Abstract
Large and rare copy number variants (CNVs) at several loci have been shown to increase risk for schizophrenia. Aiming to discover novel susceptibility CNV loci, we analyzed 6882 cases and 11 255 controls genotyped on Illumina arrays, most of which have not been used for this purpose before. We identified genes enriched for rare exonic CNVs among cases, and then attempted to replicate the findings in additional 14 568 cases and 15 274 controls. In a combined analysis of all samples, 12 distinct loci were enriched among cases with nominal levels of significance (P < 0.05); however, none would survive correction for multiple testing. These loci include recurrent deletions at 16p12.1, a locus previously associated with neurodevelopmental disorders (P = 0.0084 in the discovery sample and P = 0.023 in the replication sample). Other plausible candidates include non-recurrent deletions at the glutamate transporter gene SLC1A1, a CNV locus recently suggested to be involved in schizophrenia through linkage analysis, and duplications at 1p36.33 and CGNL1. A burden analysis of large (>500 kb), rare CNVs showed a 1.2% excess in cases after excluding known schizophrenia-associated loci, suggesting that additional susceptibility loci exist. However, even larger samples are required for their discovery.
Highlights
Copy number variants (CNVs) at several loci are robustly associated with schizophrenia (1 – 7)
After excluding genes within previously implicated loci (13 loci flanked by low copy repeats (LCRs), and two individual genes, NRXN1 and VIPR2, listed in Supplementary Material, Table S3), genes in 37 regions were enriched among our discovery cases with nominal levels of significance
It is well established that specific CNVs contribute to schizophrenia susceptibility and that many of the same CNVs increase risk for other neurodevelopmental disorders (2 – 4,14,17)
Summary
Copy number variants (CNVs) at several loci are robustly associated with schizophrenia (1 – 7) The majority of these are flanked by low copy repeats (LCRs) which mediate their formation through non-allelic homologous recombination (NAHR). All strongly implicated CNV loci in schizophrenia are rare, CNVs at each locus being found in 0.082 – 0.59% of cases and even less often in controls [5,6]. Due to their rarity, very large sample sizes have been required to identify these loci. Loci that showed evidence for association were followed up in the additional 568 cases and 274 controls, bringing the total number of samples analyzed to 48 000
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