Mosaic copy number variation in schizophrenia

Abstract

Recent reports suggest that somatic structural changes occur in the human genome, but how these genomic alterations might contribute to disease is unknown. Using samples collected as part of the International Schizophrenia Consortium (schizophrenia, n=3518; control, n=4238) recruited across multiple university research centers, we assessed single-nucleotide polymorphism genotyping arrays for evidence of chromosomal anomalies. Data from genotyping arrays on each individual were processed using Birdsuite and analyzed with PLINK. We validated potential chromosomal anomalies using custom nanostring probes and quantitative PCR. We estimate chromosomal alterations in the schizophrenia population to be 0.42%, which is not significantly different from controls (0.26%). We identified and validated a set of four extremely large (>10 Mb) chromosomal anomalies in subjects with schizophrenia, including a chromosome 8 trisomy and deletion of the q arm of chromosome 7. These data demonstrate that chromosomal anomalies are present at low frequency in blood cells of both control and schizophrenia subjects.

Figure 1

Distribution of number of rare CNVs and total extent of rare CNV by individual. Red dots represent cases and black dots represent controls. A full color version of this figure is available at the European Journal of Human Genetics journal online.

Figure 2

Size and number of CNVs in the outlier sample.

Figure 3

Non-centromeric CNVs >10 Mb identified in a refined set of outlier subjects. Red squares indicate where on the chromosome the loss (del) or gain (dup) occurred. Regions of quantitative PCR (qPCR) and nanostring probe binding are marked by small squares adjacent to chromosome images. A full color version of this figure is available at the European Journal of Human Genetics journal online.