medium effect size range, over a diverse array of tasks, with the largest effect sizes seen in complex versions of continuous performance tasks, auditory verbal learning, design copy tests, and category fluency. Three study design features were found to have significant effects on overall effect size magnitude: groups unmatched on education, groups unmatched on age, and asymmetric psychiatric exclusion criteria. After excluding studies with the latter 2 design features, reliable performance differences were still observed over a smaller subset of cognitive test variables, with the largest effect sizes seen in Trails B (d = 0.50) and performance measures from both simple (d = 0.56) and complex (d = 0.60-0.66) versions of continuous performance tasks. Four of the 6 largest effect sizes reflect tasks with high executive control demands in common, such as working memory demands, set shifting, and inhibition of prepotent responses. Cognitive deficits, particularly those tapping such executive control functions, should continue to prove valuable as endophenotypes of interest in the search for specific genetic factors related to schizophrenia.