The rarest CNVs are interesting because they are presumably enriched in de novo
events. Under a rare-variant hypothesis of common diseases, where multiple rare variants with high effect sizes would, in aggregate, make a substantial contribution to illness, these would be a prime type of variant to study because they have not yet been subject to selection. There have been several recent studies supporting a very rare-variants hypothesis for Schizophrenia and Autism.7
In the current data, singleton deletions showed a 1.31-fold increase in BD. 16.2% of BD cases possessed at least one singleton deletion, in contrast to 12.3% of controls. Singleton deletions were significantly enriched in BD individuals, unlike slightly more frequent rare CNVs (2–6 occurrences). These data suggest that the burden of very rare (occurring in under 1/2,000 individuals) de novo
deletions increases risk of BD.
Considering the sample size of the present study, our burden corresponds to the increased singleton and rare deletion (2–6 events) frequencies in Schizophrenia and autism reported in much larger samples in recent publications.8, 9, 11
It is interesting that we observe a marginally greater overall burden in BD with earlier age at onset of mania. Among these cases, 18.9% possessed at least one singleton deletion. In contrast, 14.7% of BD cases with older onset carried at least one singleton deletion. We would speculate that early-onset BD might be more severe and more likely to be caused by de novo mutations.
Genes disrupted by singleton deletion CNVs in our cases were significantly overrepresented in IPA for psychological disorders and learning behaviors, even though the pathways assembled in IPA may not form a one true biological pathway. One gene (GRM7
) was implicated in two prior BD GWAS studies.4, 6
Sixteen genes partially or wholly included in CNVs in the current study, including CNTNAP2
, are included in the IPA psychological disorders pathway. Genomic deletions of the CNTNAP2
locus in chromosome 7 were found in three patients with Schizophrenia.24
Catechol-O-methyltransferase regulates dopamine levels in the brain and has long been proposed to be involved in the development of Schizophrenia.25 GNB1L
is located in the chr22q11.2 susceptibility region for Schizophrenia, and may be associated BD.26
Two genes (GRM7, LARGE
) were also among the list of disrupted genes in the Walsh et al
There is evidence that BD and Schizophrenia share genetic susceptibility, and the current data suggest they share some rare CNV regions.
We have found suggestive evidence that individuals with BD have a greater burden than controls of singleton deletions across their genomes, which is even greater among patients with earlier onset of mania. Taken together, these singleton findings could account for an appreciable fraction of susceptibility to BD, since the excess frequency of singleton deletions in BD vs. controls is close to 4%.