Some of the earliest conclusive evidence for the role of rare CNVs in psychiatric disorders has come from family-based studies that examined the genomic burden of spontaneously occurring (de novo) CNVs (Marshall et al., 2008, Sebat et al., 2007 and Xu et al., 2008). De novo CNVs have consistently shown the strongest association with risk for autism (Itsara et al., 2010, Levy et al., 2011, Pinto et al., 2010 and Sanders et al., 2011) or schizophrenia (Xu et al., 2008), with a 5- to 10-fold enrichment in patients as compared with controls. We reasoned that if rare highly penetrant CNVs contribute to risk for bipolar disorder, the genetic effect would be most evident for de novo mutations. We further reasoned that the contribution of de novo CNVs to risk of bipolar disorder would be greatest in patients with an earlier disease onset (AAO ≤ 18). We screened for de novo CNVs ≥ 10 kb in size in blood-derived DNAs from 788 subject-mother-father trios including subjects with diagnoses of bipolar disorder and schizophrenia, and normal healthy controls. Here, we show that rare de novo copy-number mutations are significantly enriched in bipolar disorder and in schizophrenia.
