TY - JOUR

T1 - Maternally Derived Microduplications at 15q11-q13: Implication of Imprinted Genes in Psychotic Illness

AU - Ingason, Andrés

AU - Kirov, George

AU - Giegling, Ina

AU - Hansen, Thomas

AU - Isles, Anthony R

AU - Jakobsen, Klaus D

AU - Kristinsson, Kari T

AU - le Roux, Louise

AU - Gustafsson, Omar

AU - Craddock, Nick

AU - Möller, Hans-Jürgen

AU - McQuillin, Andrew

AU - Muglia, Pierandrea

AU - Cichon, Sven

AU - Rietschel, Marcella

AU - Ophoff, Roel A

AU - Djurovic, Srdjan

AU - Andreassen, Ole A

AU - Pietiläinen, Olli P H

AU - Peltonen, Leena

AU - Dempster, Emma

AU - Collier, David A

AU - St Clair, David

AU - Rasmussen, Henrik B

AU - Glenthøj, Birte Y

AU - Kiemeney, Lambertus A

AU - Franke, Barbara

AU - Tosato, Sarah

AU - Bonetto, Chiara

AU - Saemundsen, Evald

AU - Hreidarsson, Stefán J

AU - Nöthen, Markus M

AU - Gurling, Hugh

AU - O'Donovan, Michael C

AU - Owen, Michael J

AU - Sigurdsson, Engilbert

AU - Petursson, Hannes

AU - Stefansson, Hreinn

AU - Rujescu, Dan

AU - Stefansson, Kari

AU - Werge, Thomas

AU - GROUP Investigators

PY - 2011/4/1

Y1 - 2011/4/1

N2 - 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.

AB - 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.

U2 - 10.1176/appi.ajp.2010.09111660

DO - 10.1176/appi.ajp.2010.09111660

M3 - Journal article

C2 - 21324950

VL - 168

SP - 408

EP - 417

JO - The American Journal of Psychiatry

JF - The American Journal of Psychiatry

SN - 0002-953X

IS - 4

ER -