, 2011). However, the paucity of significant findings in very large samples of cases and controls suggests that the

contribution of common genetic variants to heritability of BD is limited. Alternative Ribociclib datasheet approaches that focus on rare genetic variants are needed. One genetic approach that has been used effectively to overcome some of the problems of heterogeneity is the genome-wide analysis of rare copy-number variants (CNVs). Studies from our group (McCarthy et al., 2009, Sebat et al., 2007, Vacic et al., 2011 and Walsh et al., 2008) and from multiple independent groups (International Schizophrenia Consortium, 2008, Pinto et al., 2010, Stefansson et al., 2008 and Xu et al., 2008) have now firmly established that rare CNVs contribute Selleckchem BGB324 to genetic risk for schizophrenia (SCZ) and autism spectrum disorder (ASD) and, in particular, that spontaneous (de novo) CNVs are important risk factors in the sporadic form of these disorders (Levy et al., 2011, Marshall et al., 2008, Sanders et al., 2011, Sebat et al., 2007 and Xu et al., 2008). Observations of a similar nature have been made in studies of BD. CNV loci at 16p11.2 (McCarthy et al., 2009) and 3q29 (Clayton-Smith et al., 2010, Mulle et al., 2010 and Quintero-Rivera et al., 2010) confer risk for multiple psychiatric disorders, and two studies have found preliminary evidence implicating both in BD (McCarthy et al., 2009 and Quintero-Rivera

et al., 2010). Two studies have demonstrated an enrichment of rare CNVs in patients with bipolar disorder (Priebe et al., 2011 and Zhang et al., 2009) as compared with healthy controls. In both studies, the greatest enrichment was observed in subjects with an earlier disease onset, defined as an age at onset (AAO) < 18 and < 21 in Zhang et al. (2009) and Priebe et al. (2011), respectively. However, two subsequent studies did not support these findings (Grozeva et al., 2010 and McQuillin et al., 2011). Thus, the role of copy-number variation in

conferring risk for bipolar disorder remains in question (Grozeva et al., 2010 and Zhang et al., 2009). 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., whatever 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).