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dc.contributor.authorToulopoulou, Timotheaen_US
dc.contributor.authorZhang, X.en_US
dc.contributor.authorCherny, S.en_US
dc.contributor.authorDickinson, D.en_US
dc.contributor.authorBerman, K. F.en_US
dc.contributor.authorStraub, R. E.en_US
dc.contributor.authorSham, P.en_US
dc.contributor.authorWeinberger, D. R.en_US
dc.date.accessioned2020-02-12T11:21:52Z
dc.date.available2020-02-12T11:21:52Z
dc.date.issued2019en_US
dc.identifier.issn0006-8950
dc.identifier.urihttp://hdl.handle.net/11693/53306
dc.description.abstractCognitive deficit is thought to represent, at least in part, genetic mechanisms of risk for schizophrenia, with recent evidence from statistical modelling of twin data suggesting direct causality from the former to the latter. However, earlier evidence was based on inferences from twin not molecular genetic data and it is unclear how much genetic influence ‘passes through’ cognition on the way to diagnosis. Thus, we included direct measurements of genetic risk (e.g. schizophrenia polygenic risk scores) in causation models to assess the extent to which cognitive deficit mediates some of the effect of polygenic risk scores on the disorder. Causal models of family data tested relationships among key variables and allowed parsing of genetic variance components. Polygenic risk scores were calculated from summary statistics from the current largest genome-wide association study of schizophrenia and were represented as a latent trait. Cognition was also modelled as a latent trait. Participants were 1313 members of 1078 families: 416 patients with schizophrenia, 290 unaffected siblings, and 607 controls. Modelling supported earlier findings that cognitive deficit has a putatively causal role in schizophrenia. In total, polygenic risk score explained 8.07% [confidence interval (CI) 5.45–10.74%] of schizophrenia risk in our sample. Of this, more than a third (2.71%, CI 2.41–3.85%) of the polygenic risk score influence was mediated through cognition paths, exceeding the direct influence of polygenic risk score on schizophrenia risk (1.43%, CI 0.46–3.08%). The remainder of the polygenic risk score influence (3.93%, CI 2.37–4.48%) reflected reciprocal causation between schizophrenia liability and cognition (e.g. mutual influences in a cyclical manner). Analysis of genetic variance components of schizophrenia liability indicated that 26.87% (CI 21.45–32.57%) was associated with cognition-related pathways not captured by polygenic risk score. The remaining variance in schizophrenia was through pathways other than cognition-related and polygenic risk score. Although our results are based on inference through statistical modelling and do not provide an absolute proof of causality, we find that cognition pathways mediate a significant part of the influence of cumulative genetic risk on schizophrenia. We estimate from our model that 33.51% (CI 27.34–43.82%) of overall genetic risk is mediated through influences on cognition, but this requires further studies and analyses as the genetics of schizophrenia becomes better characterized.en_US
dc.language.isoEnglishen_US
dc.source.titleBrainen_US
dc.relation.isversionofhttps://dx.doi.org/10.1093/brain/awy279en_US
dc.subjectSchizophreniaen_US
dc.subjectCognitionen_US
dc.subjectPolygenic risk scoresen_US
dc.subjectIntermediate phenotypesen_US
dc.subjectEndophenotypesen_US
dc.titlePolygenic risk score increases schizophrenia liability through cognition-relevant pathwaysen_US
dc.typeArticleen_US
dc.departmentDepartment of Psychologyen_US
dc.citation.spage471en_US
dc.citation.epage485en_US
dc.citation.volumeNumber142en_US
dc.citation.issueNumber2en_US
dc.identifier.doi10.1093/brain/awy279en_US
dc.publisherOxford University Pressen_US
dc.contributor.bilkentauthorToulopoulou, Timothea
dc.identifier.eissn1460-2156


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