Maternally Derived Microduplications at 15q11-q13: Implication of Imprinted Genes in Psychotic Illness

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. 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. Lundbeck Foundation R34-A3243 Danish National Advanced Technology Foundation 001-2009-2 Danish Council for Independent Research in Medical Sciences Danish Psychiatric Research Foundation European Union (EU) LSHM-CT-2006-037761 HEALTH-2007-2.2.1-10-223423 IMI-JU-NewMeds PIAP-GA-2008-218251 National Institutes of Health MH071425 National Genomic Network (NGFNplus) of the German Federal Ministry of Education and Research (BMBF Wellcome Trust, London Medical Research Council, London info:eu-repo/grantAgreement/EC/FP7/218251