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dc.contributor.authorLegge, Sophie Een_US
dc.contributor.authorHamshere, Marian Len_US
dc.contributor.authorRipke, Stephanen_US
dc.contributor.authorPardinas, Antonio Fen_US
dc.contributor.authorGoldstein, Jacqueline Ien_US
dc.contributor.authorRees, Elliotten_US
dc.contributor.authorRichards, Alexander Len_US
dc.contributor.authorLeonenko, Gannaen_US
dc.contributor.authorJorskog, L Fredriken_US
dc.contributor.authorChambert, Kimberly Den_US
dc.contributor.authorCollier, David Aen_US
dc.contributor.authorGenovese, Giulioen_US
dc.contributor.authorGiegling, Inaen_US
dc.contributor.authorHolmans, Peteren_US
dc.contributor.authorJonasdottir, Adalbjorgen_US
dc.contributor.authorKirov, Georgeen_US
dc.contributor.authorMcCarroll, Steven Aen_US
dc.contributor.authorMacCabe, James Hen_US
dc.contributor.authorMantripragada, Kiranen_US
dc.contributor.authorMoran, Jennifer Len_US
dc.contributor.authorNeale, Benjamin Men_US
dc.contributor.authorStefansson, Hreinnen_US
dc.contributor.authorRujescu, Danen_US
dc.contributor.authorDaly, Mark Jen_US
dc.contributor.authorSullivan, Patrick Fen_US
dc.contributor.authorOwen, Michael Jen_US
dc.contributor.authorO’Donovan, Michael Cen_US
dc.contributor.authorWalters, James T Ren_US
dc.date.accessioned2017-02-18T02:00:03Z
dc.date.issued2016en_US
dc.identifier.citationLegge, S. E., M. L. Hamshere, S. Ripke, A. F. Pardinas, J. I. Goldstein, E. Rees, A. L. Richards, et al. 2016. “Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia.” Molecular psychiatry :10.1038/mp.2016.97. doi:10.1038/mp.2016.97. http://dx.doi.org/10.1038/mp.2016.97.en
dc.identifier.issn1359-4184en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:30371166
dc.description.abstractThe antipsychotic clozapine is uniquely effective in the management of schizophrenia, but its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown although genetic factors play an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed HLA alleles, exome array, and copy number variation analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (OR=4.32, P=1.79×10-8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P = 0.015, positive predictive value = 35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.en
dc.language.isoen_USen
dc.relation.isversionofdoi:10.1038/mp.2016.97en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065090/pdf/en
dash.licenseLAAen_US
dc.subjectClozapineen
dc.subjectagranulocytosisen
dc.subjectneutropeniaen
dc.subjectadverse effectsen
dc.subjectHLA-DQB1en
dc.subjectSLCO1B3en
dc.subjectSLCO1B7en
dc.titleGenome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropeniaen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalMolecular psychiatryen
dash.depositing.authorRipke, Stephanen_US
dc.date.available2017-02-18T02:00:03Z
dc.identifier.doi10.1038/mp.2016.97*
dash.authorsorderedfalse
dash.contributor.affiliatedRipke, Stephan
dash.contributor.affiliatedMcCarroll, Steven
dash.contributor.affiliatedMoran, Jennifer
dash.contributor.affiliatedNeale, Benjamin
dash.contributor.affiliatedDaly, Mark


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