Maternally derived microduplications at 15q11-q13: implication of imprinted genes in psychotic illness - PubMed (original) (raw)
. 2011 Apr;168(4):408-17.
doi: 10.1176/appi.ajp.2010.09111660. Epub 2011 Feb 15.
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 Peltonen, Emma 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; GROUP Investigators; Markus M Nöthen, Hugh Gurling, Michael C O'Donovan, Michael J Owen, Engilbert Sigurdsson, Hannes Petursson, Hreinn Stefansson, Dan Rujescu, Kari Stefansson, Thomas Werge
Affiliations
- PMID: 21324950
- PMCID: PMC3428917
- DOI: 10.1176/appi.ajp.2010.09111660
Maternally derived microduplications at 15q11-q13: implication of imprinted genes in psychotic illness
Andrés Ingason et al. Am J Psychiatry. 2011 Apr.
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.
Figures
FIGURE 1. The Chromosome 15q11.2-q13.3 regiona
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 [
]. 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).
Comment in
- Parental origin, DNA structure, and the schizophrenia spectrum.
Bassett AS. Bassett AS. Am J Psychiatry. 2011 Apr;168(4):350-3. doi: 10.1176/appi.ajp.2011.11010173. Am J Psychiatry. 2011. PMID: 21474594 Free PMC article. No abstract available. - Overexpression of chromosome 15q11-q13 gene products: a risk factor for schizophrenia and associated psychoses?
Boot E, Kant SG, Otter M, Cohen D, Nabanizadeh A, Baas RW. Boot E, et al. Am J Psychiatry. 2012 Jan;169(1):96-7; author reply 97. doi: 10.1176/appi.ajp.2011.11091382. Am J Psychiatry. 2012. PMID: 22223014 No abstract available.
Similar articles
- De novo interstitial duplication of 15q11.2-q13.1 with complex maternal uniparental trisomy for the 15q11-q13 region in a patient with Prader-Willi syndrome.
Burrage LC, Person RE, Flores A, Villanos MT, Bi W, Wiszniewska J, Bacino CA. Burrage LC, et al. Am J Med Genet A. 2012 Oct;158A(10):2557-63. doi: 10.1002/ajmg.a.35549. Epub 2012 Aug 17. Am J Med Genet A. 2012. PMID: 22903639 - Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders.
Isles AR, Ingason A, Lowther C, Walters J, Gawlick M, Stöber G, Rees E, Martin J, Little RB, Potter H, Georgieva L, Pizzo L, Ozaki N, Aleksic B, Kushima I, Ikeda M, Iwata N, Levinson DF, Gejman PV, Shi J, Sanders AR, Duan J, Willis J, Sisodiya S, Costain G, Werge TM, Degenhardt F, Giegling I, Rujescu D, Hreidarsson SJ, Saemundsen E, Ahn JW, Ogilvie C, Girirajan SD, Stefansson H, Stefansson K, O'Donovan MC, Owen MJ, Bassett A, Kirov G. Isles AR, et al. PLoS Genet. 2016 May 6;12(5):e1005993. doi: 10.1371/journal.pgen.1005993. eCollection 2016 May. PLoS Genet. 2016. PMID: 27153221 Free PMC article. - Screening for genomic rearrangements and methylation abnormalities of the 15q11-q13 region in autism spectrum disorders.
Depienne C, Moreno-De-Luca D, Heron D, Bouteiller D, Gennetier A, Delorme R, Chaste P, Siffroi JP, Chantot-Bastaraud S, Benyahia B, Trouillard O, Nygren G, Kopp S, Johansson M, Rastam M, Burglen L, Leguern E, Verloes A, Leboyer M, Brice A, Gillberg C, Betancur C. Depienne C, et al. Biol Psychiatry. 2009 Aug 15;66(4):349-59. doi: 10.1016/j.biopsych.2009.01.025. Epub 2009 Mar 17. Biol Psychiatry. 2009. PMID: 19278672 - From Prader-Willi syndrome to psychosis: translating parent-of-origin effects into schizophrenia research.
Krefft M, Frydecka D, Adamowski T, Misiak B. Krefft M, et al. Epigenomics. 2014;6(6):677-88. doi: 10.2217/epi.14.52. Epigenomics. 2014. PMID: 25531260 Review. - Prader-Willi, Angelman, and 15q11-q13 Duplication Syndromes.
Kalsner L, Chamberlain SJ. Kalsner L, et al. Pediatr Clin North Am. 2015 Jun;62(3):587-606. doi: 10.1016/j.pcl.2015.03.004. Epub 2015 Apr 22. Pediatr Clin North Am. 2015. PMID: 26022164 Free PMC article. Review.
Cited by
- Identification of novel driver risk genes in CNV loci associated with neurodevelopmental disorders.
Azidane S, Gallego X, Durham L, Cáceres M, Guney E, Pérez-Cano L. Azidane S, et al. HGG Adv. 2024 Jul 18;5(3):100316. doi: 10.1016/j.xhgg.2024.100316. Epub 2024 Jun 6. HGG Adv. 2024. PMID: 38850022 Free PMC article. - Epigenetic control and genomic imprinting dynamics of the Dlk1-Dio3 domain.
