Support for the involvement of large copy number variants in the pathogenesis of schizophrenia

Abstract

We investigated the involvement of rare (<1%) copy number variants (CNVs) in 471 cases of schizophrenia and 2792 controls that had been genotyped using the Affymetrix GeneChip 500K Mapping Array. Large CNVs >1 Mb were 2.26 times more common in cases (P = 0.00027), with the effect coming mostly from deletions (odds ratio, OR = 4.53, P = 0.00013) although duplications were also more common (OR = 1.71, P = 0.04). Two large deletions were found in two cases each, but in no controls: a deletion at 22q11.2 known to be a susceptibility factor for schizophrenia and a deletion on 17p12, at 14.0-15.4 Mb. The latter is known to cause hereditary neuropathy with liability to pressure palsies. The same deletion was found in 6 of 4618 (0.13%) cases and 6 of 36 092 (0.017%) controls in the re-analysed data of two recent large CNV studies of schizophrenia (OR = 7.82, P = 0.001), with the combined significance level for all three studies achieving P = 5 x 10(-5). One large duplication on 16p13.1, which has been previously implicated as a susceptibility factor for autism, was found in three cases and six controls (0.6% versus 0.2%, OR = 2.98, P = 0.13). We also provide the first support for a recently reported association between deletions at 15q11.2 and schizophrenia (P = 0.026). This study confirms the involvement of rare CNVs in the pathogenesis of schizophrenia and contributes to the growing list of specific CNVs that are implicated.

Figure 1.

Positions of the deletions in 15q11.2, between 20.35 and 20.6 Mb (the interval containing genes), that were identified in the current (Cardiff) and ISC studies (4). Red, cases; brown, controls. The positions of genes and segmental duplications in the region are also shown. Produced with the UCSC Genome Browser (http://www.genome.ucsc.edu).

Figure 2.

Positions of CNVs on 17p12 between 14.05 and 15.36 Mb that were identified in the current (Cardiff), ISC (4) and Stefansson et al. (5) studies. Deletions in cases are in red. The positions of genes and segmental duplications in the region are also shown. Produced with the UCSC Genome Browser (http://www.genome.ucsc.edu).