TY - JOUR
T1 - Transdiagnostic Neurocognitive Endophenotypes for Schizophrenia, Bipolar I Disorder and a Broad Psychosis/Bipolar I Disorder Phenotype
T2 - A Mega-Analysis of Twin and Sibling Data
AU - Kravariti, Eugenia
AU - Fragkaki, Anna-Maria
AU - Georgiades, Anna
AU - Cardno, Alastair G
AU - Kane, Fergus
AU - Kalidindi, Sridevi
AU - Schulze, Katja K
AU - McDonald, Colm
AU - Picchioni, Marco M
AU - Hall, Mei-Hua
AU - Watson, Cameron J
AU - Glenthøj, Birte Y
AU - Ebdrup, Bjørn H
AU - Fagerlund, Birgitte
AU - Lemvigh, Cecilie K
AU - Van Haren, Neeltje E M
AU - Kahn, Rene
AU - Murray, Robin M
AU - Rijsdijk, Fruhling
AU - Toulopoulou, Timothea
N1 - Publisher Copyright:
© The Author(s) 2025. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.
PY - 2026/1/1
Y1 - 2026/1/1
N2 - 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.
AB - 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.
KW - bipolar I disorder
KW - cognition
KW - endophenotypes
KW - schizophrenia
KW - transdiagnostic
KW - twins
UR - https://www.scopus.com/pages/publications/105027654741
U2 - 10.1093/schbul/sbaf050
DO - 10.1093/schbul/sbaf050
M3 - Article
C2 - 40341418
SN - 0586-7614
VL - 52
JO - Schizophrenia bulletin
JF - Schizophrenia bulletin
IS - 1
M1 - sbaf050
ER -