Weinberg-Shukron A, Youngson NA, Ferguson-Smith AC, Edwards CA. Weinberg-Shukron A, et al. Front Cell Dev Biol. 2023 Dec 12;11:1328806. doi: 10.3389/fcell.2023.1328806. eCollection 2023. Front Cell Dev Biol. 2023. PMID: 38155837 Free PMC article. Review. - Population-based Risk of Psychiatric Disorders Associated with Recurrent CNVs.
Vaez M, Montalbano S, Sánchez XC, Georgii Hellberg KL, Rasekhi Dehkordi S, Dybdahl Krebs M, Meijsen J, Shorter J, Byberg-Grauholm J, Mortensen PB, Børglum AD, Hougaard DM, Nordentoft M, Geschwind DH, Buil A, Schork AJ; iPSYCH Investigators; Helenius D, Raznahan A, Thompson WK, Werge T, Ingason A. Vaez M, et al. medRxiv [Preprint]. 2023 Sep 5:2023.09.04.23294975. doi: 10.1101/2023.09.04.23294975. medRxiv. 2023. PMID: 37886536 Free PMC article. Updated. Preprint. - Adaptive, behavioral, and cognitive outcomes in individuals with fragile X syndrome with varying autism severity.
Aishworiya R, Tak YE, Ponzini MD, Biag HMB, Salcedo-Arellano MJ, Kim K, Tassone F, Schneider A, Thurman AJ, Abbeduto L, Hessl D, Randol JL, Bolduc FV, Lippe S, Hagerman P, Hagerman R. Aishworiya R, et al. Int J Dev Neurosci. 2023 Dec;83(8):715-727. doi: 10.1002/jdn.10299. Epub 2023 Sep 19. Int J Dev Neurosci. 2023. PMID: 37724826 Free PMC article. - Combining Z-Score and Maternal Copy Number Variation Analysis Increases the Positive Rate and Accuracy in Non-Invasive Prenatal Testing.
Chen L, Wang L, Hu Z, Tao Y, Song W, An Y, Li X. Chen L, et al. Front Genet. 2022 Jun 2;13:887176. doi: 10.3389/fgene.2022.887176. eCollection 2022. Front Genet. 2022. PMID: 35719402 Free PMC article.
References
- Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM, Nord AS, Kusenda M, Malhotra D, Bhandari A, Stray SM, Rippey CF, Roccanova P, Makarov V, Lakshmi B, Findling RL, Sikich L, Stromberg T, Merriman B, Gogtay N, Butler P, Eckstrand K, Noory L, Gochman P, Long R, Chen Z, Davis S, Baker C, Eichler EE, Meltzer PS, Nelson SF, Singleton AB, Lee MK, Rapoport JL, King MC, Sebat J. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science. 2008;320:539–543. - PubMed
- Stefansson H, Rujescu D, Cichon S, Pietiläinen OP, Ingason A, Steinberg S, Fossdal R, Sigurdsson E, Sigmundsson T, Buizer-Voskamp JE, Hansen T, Jakobsen KD, Muglia P, Francks C, Matthews PM, Gylfason A, Halldorsson BV, Gudbjartsson D, Thorgeirsson TE, Sigurdsson A, Jonasdottir A, Jonasdottir A, Bjornsson A, Mattiasdottir S, Blondal T, Haraldsson M, Magnusdottir BB, Giegling I, Möller HJ, Hartmann A, Shianna KV, Ge D, Need AC, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Paunio T, Toulopoulou T, Bramon E, Di Forti M, Murray R, Ruggeri M, Vassos E, Tosato S, Walshe M, Li T, Vasilescu C, Mühleisen TW, Wang AG, Ullum H, Djurovic S, Melle I, Olesen J, Kiemeney LA, Franke B, GROUP Investigators. Sabatti C, Freimer NB, Gulcher JR, Thorsteinsdottir U, Kong A, Andreassen OA, Ophoff RA, Georgi A, Rietschel M, Werge T, Petursson H, Goldstein DB, Nöthen MM, Peltonen L, Collier DA, St Clair D, Stefansson K. Large recurrent microdeletions associated with schizophrenia. Nature. 2008;455:232–236. - PMC - PubMed
- Kirov G, Grozeva D, Norton N, Ivanov D, Mantripragada KK, Holmans P, International Schizophrenia Consortium. Wellcome Trust Case Control Consortium. Craddock N, Owen MJ, O’Donovan MC. Support for the involvement of large copy number variants in the pathogenesis of schizophrenia. Hum Mol Genet. 2009;18:1497–1503. - PMC - PubMed
- Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee YH, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimäki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W, Warburton D, King MC, Skuse D, Geschwind DH, Gilliam TC, Ye K, Wigler M. Strong association of de novo copy number mutations with autism. Science. 2007;316:445–449. - PMC - PubMed
Publication types
MeSH terms
Grants and funding
- G0701007/MRC_/Medical Research Council/United Kingdom
- G1000708/MRC_/Medical Research Council/United Kingdom
- R01 MH071425/MH/NIMH NIH HHS/United States
- MH071425/MH/NIMH NIH HHS/United States
- WT_/Wellcome Trust/United Kingdom
- 089061/WT_/Wellcome Trust/United Kingdom
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical