Are intelligence and memory good endophenotypes for schizophrenia? Genetic models in a harvard, IOP, and NIH collaboration

Abstract

Context: Impairments in verbal and visual memory, verbal learning and intelligence are among the most promising indicators of increased risk for schizophrenia making them candidate endophenotypes; however it is not clear to what extent these deficits are genetically linked to the disorder. Objective: To quantify the net genetic relationship between episodic memory, learning, intelligence and schizophrenia in a large multi-site data. Design: Family and twin study. Setting: US and UK Research Institutes. Participants: Data from 2057 individuals were pooled across three sites: 1) Harvard University,USA (2) Institute of Psychiatry,UK and (3) National Institute of Health,USA. Of these individuals 657 were patients, 674 1st degree relatives and 726 were controls. Main outcome measures: The heritabilities of memory, learning and intelligence were estimated and the genetic relationship between each one of these and schizophrenia quantified. Results: Genetic influences contributed to all cognitive domains with intelligence showing the highest heritability (h2 = 0.69) and immediate recall of verbal memory the least (h2 = 0.30). Significant genetic correlations were found between schizophrenia and 1) immediate (I)/delayed (D) verbal recall (I: 0.96; D: 0.94); 2) I/D verbal learning (I: 0.47; D: 0.30) and 3) I/D visual recall (I: 0.62; D: 0.68) suggesting that schizophrenia and these measures share to some extent the same genes. When the heritabilities of these measures were taken into account, intelligence showed the biggest phenotypic correlation with schizophrenia ( .49) with shared genetic influences explaining chiefly the phenotypic co-variance. Conclusion: Unlike molecular genetic approaches which estimate the extent to which allelic variation explains endophenotypic variance, genetic modeling quantifies the net shared genetic influences between the candidate endophenotype and the illness, giving a broader view of the degree of genetic overlap between the two. Supporting our previous work in twins (Toulopoulou et al. 2007) intelligence appears to be the best endophenotype for schizophrenia sharing the greatest genetic variance with the illness. Genome wide searches using a bivariate phenotype such as schizophrenia and intelligence should assist in the search to find quantitative trait loci for schizophrenia.