Notably, inherited CNVs detected in this study included variants at loci that have been previously linked to schizophrenia (International Schizophrenia Consortium, 2008 and Stefansson et al., 2008), including a duplication at 1q21.1 in a subject with bipolar disorder

and a duplication and a deletion at 15q13.3 detected in subjects with bipolar disorder and schizophrenia, respectively (Document S2, bed file). Therefore, we examined the burden of rare inherited CNVs overlapping with genes in BD, SCZ, and controls, and subjects were stratified based on family history. We observed a trend of enrichment for large (≥500 Gemcitabine in vivo kb) inherited duplications in familial cases of bipolar disorder (OR = 1.77, p = 0.03, Table 3). We did not observe an enrichment of deletions in familial bipolar disorder. Likewise, we did not observe a significant enrichment of deletions or duplications in sporadic bipolar disorder or in schizophrenia (Table 3).

These results Protein Tyrosine Kinase inhibitor are consistent with a role for inherited CNVs in familial BD, particularly for large duplications; however, data from a much larger sample are needed to draw firm conclusions. We sought additional genetic evidence for the loci at which we found de novo CNVs by performing follow-up analyses of the 23 de novo CNV regions in additional cohorts and families. We performed an analysis of CNVs in SNP genotyping data from multiple case-control studies, including the Bipolar Genome Study (BiGS) and Molecular Genetics of Schizophrenia (MGS) study (see Supplemental Experimental Procedures). De novo CNV regions were tested for association with BD and SCZ using a permutation-based method described previously (Vacic et al., 2011) (see Supplemental Experimental Procedures). No significant associations

were detected in bipolar disorder (Table S6A). In schizophrenia, three genomic regions were significant (Table S6B), all corresponding to CNVs that have been previously implicated in schizophrenia at 3q29 (Mulle et al., 2010), 7q36.3 (Vacic et al., 2011), and 16p11.2 (McCarthy et al., 2009). Previous studies have reported that rare CNVs associated with neuropsychiatric many disorders are enriched for genes involved in neurodevelopment (Walsh et al., 2008 and Zhang et al., 2009). Here we examined whether genes impacted by de novo CNVs in SCZ and BD are enriched in specific functional categories. Pathway enrichment analysis was performed on the sets of genes overlapping with de novo CNVs in SCZ, BD, and controls (see Experimental Procedures). Enrichment of functional classes of genes was tested using the DAVID software (http://david.abcc.ncifcrf.gov/), followed by two additional permutation-based tests to correct for the known bias of CNVs toward large genes (Raychaudhuri et al., 2010), one implemented as a case-only analysis and a second implemented as a case-control analysis in PLINK (http://pngu.mgh.harvard.edu/∼purcell/plink/cnv.shtml#burden2).