Maternally Derived Microduplications at 15q11-q13: Implication of Imprinted Genes in Psychotic Illness
Open accessAbstract
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.
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Several individual CNV loci have been strongly implicated as risk factors for schizophrenia.
“several individual CNV loci have been strongly implicated as risk factors for schizophrenia with high degrees of statistical confidence. These include deletions at 1q21.1, NRXN1, 3q29, 15q11.2, 15q13.3, 22q11.2 and duplications at VIPR2, 16p11.2, 16p13.1 and 15q11-q13.2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [9]
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Cites
Strong association of de novo copy number mutations with autism
Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., Yamrom, B., Yoon, S., Krasnitz, A., Kendall, J., et al. (2007) · Science · doi:10.1126/science.1138659 · Cited by 2,795 · see citing works
The Wellcome Trust Case Control Consortium, U.K.
Mossman, K. (2008) · Scientific American · doi:10.1038/scientificamerican0108-42a · Cited by 2,714 · see citing works
Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia
Walsh, T., McClellan, J. M., McCarthy, S. E., Addington, A. M., Pierce, S. B., Cooper, G. M., Nord, A. S., Kusenda, M., Malhotra, D., Bhandari, A., et al. (2008) · Science · doi:10.1126/science.1155174 · Cited by 1,800 · see citing works
Wang, K., Li, M., Hadley, D., Liu, R., Glessner, J., Grant, S. F. A., Hakonarson, H., & Bucan, M. (2007) · Genome Research · doi:10.1101/gr.6861907 · Cited by 1,792 · see citing works
Large recurrent microdeletions associated with schizophrenia.
GROUP, Stefansson, H., Rujescu, D., Cichon, S., Pietiläinen, O. P. H., Ingason, A., Steinberg, S., Fossdal, R., Sigurdsson, E., Sigmundsson, T., et al. (2008) · Nature · doi:10.1038/nature07229 · Cited by 1,745 · see citing works
Self-citationAssociation between Microdeletion and Microduplication at 16p11.2 and Autism
Weiss, L. A., Shen, Y., Korn, J. M., Arking, D. E., Miller, D. T., Fossdal, R., Saemundsen, E., Stefansson, H., Ferreira, M. A. R., Green, T., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa075974 · Cited by 1,666 · see citing works
Self-citationLifetime Prevalence of Psychotic and Bipolar I Disorders in a General Population
Perälä, J., Suvisaari, J., Saarni, S. I., Kuoppasalmi, K. I., Isometsä, E. T., Pirkola, S. P., Partonen, T., Tuulio‐Henriksson, A., Hintikka, J., Kieseppä, T., et al. (2007) · Archives of General Psychiatry · doi:10.1001/archpsyc.64.1.19 · Cited by 1,523 · see citing works
Rare chromosomal deletions and duplications increase risk of schizophrenia
The International Schizophrenia Consortium (2008) · Nature · doi:10.1038/nature07239 · Cited by 1,475 · see citing works
Autism genome-wide copy number variation reveals ubiquitin and neuronal genes
Glessner, J. T., Wang, K., Cai, G., Korvatska, O., Kim, C. E., Wood, S., Zhang, H., Estes, A., Brune, C. W., Bradfield, J. P., et al. (2009) · Nature · doi:10.1038/nature07953 · Cited by 1,421 · see citing works
Jiang, Y.-H., Armstrong, D., Albrecht, U., Atkins, C. M., Noebels, J. L., Eichele, G., Sweatt, J. D., & Beaudet, A. L. (1998) · Neuron · doi:10.1016/s0896-6273(00)80596-6 · Cited by 852 · see citing works
Microduplications of 16p11.2 are associated with schizophrenia
Wellcome Trust Case Control Consortium, McCarthy, S. E., Makarov, V., Kirov, G., Addington, A. M., McClellan, J., Yoon, S., Perkins, D. O., Dickel, D. E., Kusenda, M., et al. (2009) · Nature Genetics · doi:10.1038/ng.474 · Cited by 711 · see citing works
Self-citationThe Danish Psychiatric Central Register.
