Maternally derived microduplications at 15q11-q13: implication of imprinted genes in psychotic illness

Abstract

Objective: Rare copy number variants have been implicated in different neurodevelopmental disorders, with the same copy number variants often increasing risk of more than one of these phenotypes. In a discovery sample of 22 schizophrenia patients with an early onset of illness (10-15 years of age), the authors observed in one patient a maternally derived 15q11-q13 duplication overlapping the Prader-Willi/Angelman syndrome critical region. This prompted investigation of the role of 15q11-q13 duplications in psychotic illness.

Method: The authors scanned 7,582 patients with schizophrenia or schizoaffective disorder and 41,370 comparison subjects without known psychiatric illness for copy number variants at 15q11-q13 and determined the parental origin of duplications using methylation-sensitive Southern hybridization analysis.

Results: Duplications were found in four case patients and five comparison subjects. All four case patients had maternally derived duplications (0.05%), while only three of the five comparison duplications were maternally derived (0.007%), resulting in a significant excess of maternally derived duplications in case patients (odds ratio=7.3). This excess is compatible with earlier observations that risk for psychosis in people with Prader-Willi syndrome caused by maternal uniparental disomy is much higher than in those caused by deletion of the paternal chromosome.

Conclusions: These findings suggest that the presence of two maternal copies of a fragment of chromosome 15q11.2-q13.1 that overlaps with the Prader-Willi/Angelman syndrome critical region may be a rare risk factor for schizophrenia and other psychoses. Given that maternal duplications of this region are among the most consistent cytogenetic observations in autism, the findings provide further support for a shared genetic etiology between autism and psychosis.

FIGURE 1. The Chromosome 15q11.2-q13.3 region^a

^a The data depict chromosomal coordinates according to the National Center for Biotechnology Information Build 36 (top), followed by chromosome bands, annotated genes from the National Center for Biotechnology Information Reference Sequence database, tracks indicating the Southern hybridization probe, microsatellites used to determine duplication origin, tracks indicating the duplications identified in the present study, and segmental duplications in the region, with common breakpoints (BPs) of Prader-Willi and Angelman syndromes (BP1–BP5). All duplications were maternally derived except two of the comparison duplications, which were paternally derived (gray bars). (Figure adapted with permission from the Human [Homo Sapiens] Genome Browser Gateway [http://genome.ucsc.edu/]. Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, Haussler D: The Human Genome Browser at UCSC. Genome Res 2002; 12:996-1006).