Rare chromosomal deletions and duplications increase risk of schizophrenia

Abstract

Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73-90% (ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants (CNVs) have been identified in individual patients with schizophrenia and also in neurodevelopmental disorders, but large-scale genome-wide surveys have not been performed. Here we report a genome-wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high-density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15-fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single-occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo-cardio-facial syndrome, which includes psychotic symptoms in 30% of patients. Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome-wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome-wide and at specific loci.

Figure 1. Regions with excess large deletions in cases

a)The positions of CNVs >500kb across chromosome 22q11.2 region. Case deletions: red lines. Horizontal dashed sections: qPCR or visual inspection of array intensity data suggest an extended deletion. Green lines: locations of low-copy repeats (LCR22-2-LCR22-4). Gray lines: recurrent ∼3MB and ∼1.5MB VCFS deletions. qPCR primers marked by vertical dashed lines. b) Chromosome 15q13.2 region, as above, except for the locations of breakpoint regions (BP4, BP5) (green) and the MR critical region previously defined. c) Chromosome 1q21.1: as above, except single deletion identified in a control subject is marked by blue line.