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Article: Polygenic risk score increases schizophrenia liability through cognition-relevant pathways

TitlePolygenic risk score increases schizophrenia liability through cognition-relevant pathways
Authors
Keywordsschizophrenia
cognition
polygenic risk scores
intermediate phenotypes
endophenotypes
Issue Date2019
PublisherOxford University Press. The Journal's web site is located at http://brain.oxfordjournals.org/
Citation
Brain, 2019, v. 142 n. 2, p. 471-485 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/274015
ISSN
2019 Impact Factor: 11.337
2015 SCImago Journal Rankings: 6.097
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorToulopoulou, T-
dc.contributor.authorZhang, X-
dc.contributor.authorCherny, SS-
dc.contributor.authorDickinson, D-
dc.contributor.authorBerman, KF-
dc.contributor.authorStraub, RE-
dc.contributor.authorSham, PC-
dc.contributor.authorWeinberger, DR-
dc.date.accessioned2019-08-18T14:53:19Z-
dc.date.available2019-08-18T14:53:19Z-
dc.date.issued2019-
dc.identifier.citationBrain, 2019, v. 142 n. 2, p. 471-485-
dc.identifier.issn0006-8950-
dc.identifier.urihttp://hdl.handle.net/10722/274015-
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.-
dc.languageeng-
dc.publisherOxford University Press. The Journal's web site is located at http://brain.oxfordjournals.org/-
dc.relation.ispartofBrain-
dc.rightsPre-print: Journal Title] ©: [year] [owner as specified on the article] Published by Oxford University Press [on behalf of xxxxxx]. All rights reserved. Pre-print (Once an article is published, preprint notice should be amended to): This is an electronic version of an article published in [include the complete citation information for the final version of the Article as published in the print edition of the Journal.] Post-print: This is a pre-copy-editing, author-produced PDF of an article accepted for publication in [insert journal title] following peer review. The definitive publisher-authenticated version [insert complete citation information here] is available online at: xxxxxxx [insert URL that the author will receive upon publication here].-
dc.subjectschizophrenia-
dc.subjectcognition-
dc.subjectpolygenic risk scores-
dc.subjectintermediate phenotypes-
dc.subjectendophenotypes-
dc.titlePolygenic risk score increases schizophrenia liability through cognition-relevant pathways-
dc.typeArticle-
dc.identifier.emailToulopoulou, T: timothea@hku.hk-
dc.identifier.emailCherny, SS: cherny@hku.hk-
dc.identifier.emailSham, PC: pcsham@hku.hk-
dc.identifier.authorityToulopoulou, T=rp01542-
dc.identifier.authorityCherny, SS=rp00232-
dc.identifier.authoritySham, PC=rp00459-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1093/brain/awy279-
dc.identifier.pmid30535067-
dc.identifier.scopuseid_2-s2.0-85060790821-
dc.identifier.hkuros300992-
dc.identifier.volume142-
dc.identifier.issue2-
dc.identifier.spage471-
dc.identifier.epage485-
dc.identifier.isiWOS:000462616700027-
dc.publisher.placeUnited Kingdom-

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