Identifying rare, highly penetrant risk mutationsmay be an important step in dissectingthe 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 Consortium2 (WTCCC2)schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls.Wefound association with duplications at chr20p12.2 (P = 0.007) and evidence of replication in large independent European schizophrenia (P 5 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 5 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 singleancestral duplication event.Weconfirmedthe breakpoints in 8/8carriers testedandfound co-segregation of the duplication with illness in two additional familymembers of one of the affectedprobands.Wedemonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.
Funding for this study was provided by the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z), the Wellcome Trust (072894/Z/03/Z, 090532/Z/09/Z and 075491/Z/04/B), NIMH grants (MH 41953 and MH083094) and Science Foundation Ireland (08/IN.1/B1916). We acknowledge use of the Trinity Biobank sample from the Irish Blood Transfusion Service; the Trinity Centre for High Performance Computing; British 1958 Birth Cohort DNA collection funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02) and of the UK National Blood Service controls funded by the Wellcome Trust. Chris Spencer is supported by a Wellcome Trust Career Development Fellowship (097364/Z/11/Z). Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust.
The authors sincerely thank all patients who contributed to this study and all staff who facilitated their involvement. We thank W. Bodmer and B. Winney for use of the People of the British Isles DNA collection, which was funded by the Wellcome Trust. We thank Akira Sawa and Koko Ishzuki for advice on the PAK7–DISC1 interaction experiment and Jan Korbel for discussions on mechanism of structural variation.