TY - JOUR
T1 - Genomic insights into the shared and distinct genetic architecture of cognitive function and schizophrenia
AU - Wootton, Olivia
AU - Shadrin, Alexey A.
AU - Bjella, Thomas
AU - Smeland, Olav B.
AU - van der Meer, Dennis
AU - Frei, Oleksandr
AU - O'Connell, Kevin S.
AU - Ueland, Torill
AU - Andreassen, Ole A.
AU - Stein, Dan J.
AU - Dalvie, Shareefa
N1 - Funding Information:
We would like to thank the participants and members of the research teams involved in the UK Biobank and TOP Study. The current study was supported by National Institute of Mental Health (NIMH: Grant number U01MH125053), and The Research Council of Norway (275054). This research has been conducted using data from UK Biobank, a major biomedical database (Project ID number 27412; www.ukbiobank.ac.uk ). This work was performed on the TSD (Tjeneste for Sensitive Data) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department (USIT) ([email protected]). We gratefully acknowledge support from the Research Council of Norway (324499, 324252, 273291, 223273, 248980, 326813), the South-East Norway Regional Health Authority (2019-108, 2022-073), European Economic Area and Norway grants (no. EEA-RO-NO-2018-0573), KG Jebsen Stiftelsen (SKGJ-MED-021), and the South African Medical Research Council. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.
Funding Information:
We would like to thank the participants and members of the research teams involved in the UK Biobank and TOP Study. The current study was supported by National Institute of Mental Health (NIMH: Grant number U01MH125053), and The Research Council of Norway\u00A0(275054). This research has been conducted using data from UK Biobank, a major biomedical database (Project ID number 27412;\u00A0www.ukbiobank.ac.uk). This work was performed on the TSD (Tjeneste for Sensitive Data) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department (USIT) ([email protected]). We gratefully acknowledge support from the Research Council of Norway (324499, 324252, 273291, 223273, 248980, 326813), the South-East Norway Regional Health Authority (2019-108, 2022-073), European Economic Area and Norway grants (no. EEA-RO-NO-2018-0573), KG Jebsen Stiftelsen (SKGJ-MED-021), and the South African Medical Research Council. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.
Publisher Copyright:
© The Author(s) 2024.
PY - 2024/7/4
Y1 - 2024/7/4
N2 - Cognitive impairment is a major determinant of functional outcomes in schizophrenia, however, understanding of the biological mechanisms underpinning cognitive dysfunction in the disorder remains incomplete. Here, we apply Genomic Structural Equation Modelling to identify latent cognitive factors capturing genetic liabilities to 12 cognitive traits measured in the UK Biobank. We identified three broad factors that underly the genetic correlations between the cognitive tests. We explore the overlap between latent cognitive factors, schizophrenia, and schizophrenia symptom dimensions using a complementary set of statistical approaches, applied to data from the latest schizophrenia genome-wide association study (Ncase = 53,386, Ncontrol = 77,258) and the Thematically Organised Psychosis study (Ncase = 306, Ncontrol = 1060). Global genetic correlations showed a significant moderate negative genetic correlation between each cognitive factor and schizophrenia. Local genetic correlations implicated unique genomic regions underlying the overlap between schizophrenia and each cognitive factor. We found substantial polygenic overlap between each cognitive factor and schizophrenia and biological annotation of the shared loci implicated gene-sets related to neurodevelopment and neuronal function. Lastly, we show that the common genetic determinants of the latent cognitive factors are not predictive of schizophrenia symptoms in the Norwegian Thematically Organized Psychosis cohort. Overall, these findings inform our understanding of cognitive function in schizophrenia by demonstrating important differences in the shared genetic architecture of schizophrenia and cognitive abilities.
AB - Cognitive impairment is a major determinant of functional outcomes in schizophrenia, however, understanding of the biological mechanisms underpinning cognitive dysfunction in the disorder remains incomplete. Here, we apply Genomic Structural Equation Modelling to identify latent cognitive factors capturing genetic liabilities to 12 cognitive traits measured in the UK Biobank. We identified three broad factors that underly the genetic correlations between the cognitive tests. We explore the overlap between latent cognitive factors, schizophrenia, and schizophrenia symptom dimensions using a complementary set of statistical approaches, applied to data from the latest schizophrenia genome-wide association study (Ncase = 53,386, Ncontrol = 77,258) and the Thematically Organised Psychosis study (Ncase = 306, Ncontrol = 1060). Global genetic correlations showed a significant moderate negative genetic correlation between each cognitive factor and schizophrenia. Local genetic correlations implicated unique genomic regions underlying the overlap between schizophrenia and each cognitive factor. We found substantial polygenic overlap between each cognitive factor and schizophrenia and biological annotation of the shared loci implicated gene-sets related to neurodevelopment and neuronal function. Lastly, we show that the common genetic determinants of the latent cognitive factors are not predictive of schizophrenia symptoms in the Norwegian Thematically Organized Psychosis cohort. Overall, these findings inform our understanding of cognitive function in schizophrenia by demonstrating important differences in the shared genetic architecture of schizophrenia and cognitive abilities.
U2 - 10.1038/s41598-024-66085-y
DO - 10.1038/s41598-024-66085-y
M3 - Article
SN - 2045-2322
VL - 14
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 15356
ER -