Type

Journal Article

Authors

Aiden Corvin
Chris C A Spencer
Brien P Riley
Michael Gill
Kenneth S Kendler
Francis A O'Neill
Gary Donohoe
Mandy Johnstone
Douglas Blackwood
James Walters
and 46 others

Subjects

Psychiatry

Topics
odds ratio genes society meta analysis gene duplication p21 linkage disequilibrium neuroscience family members bipolar disorder psychosis risk factor protein kinase

An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis. (2014)

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 (>100kb), rare copy number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1,564 cases and 1,748 controls all from Ireland, and further extended the analysis to include an additional 5,196 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 CMH P value=2x10(-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 9.68Mb with similar breakpoints across samples. By haplotype analysis and sequencing we identified a tandem ∼149kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P=2.5x10(-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.
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Full list of authors on original publication

Aiden Corvin, Chris C A Spencer, Brien P Riley, Michael Gill, Kenneth S Kendler, Francis A O'Neill, Gary Donohoe, Mandy Johnstone, Douglas Blackwood, James Walters and 46 others

Experts in our system

1
Aiden Corvin
Trinity College Dublin
Total Publications: 190
 
2
Michael Gill
Trinity College Dublin
Total Publications: 260
 
3
Gary Donohoe
Trinity College Dublin
Total Publications: 130
 
4
James T R Walters
Royal College of Surgeons in Ireland
Total Publications: 9