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Polygenic Risk for Schizophrenia Has Sex-Specific Effects on Brain Activity during Memory Processing in Healthy Individuals
Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI).ORCID-id: 0000-0003-3727-4470
Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi.ORCID-id: 0000-0002-3367-1746
Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.ORCID-id: 0000-0003-1524-0851
Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Solna, Sweden.ORCID-id: 0000-0003-4908-341X
2022 (engelsk)Inngår i: Genes, E-ISSN 2073-4425, Vol. 13, nr 3, artikkel-id 412Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
MDPI, 2022. Vol. 13, nr 3, artikkel-id 412
Emneord [en]
memory processing, brain activity, fMRI, polygenic risk, schizophrenia, sex differences, dorsolateral prefrontal cortex, superior parietal lobule
HSV kategori
Identifikatorer
URN: urn:nbn:se:umu:diva-192804DOI: 10.3390/genes13030412ISI: 000775272700001Scopus ID: 2-s2.0-85125670255OAI: oai:DiVA.org:umu-192804DiVA, id: diva2:1640941
Forskningsfinansiär
Swedish Research Council, 2017-03011Swedish Research Council, 2017-03011Tilgjengelig fra: 2022-02-28 Laget: 2022-02-28 Sist oppdatert: 2025-02-07bibliografisk kontrollert
Inngår i avhandling
1. The genetics of schizophrenia: sex, drugs, and cognition
Åpne denne publikasjonen i ny fane eller vindu >>The genetics of schizophrenia: sex, drugs, and cognition
2022 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Alternativ tittel[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.

sted, utgiver, år, opplag, sider
Umeå: Umeå universitet, 2022. s. 65
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2185
Emneord
schizophrenia, genetics, cognition, sex differences, polygenic risk, fMRI, network medicine, drug repurposing, precision medicine
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-193660 (URN)978-91-7855-755-4 (ISBN)978-91-7855-756-1 (ISBN)
Disputas
2022-05-06, KBE303, stora hörsalen, KBC-huset, Umeå, 13:00 (engelsk)
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Tilgjengelig fra: 2022-04-14 Laget: 2022-04-10 Sist oppdatert: 2025-02-10bibliografisk kontrollert

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