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Cognitive characterization of schizophrenia risk variants involved in synaptic transmission: evidence of CACNA1C's role in working memory

Cosgrove, Donna, Mothersill, Omar, Kendall, Kimberley ORCID:, Konte, Bettina, Harold, Denise ORCID:, Giegling, Ina, Hartmann, Annette, Richards, Alexander, Mantripragada, Kiran ORCID:, Owen, Michael J. ORCID:, O'Donovan, Michael C. ORCID:, Gill, Michael, Rujescu, Dan, Walters, James ORCID:, Corvin, Aiden, Morris, Derek W. and Donohoe, Gary 2017. Cognitive characterization of schizophrenia risk variants involved in synaptic transmission: evidence of CACNA1C's role in working memory. Neuropsychopharmacology 42 , pp. 2612-2622. 10.1038/npp.2017.123

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With >100 common variants associated with schizophrenia risk, establishing their biological significance is a priority. We sought to establish cognitive effects of risk variants at loci implicated in synaptic transmission by (1) identifying GWAS schizophrenia variants whose associated gene function is related to synaptic transmission, and (2) testing for association between these and measures of neurocognitive function. We selected variants, reported in the largest GWAS to date, associated with genes involved in synaptic transmission. Associations between genotype and cognitive test score were analyzed in a discovery sample (988 Irish participants, including 798 with psychosis), and replication samples (528 UK patients with schizophrenia/schizoaffective disorder; 921 German participants including 362 patients with schizophrenia). Three loci showed significant associations with neuropsychological performance in the discovery samples. This included an association between the rs2007044 (risk allele G) within CACNA1C and poorer working memory performance (increased errors B (95% CI)=0.635–4.535, p=0.012), an effect driven mainly by the psychosis groups. In an fMRI analysis of working memory performance (n=84 healthy participants, a subset of the discovery sample), we further found evidence that the same CACNA1C allele was associated with decreased functional connectivity between the right dorsolateral prefrontal cortex and right superior occipital gyrus/cuneus and anterior cingulate cortex. In conclusion, these data provide evidence to suggest that the CACNA1C risk variant rs2007044 is associated with poorer memory function that may result from risk carriers’ difficulty with top-down initiated responses caused by dysconnectivity between the right DLPFC and several cortical regions.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Neuroscience and Mental Health Research Institute (NMHRI)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Springer Nature
ISSN: 0893-133X
Date of First Compliant Deposit: 4 October 2017
Date of Acceptance: 19 May 2017
Last Modified: 13 Nov 2023 17:11

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