Independent estimation of the frequency of rare CNVs in the UK population confirms their role in schizophrenia

Background: Several large, rare chromosomal copy number variants (CNVs) have recently been shown to increase risk for schizophrenia and other neuropsychiatric disorders including autism, ADHD, learning difficulties and epilepsy. Aims: We wanted to examine the frequencies of these schizophrenia-associated variants in a large sample of individuals with non-psychiatric illnesses to better understand the robustness and specificity of the association with schizophrenia. Methods: We used Affymetrix 500K microarray data from 10,259 individuals from the UK Wellcome Trust Case Control Consortium (WTCCC) who are affected with six non-psychiatric disorders (coronary artery disease, Crohn's disease, hypertension, rheumatoid arthritis, types 1 and 2 diabetes) to establish the frequencies of nine CNV loci strongly implicated in schizophrenia, and compared them with the previous findings. Results: Deletions at 1q21.1, 3q29, 15q11.2, 15q13.1 and 22q11.2 (VCFS region), and duplications at 16p11.2 were found significantly more often in schizophrenia cases, compared with theWTCCC reference set. Deletions at 17p12 and 17q12,were also more common in schizophrenia cases but not significantly so, while duplications at 16p13.1 were found at nearly the same rate as in previous schizophrenia samples. The frequencies of CNVs in theWTCCC non-psychiatric controls at three of the loci (15q11.2, 16p13.1 and 17p12) were significantly higher than those reported in previous control populations. Conclusions: The evidence for association with schizophrenia is compelling for six rare CNV loci, while the remaining three require further replication in large studies. Risk at these loci extends to other neurodevelopmental disorders but their involvement in common non-psychiatric disorders should also be investigated. © 2011 Elsevier B.V. All rights reserved