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

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.

Dendritic spine alterations in schizophrenia

“…Finally, Rubio et al noted that chronic exposure to haloperidol in rats did not recapitulate any of the observed changes in protein levels [71]. These findings provide support for the hypothesis that signaling to the actin cytoskeleton may be altered in schizophrenia, an interpretation further supported by genetic evidence that copy number variations affecting the PAK1 paralogues, PAK2 [73] and PAK7 [74], are associated with schizophrenia risk. Similarly a recent report identified a rare coding variant in the KALRN gene, located in the catalytic domain of kalirin-7, in a schizophrenia patient and his sibling with major depressive disorder.…”

Structure, biochemistry, and biology of PAK kinases

“…Studies from Pak5- knockout mice show PAK5 has roles in mobility, learning, and memory related functions (Nekrasova et al, 2008; Furnari et al, 2013). In addition, PAK5 is also believed to be involved in synaptic plasticity because of its coexpression with a psychosis risk gene DISC1 (Morris et al, 2014). Neuronal function of PAK5 may be associated with its ability to phosphorylate two critical regulators of synaptic vesicle trafficking, the Pacsin-1 and Synaptojanin-1 (Strochlic et al, 2012).…”

Contribution of common and rare variants to bipolar disorder susceptibility in extended pedigrees from population isolates

“…It has one damaging missense rare SNV that is very rare in the Latino population of ExAC, but has a relatively high MAF in one of our pedigrees, with the rare allele occurring at about 170X increased frequency compared to reference samples. A previous CNV analysis using WTCCC2 SCZ data found an association between the large duplication around ACTR1B and SCZ, but it was not replicated(46). GOLPH3 is the top gene from the CNV segregation analysis, which contains one rare and relatively small deletion appearing only in one family.…”