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

Molecular Psychiatry volume 15, pages 1101–1111 (2010)Cite this article

Abstract

We 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 N=3580 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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Psychological Medicine, School of Medicine, Cardiff University, Henry Wellcome Building for Biomedical Research in Wales, Cardiff, UK

    L S Carroll, N M Williams, V Moskvina, E Russell, N Norton, H J Williams, T Peirce, L Georgieva, S Dwyer, D Grozeva, E Greene, P Holmans, I Jones, G Kirov, N Craddock, M C O'Donovan & M J Owen

  2. Department of Psychological Medicine, King's College London, Institute of Psychiatry, London, UK

    A Farmer & P McGuffin

  3. Neuropsychiatric Genetics Group, Institute of Molecular Medicine, Trinity College Dublin, St James Hospital, Dublin, Ireland

    D W Morris, A Corvin & M Gill

  4. Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany

    D Rujescu

  5. Department of Psychiatry and State Key Lab for Cognitive and Brain Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China

    P Sham

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  1. L S Carroll
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  2. N M Williams
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Correspondence to M C O'Donovan or M J Owen.

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Carroll, L., Williams, N., Moskvina, V. et al. Evidence for rare and common genetic risk variants for schizophrenia at protein kinase C, alpha. Mol Psychiatry 15, 1101–1111 (2010). https://doi.org/10.1038/mp.2009.96

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