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

Hum Mol Genet

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.

Year of Publication
Hum Mol Genet
Date Published
2014 Jun 15
PubMed ID
PubMed Central ID
Grant list
090532/Z/09/Z / Wellcome Trust / United Kingdom
G1000708 / Medical Research Council / United Kingdom
MH083094 / MH / NIMH NIH HHS / United States
075491/Z/04/B / Wellcome Trust / United Kingdom
G0601635 / Medical Research Council / United Kingdom
MH 41953 / MH / NIMH NIH HHS / United States
090532 / Wellcome Trust / United Kingdom
085475/B/08/Z / Wellcome Trust / United Kingdom
R01 MH083094 / MH / NIMH NIH HHS / United States
068545/Z/02 / Wellcome Trust / United Kingdom
097364/Z/11/Z / Wellcome Trust / United Kingdom
MR/L010305/1 / Medical Research Council / United Kingdom
G0800509 / Medical Research Council / United Kingdom
G0000934 / Medical Research Council / United Kingdom
085475/Z/08/Z / Wellcome Trust / United Kingdom
072894/Z/03/Z / Wellcome Trust / United Kingdom