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

International Schizophrenia Consortium, SGENE+ Consortium, Derek W Morris, Richard D Pearson, Paul Cormican, Elaine M Kenny, Colm T O'Dushlaine, Louis-Philippe Lemieux Perreault, Eleni Giannoulatou, Daniela Tropea, Brion S Maher, Brandon Wormley, Eric Kelleher, Ciara Fahey, Ines Molinos, Stefania Bellini, Matti Pirinen, Amy Strange, Colin Freeman, Dawn L Thiselton, Rachel L ElvesRegina Regan, Sean Ennis, Timothy G Dinan, Colm McDonald, Kieran C Murphy, Eadbhard O'Callaghan, John L Waddington, Dermot Walsh, Michael O'Donovan, Detelina Grozeva, Nick Craddock, Jennifer Stone, Ed Scolnick, Shaun Purcell, Pamela Sklar, Bradley Coe, Evan E Eichler, Roel Ophoff, Jacobine Buizer, Jin Szatkiewicz, Christina Hultman, Patrick Sullivan, Hugh Gurling, Andrew Mcquillin, David St Clair, Elliott Rees, George Kirov, James Walters, Douglas Blackwood, Mandy Johnstone, Gary Donohoe

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)3316-26
Number of pages11
JournalHuman Molecular Genetics
Issue number12
Publication statusPublished - 15 Jun 2014


  • Bipolar Disorder
  • Case-Control Studies
  • Chromosome Breakpoints
  • Chromosome Duplication
  • DNA Copy Number Variations
  • European Continental Ancestry Group
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Linkage Disequilibrium
  • Male
  • Nerve Tissue Proteins
  • Neuronal Plasticity
  • Psychotic Disorders
  • Schizophrenia
  • p21-Activated Kinases


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