We conclude that a small fraction of the heritability in schizophrenia can be found among intermediate sized de novo structural variants. The effect of de novo CNV on age at onset in bipolar disorder was nominally significant. These preliminary findings and similar results from previous studies (Priebe et al., 2011 and Zhang et al., 2009) suggest that individuals with an early onset of mania might constitute a subclass of bipolar disorder in which there is a greater contribution from rare alleles of large effect. Also consistent with this notion is a previous study (Grigoroiu-Serbanescu et al., 2001), which found that segregation of early-onset

BD in families was consistent with major gene effects, while familial segregation of late-onset BD was consistent with Selleck Venetoclax a multifactorial etiology. The observed rate of de novo CNVs in cases of bipolar disorder or schizophrenia with a positive family history of mental illness was similar to the rate Selleck Bortezomib in sporadic cases. These results contrast

with earlier findings by our group and others in autism (Marshall et al., 2008 and Sebat et al., 2007) and schizophrenia (Xu et al., 2008) documenting a higher rate of CNVs in sporadic cases as compared with subjects who have a positive family history. These early observations have not been universally replicated (Kirov et al., 2011 and Pinto et al., 2010). The reason for the inconsistency is not clear. Possibly, the initial findings were incorrect. Alternatively, variation in the observed effect could occur by chance or it could potentially be explained by methodological differences between cohorts in how mental illness in first-degree relatives Chlormezanone is ascertained. Pathway analysis

of genes impacted by de novo CNVs in SCZ lends support to independent findings from our group (Walsh et al., 2008) and others (Kirov et al., 2011) that rare CNVs in SCZ are enriched for genes that are related to synaptic function and other genes involved in neurodevelopment. By contrast, categories that were found to be enriched among de novo CNVs in BD were related to cell proliferation and shape and phospholipid metabolism (Table 5), the biological relevance of which is far from obvious. Greater knowledge of the specific genes involved in these disorders is needed to determine how these pathways might relate to the pathophysiology of disease. Our findings establish a contribution of rare CNVs and spontaneous mutation to risk for bipolar disorder. This can only be regarded as a starting point for studies of rare alleles in BD and SCZ. A larger fraction of the heritability must lie among different classes of alleles and will probably include rare and de novo point mutations and small insertions or deletions (indels).