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Hum Mol Genet. 2014 Jun 15;23(12):3316-26. doi: 10.1093/hmg/ddu025. Epub 2014 Jan 28.

An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis.

Author information

  • 1Department of Psychiatry and Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
  • 2Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
  • 3Broad Institute and Center for Human Genetics Research of Massachusetts General Hospital, Boston, MA 02142, USA.
  • 4Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK Montreal Heart Institute, Université de Montréal, Montréal, Québec H1T 1C8, Canada.
  • 5Departments of Psychiatry and Human Genetics, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23284, USA.
  • 6School of Medicine and Medical Science, University College Dublin, Ireland.
  • 7Department of Psychiatry, University College Cork, Cork, Ireland.
  • 8Department of Psychiatry, National University of Ireland, Galway, University Road, Galway, Ireland.
  • 9Department of Psychiatry, RCSI Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
  • 10DETECT Early Intervention in Psychosis Services, Dun Laoghaire, Co. Dublin, Ireland.
  • 11Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
  • 12Health Research Board, 73 Lower Baggot St, Dublin 2, Ireland.
  • 13MRC Centre for Neuropsychiatric Genetics and Genomics, and Neuroscience and Mental Health Research Institute, Cardiff University, Heath Park, Cardiff CF4 4XN, UK.
  • 14Broad Institute and Center for Human Genetics Research of Massachusetts General Hospital, Boston, MA 02142, USA The Mount Sinai Hospital, New York, NY 10029, USA.
  • 15University of Washington School of Medicine, Howard Hughes Medical Institute, Seattle, WA 98195, USA.
  • 16Department of Human Genetics, UCLA School of Medicine, Los Angeles, CA 90095, USA.
  • 17Rudolf Magnus Institute, University of Utrecht, 3584 CG Utrecht, Netherlands.
  • 18University of North Carolina, Chapel Hill, NC 27599-7264, USA.
  • 19Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
  • 20Molecular Psychiatry Laboratory, Mental Health Sciences Unit, University College London, London WC1E 6BT, UK.
  • 21Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
  • 22Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK and.
  • 23Department of Psychiatry, Queen's University, Belfast BT7 1NN, Northern Ireland.
  • 24Department of Psychiatry and Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland acorvin@tcd.ie.

Abstract

Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls. We found association with duplications at chr20p12.2 (P = 0.007) and evidence of replication in large independent European schizophrenia (P = 0.052) and UK bipolar disorder case-control cohorts (P = 0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11 707 cases and 10 carriers in 21 204 controls [meta-analysis Cochran-Mantel-Haenszel P-value = 2 × 10(-4); odds ratio (OR) = 11.3, 95% CI = 3.7, ∞]. Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68 Mb with similar breakpoints across samples. By haplotype analysis and sequencing, we identified a tandem ~149 kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P = 2.5 × 10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.

© The Author 2014. Published by Oxford University Press.

PMID:
24474471
[PubMed - in process]
PMCID:
PMC4030770
Free PMC Article

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