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Article: Evidence for rare and common genetic risk variants for schizophrenia at protein kinase C, alpha

TitleEvidence for rare and common genetic risk variants for schizophrenia at protein kinase C, alpha
Authors
Keywordsassociation
bipolar disorder
gene
PRKCA
schizoaffective disorder
schizophrenia
Issue Date2010
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/mp
Citation
Molecular Psychiatry, 2010, v. 15 n. 11, p. 1101-1111 How to Cite?
AbstractWe earlier reported a genome-wide significant linkage to schizophrenia at chromosome 17 that was identified in a single pedigree (C702) consisting of six affected, male siblings with DSM-IV schizophrenia and prominent mood symptoms. In this study, we adopted several approaches in an attempt to map the putative disease locus. First, mapping the source of linkage to chromosome 17 in pedigree C702. We refined the linkage region in family C702 to a 21-marker segment spanning 11.7 Mb at 17q23-q24 by genotyping a total of 50 microsatellites across chromosome 17 in the pedigree. Analysis of data from 1028 single nucleotide polymorphisms (SNPs) across the refined linkage region identified a single region of homozygosity present in pedigree C702 but not in 2938 UK controls. This spanned 432 kb of the gene encoding protein kinase C, alpha (PRKCA), the encoded protein of which has been implicated in the pathogenesis of psychiatric disorders. Analysis of pedigree C702 by oligonucleotide-array comparative genome hybridization excluded the possibility that this region of homozygosity was because of a deletion. Mutation screening of PRKCA identified a rare, four-marker haplotype (C-HAP) in the 3′ untranslated region of the gene, which was present in the homozygous state in all six affected members of pedigree C702. No other homozygotes were observed in genotype data for a total of 6597 unrelated Europeans (case N=1755, control N3580 and parents of probands N=1262). Second, association analysis of C702 alleles at PRKCA. The low-frequency haplotype (C-HAP) showed a trend for association in a study of unrelated schizophrenia cases and controls from the UK (661 cases, 2824 controls, P=0.078 and odd ratio (OR)=1.9) and significant evidence for association when the sample was expanded to include cases with bipolar (N=710) and schizoaffective disorder (N=50) (psychosis sample: 1421 cases, 2824 controls, P=0.037 and OR=1.9). Given that all the affected members of C702 are male, we also undertook sex-specific analyses. This revealed that the association was strongest in males for both schizophrenia (446 male cases, 1421 male controls, P=0.008 and OR=3.9) and in the broader psychosis group (730 male cases, 1421 male controls, P=0.008 and OR=3.6). Analysis of C-HAP in follow-up samples from Ireland and Bulgaria revealed no evidence for association in either the whole sample or in males alone, and meta-analysis of all male psychosis samples yielded no significant evidence of association (969 male cases, 1939 male controls, 311 male probands P=0.304 and OR=1.4). Third, association mapping of the pedigree C702 linkage region. Independent of pedigree C702, genotype data from the Affymetrix 500k GeneChip set were available for 476 patients with schizophrenia and 2938 controls from the United Kingdom. SNPs in PRKCA showed evidence for association with schizophrenia that achieved gene-wide significance (P=0.027). Moreover, the same SNP was the most significantly associated marker out of the 1028 SNPs genotyped across the linkage region (rs873417, allelic P=0.0004). Follow-up genotyping in samples from Ireland, Bulgaria and Germany did not show consistent replication, but meta-analysis of all samples (4116 cases and 6491 controls) remained nominally significant (meta-analysis P=0.026, OR=1.1). We conclude that, although we have obtained convergent lines of evidence implicating both rare and common schizophrenia risk variants at PRKCA, none of these is individually compelling. However, the evidence across all approaches suggests that further study of this locus is warranted. © 2010 Macmillan Publishers Limited All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/137507
ISSN
2015 Impact Factor: 13.314
2015 SCImago Journal Rankings: 6.790
ISI Accession Number ID
Funding AgencyGrant Number
Wellcome Trust076113
MRC
NIMH (USA)CONTE: 2 P50MH066392-05A1
Science Foundation Ireland
Health Research Board (Ireland)
Funding Information:

This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. The UK research was supported by grants from the MRC, the Wellcome Trust and by a NIMH (USA) CONTE: 2 P50MH066392-05A1. In Dublin, the research was supported by Science Foundation Ireland, the Health Research Board (Ireland), and the Wellcome Trust. We are grateful to Professor John Waddington for sample recruitment. Irish controls were supplied by Dr Joe McPartlin and the Trinity College Biobank. We also thank the Department of Psychiatry, LMU Munich for clinical characterization of the Munich subjects and the processing of the samples. Recruitment in Munich was partially supported by GlaxoSmithKline.

