Abstract
BACKGROUND: Psychiatric research is increasingly embracing a paradigm shift from categorical diagnoses to neurobiologically meaningful dimensions that cross current diagnostic boundaries. This transposition calls for redefining endophenotypes to accommodate transdiagnostic vulnerabilities. We sought to identify shared and disorder-specific neurocognitive endophenotypes for schizophrenia, bipolar I disorder (BD-I) and a broad psychosis/BD-I phenotype in a mega-analysis of twin/sibling data. STUDY DESIGN: We performed genetic model fitting to intelligence (IQ) and computerised neurocognitive data derived from 1050 twins/siblings from three research centres in the UK, Denmark and the Netherlands, affected (n = 257) or unaffected (n = 793) by schizophrenia, other primary psychoses and BD-I. We examined the endophenotypic status of IQ, spatial working memory (SWM), visual recognition, sustained attention/rapid visual processing (RVP), mental flexibility, and spatial planning/problem solving (all validated as endophenotypes for schizophrenia in previous studies) in relation to schizophrenia, BD-I and the broad phenotype. STUDY RESULTS: After covarying for age, gender, education and research centre, IQ and SWM emerged as transdiagnostic endophenotypes, showing statistically significant heritabilities (h2 67-75% and 28-30%, respectively), phenotypic correlations (rph |0.14|-|0.25|) and genetic correlations (rg |0.18|-|0.42|) with all diagnostic phenotypes. Additionally, all remaining cognitive domains received validation as endophenotypes for the broad phenotype, and all, but RVP, for schizophrenia. CONCLUSIONS: IQ and SWM tap into transdiagnostic elements of the genetic vulnerabilities to psychosis and BD-I. Our findings add to emergent evidence which spurs cautious optimism that a psychiatric nosology based on aetiology rather than phenotypical classifications may be feasible in the future, enabling biotyping and novel approaches to treatment.