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Polygenic Risk for Schizophrenia Has Sex-Specific Effects on Brain Activity during Memory Processing in Healthy Individuals
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).ORCID iD: 0000-0003-3727-4470
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.ORCID iD: 0000-0002-3367-1746
Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). 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). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Solna, Sweden.ORCID iD: 0000-0003-4908-341X
2022 (English)In: Genes, E-ISSN 2073-4425, Vol. 13, no 3, article id 412Article in journal (Refereed) Published
Abstract [en]

Genetic risk for schizophrenia has a negative impact on memory and other cognitive abilities in unaffected individuals, and it was recently shown that this effect is specific to males. Using functional MRI, we investigated the effect of a polygenic risk score (PRS) for schizophrenia on brain activation during working memory and episodic memory in 351 unaffected participants (167 males and 184 females, 25–95 years), and specifically tested if any effect of PRS on brain activation is sex-specific. Schizophrenia PRS was significantly associated with decreased brain activation in the left dorsolateral prefrontal cortex (DLPFC) during working-memory manipulation and in the bilateral superior parietal lobule (SPL) during episodic-memory encoding and retrieval. A significant interaction effect between sex and PRS was seen in the bilateral SPL during episodic-memory encoding and retrieval, and sex-stratified analyses showed that the effect of PRS on SPL activation was male-specific. These results confirm previous findings of DLPFC inefficiency in schizophrenia, and highlight the SPL as another important genetic intermediate phenotype of the disease. The observed sex differences suggest that the previously shown male-specific effect of schizophrenia PRS on cognition translates into an additional corresponding effect on brain functioning.

Place, publisher, year, edition, pages
MDPI, 2022. Vol. 13, no 3, article id 412
Keywords [en]
memory processing, brain activity, fMRI, polygenic risk, schizophrenia, sex differences, dorsolateral prefrontal cortex, superior parietal lobule
National Category
Genetics and Genomics
Identifiers
URN: urn:nbn:se:umu:diva-192804DOI: 10.3390/genes13030412ISI: 000775272700001Scopus ID: 2-s2.0-85125670255OAI: oai:DiVA.org:umu-192804DiVA, id: diva2:1640941
Funder
Swedish Research Council, 2017-03011Swedish Research Council, 2017-03011Available from: 2022-02-28 Created: 2022-02-28 Last updated: 2025-02-07Bibliographically 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 and Genomics 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: 2025-02-10Bibliographically approved

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Koch, EliseNyberg, LarsLundquist, AndersKauppi, Karolina

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