References

 

DC FieldValueLanguage
dc.contributor.authorCarroll, LSen_HK
dc.contributor.authorWilliams, NMen_HK
dc.contributor.authorMoskvina, Ven_HK
dc.contributor.authorRussell, Een_HK
dc.contributor.authorNorton, Nen_HK
dc.contributor.authorWilliams, HJen_HK
dc.contributor.authorPeirce, Ten_HK
dc.contributor.authorGeorgieva, Len_HK
dc.contributor.authorDwyer, Sen_HK
dc.contributor.authorGrozeva, Den_HK
dc.contributor.authorGreene, Een_HK
dc.contributor.authorFarmer, Aen_HK
dc.contributor.authorMcGuffin, Pen_HK
dc.contributor.authorMorris, DWen_HK
dc.contributor.authorCorvin, Aen_HK
dc.contributor.authorGill, Men_HK
dc.contributor.authorRujescu, Den_HK
dc.contributor.authorSham, Pen_HK
dc.contributor.authorHolmans, Pen_HK
dc.contributor.authorJones, Ien_HK
dc.contributor.authorKirov, Gen_HK
dc.contributor.authorCraddock, Nen_HK
dc.contributor.authorO'Donovan, MCen_HK
dc.contributor.authorOwen, MJen_HK
dc.date.accessioned2011-08-26T14:26:47Z-
dc.date.available2011-08-26T14:26:47Z-
dc.date.issued2010en_HK
dc.identifier.citationMolecular Psychiatry, 2010, v. 15 n. 11, p. 1101-1111en_HK
dc.identifier.issn1359-4184en_HK
dc.identifier.urihttp://hdl.handle.net/10722/137507-
dc.description.abstractWe earlier reported a genome-wide significant linkage to schizophrenia at chromosome 17 that was identified in a single pedigree (C702) consisting of six affected, male siblings with DSM-IV schizophrenia and prominent mood symptoms. In this study, we adopted several approaches in an attempt to map the putative disease locus. First, mapping the source of linkage to chromosome 17 in pedigree C702. We refined the linkage region in family C702 to a 21-marker segment spanning 11.7 Mb at 17q23-q24 by genotyping a total of 50 microsatellites across chromosome 17 in the pedigree. Analysis of data from 1028 single nucleotide polymorphisms (SNPs) across the refined linkage region identified a single region of homozygosity present in pedigree C702 but not in 2938 UK controls. This spanned 432 kb of the gene encoding protein kinase C, alpha (PRKCA), the encoded protein of which has been implicated in the pathogenesis of psychiatric disorders. Analysis of pedigree C702 by oligonucleotide-array comparative genome hybridization excluded the possibility that this region of homozygosity was because of a deletion. Mutation screening of PRKCA identified a rare, four-marker haplotype (C-HAP) in the 3′ untranslated region of the gene, which was present in the homozygous state in all six affected members of pedigree C702. No other homozygotes were observed in genotype data for a total of 6597 unrelated Europeans (case N=1755, control N3580 and parents of probands N=1262). Second, association analysis of C702 alleles at PRKCA. The low-frequency haplotype (C-HAP) showed a trend for association in a study of unrelated schizophrenia cases and controls from the UK (661 cases, 2824 controls, P=0.078 and odd ratio (OR)=1.9) and significant evidence for association when the sample was expanded to include cases with bipolar (N=710) and schizoaffective disorder (N=50) (psychosis sample: 1421 cases, 2824 controls, P=0.037 and OR=1.9). Given that all the affected members of C702 are male, we also undertook sex-specific analyses. This revealed that the association was strongest in males for both schizophrenia (446 male cases, 1421 male controls, P=0.008 and OR=3.9) and in the broader psychosis group (730 male cases, 1421 male controls, P=0.008 and OR=3.6). Analysis of C-HAP in follow-up samples from Ireland and Bulgaria revealed no evidence for association in either the whole sample or in males alone, and meta-analysis of all male psychosis samples yielded no significant evidence of association (969 male cases, 