Rare chromosomal deletions and duplications increase risk of schizophrenia

• Published in: Nature Vol. 455; no. 7210; pp. 237 - 241
• Main Authors: Stone, Jennifer L., O'Donovan, Michael C., Gurling, Hugh, Kirov, George K., Blackwood, Douglas H. R., Corvin, Aiden, Craddock, Nick J., Gill, Michael, Hultman, Christina M., Lichtenstein, Paul, McQuillin, Andrew, Pato, Carlos N., Ruderfer, Douglas M., Owen, Michael J., St Clair, David, Sullivan, Patrick F., Sklar, Pamela, Purcell, Shaun M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.09.2008; Nature Publishing; Nature Publishing Group
• Subjects: Adult and adolescent clinical studies; Biological and medical sciences; Case-Control Studies; Chromosome Deletion; Chromosomes; Chromosomes, Human - genetics; Colleges & universities; Gene Dosage - genetics; Gene Duplication; Genes; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetic variance; Genetic variation; Genome, Human - genetics; Humanities and Social Sciences; Humans; Intellectual disabilities; letter; Medical sciences; MEDICIN; Medicin och hälsovetenskap; MEDICINE; Mental disorders; Models, Genetic; multidisciplinary; Oligonucleotide Array Sequence Analysis; Polymorphism, Single Nucleotide - genetics; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Risk factors; Schizophrenia; Schizophrenia - genetics; Science; Science (multidisciplinary); Sequence Deletion - genetics; Psychosis; Human; Duplication; Risk factor; Deletion; Schizophrenia; Genetics; Genome
• ISSN: 0028-0836; 1476-4687; 1476-4687; 1476-4679
• DOI: 10.1038/nature07239

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.