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Sex-specific effects of polygenic risk for schizophrenia on lifespan cognitive functioning in healthy individuals
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).ORCID iD: 0000-0003-3727-4470
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.ORCID iD: 0000-0002-3367-1746
Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.ORCID iD: 0000-0003-1524-0851
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).ORCID iD: 0000-0001-9512-3289
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2021 (English)In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 520Article in journal (Refereed) Published
Abstract [en]

Polygenic risk for schizophrenia has been associated with lower cognitive ability and age-related cognitive change in healthy individuals. Despite well-established neuropsychological sex differences in schizophrenia patients, genetic studies on sex differences in schizophrenia in relation to cognitive phenotypes are scarce. Here, we investigated whether the effect of a polygenic risk score (PRS) for schizophrenia on childhood, midlife, and late-life cognitive function in healthy individuals is modified by sex, and if PRS is linked to accelerated cognitive decline. Using a longitudinal data set from healthy individuals aged 25–100 years (N = 1459) spanning a 25-year period, we found that PRS was associated with lower cognitive ability (episodic memory, semantic memory, visuospatial ability), but not with accelerated cognitive decline. A significant interaction effect between sex and PRS was seen on cognitive task performance, and sex-stratified analyses showed that the effect of PRS was male-specific. In a sub-sample, we observed a male-specific effect of the PRS on school performance at age 12 (N = 496). Our findings of sex-specific effects of schizophrenia genetics on cognitive functioning across the lifespan indicate that the effects of underlying disease genetics on cognitive functioning is dependent on biological processes that differ between the sexes.

Place, publisher, year, edition, pages
Springer Nature, 2021. Vol. 11, no 1, article id 520
Keywords [en]
Biological Psychiatry, Cellular and Molecular Neuroscience, Psychiatry and Mental health
National Category
Psychiatry
Identifiers
URN: urn:nbn:se:umu:diva-189060DOI: 10.1038/s41398-021-01649-4ISI: 000706129100002PubMedID: 34635642Scopus ID: 2-s2.0-85116814483OAI: oai:DiVA.org:umu-189060DiVA, id: diva2:1608174
Funder
The Royal Swedish Academy of Sciences, AS2015-0004Swedish Research Council, 2017-03011Available from: 2021-11-03 Created: 2021-11-03 Last updated: 2024-04-08Bibliographically approved
In thesis
1. The genetics of schizophrenia: sex, drugs, and cognition
Open this publication in new window or tab >>The genetics of schizophrenia: sex, drugs, and cognition
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Genetiken bakom de kognitiva symtomen i schizofreni
Abstract [en]

Cognitive impairment constitutes an important predictor of general functional outcomes in schizophrenia. Polygenic risk for schizophrenia has been linked to cognitive ability as well as brain activation during cognitive processing. Although sex differences have long been observed in schizophrenia patients, it is not known if genetic effects on cognitive phenotypes differ between males and females. Despite attempts to develop drugs that address the cognitive symptoms in schizophrenia or to investigate existing drugs with potential procognitive effects, there are currently no available medications that efficiently treat these symptoms in schizophrenia. The aim of this PhD project was to explore the genetic underpinnings of cognitive symptoms in schizophrenia, and to identify existing drugs that potentially could be used for repurposing to address these symptoms. We identified male-specific effects of polygenic risk for schizophrenia on lifespan cognitive functioning as well as brain activation during cognitive processing. Within gene networks, we identified a significant overlap between schizophrenia risk genes and genes associated with cognitive performance, and identified novel schizophrenia risk genes that are related to cognitive functioning. Utilizing gene networks incorporating gene expression data, we identified eight existing drugs that could potentially be used for repurposing to address the cognitive symptoms in schizophrenia, most of which have anti-inflammatory and neuroprotective effects. Using sex-specific gene expression data, we identified different repurposing candidates for male and female schizophrenia patients. In conclusion, the findings of this PhD project indicate that the effects of schizophrenia genetics on cognitive functioning are dependent on biological processes that differ between the sexes, and suggest that the cognitive symptoms in schizophrenia should be addressed by sex-specific pharmacological treatments.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2022. p. 65
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2185
Keywords
schizophrenia, genetics, cognition, sex differences, polygenic risk, fMRI, network medicine, drug repurposing, precision medicine
National Category
Medical Genetics Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-193660 (URN)978-91-7855-755-4 (ISBN)978-91-7855-756-1 (ISBN)
Public defence
2022-05-06, KBE303, stora hörsalen, KBC-huset, Umeå, 13:00 (English)
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Uppgift om nummer i serie saknas i publikationen.

Available from: 2022-04-14 Created: 2022-04-10 Last updated: 2022-04-13Bibliographically approved

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Koch, EliseNyberg, LarsLundquist, AndersPudas, SaraAdolfsson, RolfKauppi, Karolina

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