1939 male controls, 311 male probands P=0.304 and OR=1.4). Third, association mapping of the pedigree C702 linkage region. Independent of pedigree C702, genotype data from the Affymetrix 500k GeneChip set were available for 476 patients with schizophrenia and 2938 controls from the United Kingdom. SNPs in PRKCA showed evidence for association with schizophrenia that achieved gene-wide significance (P=0.027). Moreover, the same SNP was the most significantly associated marker out of the 1028 SNPs genotyped across the linkage region (rs873417, allelic P=0.0004). Follow-up genotyping in samples from Ireland, Bulgaria and Germany did not show consistent replication, but meta-analysis of all samples (4116 cases and 6491 controls) remained nominally significant (meta-analysis P=0.026, OR=1.1). We conclude that, although we have obtained convergent lines of evidence implicating both rare and common schizophrenia risk variants at PRKCA, none of these is individually compelling. However, the evidence across all approaches suggests that further study of this locus is warranted. © 2010 Macmillan Publishers Limited All rights reserved.en_HK
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/mpen_HK
dc.relation.ispartofMolecular Psychiatryen_HK
dc.subjectassociationen_HK
dc.subjectbipolar disorderen_HK
dc.subjectgeneen_HK
dc.subjectPRKCAen_HK
dc.subjectschizoaffective disorderen_HK
dc.subjectschizophreniaen_HK
dc.subject.meshChromosomes, Human, Pair 17-
dc.subject.meshGenetic Predisposition to Disease-
dc.subject.meshPolymorphism, Single Nucleotide-
dc.subject.meshProtein Kinase C-alpha - genetics-
dc.subject.meshSchizophrenia - genetics-
dc.titleEvidence for rare and common genetic risk variants for schizophrenia at protein kinase C, alphaen_HK
dc.typeArticleen_HK
dc.identifier.emailSham, P: pcsham@hku.hken_HK
dc.identifier.authoritySham, P=rp00459en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/mp.2009.96en_HK
dc.identifier.pmid19786960-
dc.identifier.scopuseid_2-s2.0-77958479353en_HK
dc.identifier.hkuros189610en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77958479353&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume15en_HK
dc.identifier.issue11en_HK
dc.identifier.spage1101en_HK
dc.identifier.epage1111en_HK
dc.identifier.isiWOS:000283352400006-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridCarroll, LS=23468385900en_HK
dc.identifier.scopusauthoridWilliams, NM=7402772034en_HK
dc.identifier.scopusauthoridMoskvina, V=8308180800en_HK
dc.identifier.scopusauthoridRussell, E=26322043600en_HK
dc.identifier.scopusauthoridNorton, N=7005873516en_HK
dc.identifier.scopusauthoridWilliams, HJ=35380179700en_HK
dc.identifier.scopusauthoridPeirce, T=10839900900en_HK
dc.identifier.scopusauthoridGeorgieva, L=6701324738en_HK
dc.identifier.scopusauthoridDwyer, S=8977601500en_HK
dc.identifier.scopusauthoridGrozeva, D=8609308100en_HK
dc.identifier.scopusauthoridGreene, E=35820730600en_HK
dc.identifier.scopusauthoridFarmer, A=7102158824en_HK
dc.identifier.scopusauthoridMcGuffin, P=22954119700en_HK
dc.identifier.scopusauthoridMorris, DW=7403952214en_HK
dc.identifier.scopusauthoridCorvin, A=6602146368en_HK
dc.identifier.scopusauthoridGill, M=35228962600en_HK
dc.identifier.scopusauthoridRujescu, D=6701768114en_HK
dc.identifier.scopusauthoridSham, P=34573429300en_HK
dc.identifier.scopusauthoridHolmans, P=7004028945en_HK
dc.identifier.scopusauthoridJones, I=19134614500en_HK
dc.identifier.scopusauthoridKirov, G=26643478800en_HK
dc.identifier.scopusauthoridCraddock, N=35352014300en_HK
dc.identifier.scopusauthoridO'Donovan, MC=7103147367en_HK
dc.identifier.scopusauthoridOwen, MJ=36044041500en_HK
dc.identifier.citeulike5868898-

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