In some instances, reciprocal CNVs (i.e. deletion and duplications at the same locus) appear to have different phenotypic effects. For example, deletions and duplications at 16p11.2 are associated with obesity and low body mass index, respectively [ 37]. In schizophrenia, duplications at 22q11.2 are significantly less common than they are in controls, whereas the deletion of this locus is one of its strongest risk factors [ 38]. The CNVs in Figure 2 are considered to have fairly

high, but incomplete, penetrance for schizophrenia and for other neurodevelopmental disorders, most having lower penetrance for schizophrenia than the other disorders [28•]. However, the incomplete penetrance of these CNVs has recently been questioned in a large study which showed the level of cognitive performance in non-affected carriers find more of schizophrenia-associated CNVs to be in-between that observed in schizophrenia patients and population controls [39•]. Over the past few years, several publications have used new sequencing technology to investigate rare inherited (as opposed to de novo) alleles in schizophrenia. Intriguing findings have been reported from some studies [ 40 and 41], although their results

largely remain inconclusive owing to small sample size. Only one schizophrenia study till date has employed exome sequencing in large samples (2536 cases and 2543 controls) [ 42••]. No single rare allele (MAF < 0.1%) was associated at genome-wide levels of significance, and overall, the exome-wide burden of rare variation was not increased in cases. However, a significantly increased burden VX-765 of rare, disruptive alleles was observed in a set of 2546 genes selected for a higher probability of

being associated with schizophrenia. This burden was distributed across a large number of genes. As in the de novo CNV and SNV studies, significant enrichments for rare disruptive SNVs and indels were found in proteins affiliated Sitaxentan with ARC and NMDAR genes, and FMRP-targets, but also for voltage-gated calcium channels [ 42••]. This work demonstrates a contribution of ultra-rare damaging alleles spread across a large number of genes in schizophrenia, although larger samples are required for robust associations to be made to specific genes/alleles. Genome-wide association studies (GWAS) of SNPs have now identified a number of common schizophrenia risk alleles [43, 44 and 45••]. Individually, these alleles have a weak effect on schizophrenia risk, with ORs generally < 1.2, although collectively they are estimated to account for between a third and a half of the variation in schizophrenia genetic liability [43, 46 and 47]. Given the modest effect size of these alleles, very large samples have been required to obtain the necessary statistical power for associations to be made at genome-wide levels of significance (P < 5 × 10−8).