The genetics of developmental disorders like bipolar disorder and schizophrenia are complex, and an overlap in the genetic factors contributing to these two disorders has been found. While common variants are typically associated with small effect sizes, individually rare variants in particular copy number variants (CNVs), i.e., deletions or duplications of genomic segments, have been associated with large effect sizes, even up to an odds ratio of 63. Potentially, the relatively large effect size of CNVs could result from severa genes in the CNVs contributing to the phenotypic changes, potentially in converging pathways. We have used chromosome engineering techniques (gene targeting and cre-loxP-mediated trans-allelic recombination in vivo) to develop mice modeling a 9p24.1 duplication/triplication found in a family affected by bipolar disorder and schizoaffective disorder. As overlapping deletions have been found in other families affected by schizophrenia, we propose to study mice with 1 (deletion), 2 (wt), 3 (duplication) and 4 (triplication) copies of the 15 9p24.1 genes (collectively called 9p24.1 CNV mice). The basic hypothesis is that changes in 9p24.1 copy number, in particular increases, are sufficient to elicit phenotypic changes reminiscent of major neuropsychiatric disorders. The CNV region includes GLDC, UHRF2 and the micro RNA miR-4665. GLDC is a """"""""smoking gun"""""""". Increased expression of GLDC could result in increased degradation of glycine, a co-agonist at the NMDA receptor. NMDA receptor hypofunction has been shown to result in schizophrenia-related phenotypes in mice. We will investigate the level of glycine and D-serine, another co-agonist at the NMDA receptor at the same site, and schizophrenia-like behavior in the 9p24.1 CNV mice to test the hypothesis that duplication or triplication of GLDC may contribute to neuropsychiatric phenotypes. UHRF2, which is expressed in hippocampus and subcortical plate, encodes an ubiquitine modifier (SUMO) E3 ligase which is an important mediator of E2F1-mediated apoptosis. As increased expression of apoptotic genes has been found in bipolar disorder, an increase in UHRF2 copy number could result in increased apoptosis. miR-4665, specifically miR-4665-5p is poorly characterized so far, but has computationally predicted target genes (MECP2, ANK3, PAX5) that have been linked to neurodevelopmental disorders: MECP2 to Rett Syndrome, and ANK3 and PAX5 actually to bipolar disorder. By monitoring changes in gene expression globally, we will examine whether changes in 9p24.1 copy number will lead to changes in the expression of genes outside of this region which may be mediated by miR-4665-5p. In summary, we propose to determine copy number effects in the 9p24.1 region with specific hypotheses concerning how they may contribute to neuropsychiatric-related phenotypes. The studies form the basis for even more targeted interrogation of the role of individual genetic factors in the 9p24.1 region in the development and expression of major neuropsychiatric disorders.
Copy number variations (CNVs), i.e. structural genomic duplications and deletions have been found to be associated with neuropsychiatric disorders such as bipolar disorder and schizophrenia;however, the neurobiological mechanisms underlying this connection are only poorly understood. We have generated mice carrying a deletion and duplication, respectively, in the 9p24.1 (human) chromosomal region;patients with this duplication are studied by another investigator at McLean Hospital. We expect that the proposed molecular, morphological and behavioral characterization of 9p24.1 CNV mice provides clues as to the neurobiological mechanisms underlying genetic risk and thus leading to the development of disease, and also for the development of novel therapeutic strategies.