Copy number variations of chromosome 16p13.1 region associated with schizophrenia

Abstract

Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35,079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P = 0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.

Figure 1

The 16p13.11-p12.3 region. Chromosomal coordinates according to the Human Genome Build 36 are shown at top, followed by genes from the Reference Sequence database. The locus is marked by regions of single copy sequence interspersed with stretches of segmental duplications. The single copy regions, referred to in the article as I, II and III are shown as black bars. Copy number variants (CNVs) identified by Ullmann et al. and Hannes et al. are also indicated with black bars, gray bars reflect uncertainty of exact breakpoints. The genomic coverage of microarrays used in this study is also shown, and reflects the division of the locus into single copy regions and segmental duplications, as does the coverage of HapMap single nucleotide polymorphisms (SNPs) from the CEU trios and the track displaying segmental duplications. At the bottom, we have depicted the largest low copy repeats in the region ( < 50 kb) with high sequence homology ( > 98%), different colors denote different repeats and arrows show directionality. Finally, we show the most likely sites for NaHR causing four of the six CNVs found in the study.

Figure 2

Intensity plots for the Copy number variants (CNVs) identified in this study in the 16p13.11-p12.3 region. Chromosomal coordinates according to the Human Genome Build 36 are shown at top, followed by markers from the microarrays used in this study, HapMap single nucleotide polymorphisms (SNPs) from the CEU population and the track displaying known segmental duplications. At the bottom, intensity plots from Dosage Miner are shown for one carrier of each of the identified CNVs. The blue and green bars show the intervals of Dosage Miner automatic calls for deletions and duplications, respectively.