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

Andrés Ingason, George Kirov, Ina Giegling, Thomas Hansen, Anthony R Isles, Klaus D Jakobsen, Kari T Kristinsson, Louise le Roux, Omar Gustafsson, Nick Craddock, Hans-Jürgen Möller, Andrew McQuillin, Pierandrea Muglia, Sven Cichon, Marcella Rietschel, Roel A Ophoff, Srdjan Djurovic, Ole A Andreassen, Olli P H Pietiläinen, Leena PeltonenEmma Dempster, David A Collier, David St Clair, Henrik B Rasmussen, Birte Y Glenthøj, Lambertus A Kiemeney, Barbara Franke, Sarah Tosato, Chiara Bonetto, Evald Saemundsen, Stefán J Hreidarsson, Markus M Nöthen, Hugh Gurling, Michael C O'Donovan, Michael J Owen, Engilbert Sigurdsson, Hannes Petursson, Hreinn Stefansson, Dan Rujescu, Kari Stefansson, Thomas Werge, GROUP Investigators

    81 Citations (Scopus)

    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.

    Original languageEnglish
    JournalAmerican Journal of Psychiatry
    Volume168
    Issue number4
    Pages (from-to)408-417
    Number of pages10
    ISSN0002-953X
    DOIs
    Publication statusPublished - 1 Apr 2011

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