Large recurrent microdeletions associated with schizophrenia

Abstract

Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.

Figure 1. The genomic architecture of the 1q21.1, 15q11.2 and 15q13.3 deletions

a, DosageMiner output showing the shorter form of the 1q21 deletion (marked in blue). Ninety-nine SNPs on the HumanHap300 chip are affected by the deletion which spans 1.38 Mb. b, DosageMiner output showing the 15q11.2 deletion (marked in blue). Fifty-four SNPs on the HumanHap300 chip are affected by the deletion which spans 470 kb. c, DosageMiner output showing the 15q13.3 deletion (marked in blue). One-hundred-and-sixty-six SNPs on the HumanHap300 chip are affected by the deletion which spans 1.57 Mb. Genes affected by the deletions are shown (coordinates are based on Build 36 of the human genome and positions of genes derived from the UCSC genome browser). LCRs flank all three deletions (Supplementary Figs 1, 3 and 4).