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). Indeed, preliminary studies of a small number of families have found evidence that the exomic burden of de novo point mutations is increased in schizophrenia (Girard et al., 2011 and Xu et al., 2011). While the degree of enrichment of exonic point mutations in schizophrenia (0.73/exome in cases as compared with 0.32/exome in controls in the combined sample) is modest compared to the effect size for de novo CNVs, these results are nevertheless intriguing. It is conceivable that the overall contribution of de novo CNVs and point mutations to disease risk could be substantial. High-throughput sequencing in a much larger number of trios will be needed to determine the total contribution of de novo mutation to risk for BD and SCZ in the population.
