Double hits in schizophrenia

The co-occurrence of a copy number variant (CNV) and a functional variant on the other allele may be a relevant genetic mechanism in schizophrenia. We hypothesized that the cumulative burden of such double hits-in particular those composed of a deletion and a coding single-nucleotide variation (SNV)-is increased in patients with schizophrenia. We combined CNV data with coding variants data in 795 patients with schizophrenia and 474 controls. To limit false CNV-detection, only CNVs called by two algorithms were included. CNV-affected genes were subsequently examined for coding SNVs, which we termed CNV-SNVs. Correcting for total queried sequence, we assessed the CNV-SNV-burden and the combined predicted deleterious effect.We estimated P-values by permutation of the phenotype.We detected 105 CNV-SNVs; 67 in duplicated and 38 in deleted genic sequence. Although the difference in CNV-SNVs rates was not significant, the combined deleteriousness inferred by CNV-SNVs in deleted sequence was almost 4-fold higher in cases compared with controls (nominal P0.009). This effectmay be driven by a higher number of CNV-SNVs and/or by a higher degree of predicted deleteriousness of CNV-SNVs. No such effect was observed for duplications. We provide early evidence that deletions co-occurring with a functional variantmay be relevant, albeit ofmodest impact, for the genetic etiology of schizophrenia. Large-scale consortiumstudies are required to validate our findings. Sequence-based analyses would provide the best resolution for detection of CNVs as well as coding variants genome-wide.