Munk‐Jørgensen, P., & Mortensen, P. B. (1997) · PubMed · Cited by 703 · see citing works
A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay
Girirajan, S., Rosenfeld, J. A., Cooper, G. M., Antonacci, F., Siswara, P., Itsara, A., Vives, L., Walsh, T., McCarthy, S. E., Baker, C., et al. (2010) · Nature Genetics · doi:10.1038/ng.534 · Cited by 667 · see citing works
Association Between Microdeletion and Microduplication at 16p11.2 and Autism
Weiss, L. A., Shen, Y., Korn, J. M., Arking, D. E., Miller, D. T., Fossdal, R., Sæmundsen, E., Stefánsson, H., Ferreira, M. A. R., Green, T. J., et al. (2008) · Obstetrical & Gynecological Survey · doi:10.1097/01.ogx.0000316305.61461.6f · Cited by 647 · see citing works
(1997) · PubMed · Cited by 645 · see citing works
Diagnostic genome profiling in mental retardation
de Vries, B. B. A., Pfundt, R., Leisink, M., Koolen, D. A., Vissers, L. E. L. M., Janssen, I. M., Reijmersdal, S. V., Nillesen, W. M., Huys, E. H. L. P. G., Leeuw, N. D., et al. (2005) · The American Journal of Human Genetics · doi:10.1086/491719 · Cited by 605 · see citing works
Population analysis of large copy number variants and hotspots of human genetic disease
Itsara, A., Cooper, G. M., Baker, C., Girirajan, S., Li, J., Absher, D., Krauss, R. M., Myers, R. M., Ridker, P. M., Chasman, D. I., et al. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.12.014 · Cited by 591 · see citing works
Genomic Disorders: Molecular Mechanisms for Rearrangements and Conveyed Phenotypes
Lupski, J. R., & Stankiewicz, P. (2005) · PLoS Genetics · doi:10.1371/journal.pgen.0010049 · Cited by 582 · see citing works
Disruption of the neurexin 1 gene is associated with schizophrenia
Rujescu, D., Ingason, A., Cichon, S., Pietiläinen, O. P. H., Barnes, M. R., Toulopoulou, T., Picchioni, M., Vassos, E., Ettinger, U., Bramon, E., et al. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddn351 · Cited by 471 · see citing works
Self-citationA Genome-Wide Investigation of SNPs and CNVs in Schizophrenia
Need, A. C., Ge, D., Weale, M. E., Maia, J. M., Feng, S., Heinzen, E. L., Shianna, K. V., Yoon, W., Kasperavičiūtė, D., Gennarelli, M., et al. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000373 · Cited by 443 · see citing works
Self-citationSupport for the involvement of large copy number variants in the pathogenesis of schizophrenia.
Kirov, G., Grozeva, D., Norton, N., Ivanov, D., Mantripragada, K. K., Holmans, P., International Schizophrenia Consortium, the Wellcome Trust Case Control Consortium, Craddock, N., Owen, M. J., et al. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp043 · Cited by 390 · see citing works
Self-citationPrader-Willi syndrome: advances in genetics, pathophysiology and treatment
Goldstone, A. P. (2003) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2003.11.003 · Cited by 388 · see citing works
The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13
Hogart, A., Wu, D., LaSalle, J. M., & Schanen, N. C. (2008) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.08.011 · Cited by 354 · see citing works
Germline rates of de novo meiotic deletions and duplications causing several genomic disorders
Turner, D. J., Miretti, M., Rajan, D., Fiegler, H., Carter, N. P., Blayney, M. L., Beck, S., & Hurles, M. E. (2008) · Nature Genetics · doi:10.1038/ng.2007.40 · Cited by 320 · see citing works
Ullmann, R., TURNER, G. M., Kirchhoff, M., Chen, W., Tonge, B. J., Rosenberg, C., Field, M., Vianna‐Morgante, A. M., Christie, L., Krepischi, A. C. V., et al. (2007) · Human Mutation · doi:10.1002/humu.20546 · Cited by 287 · see citing works
Ben-Shachar, S., Lanpher, B., German, J. R., Qasaymeh, M., Potocki, L., Nagamani, S. C. S., Franco, L. M., Malphrus, A., Bottenfield, G. W., Spence, J. E., et al. (2009) · Journal of Medical Genetics · doi:10.1136/jmg.2008.064378 · Cited by 261 · see citing works
Copy number variations of chromosome 16p13.1 region associated with schizophrenia
Ingason, A., Rujescu, D., Cichon, S., Sigurdsson, E., Sigmundsson, T., Pietiläinen, O. P. H., Buizer-Voskamp, J. E., Strengman, E., Francks, C., Muglia, P., et al. (2011) · Molecular Psychiatry · doi:10.1038/mp.2009.101 · Cited by 258 · see citing works
Self-citationInherited Interstitial Duplications of Proximal 15q: Genotype-Phenotype Correlations
Browne, C. E., Dennis, N. R., Maher, E. R., Long, F., Nicholson, J. C., Sillibourne, J., & Barber, J. C. K. (1997) · The American Journal of Human Genetics · doi:10.1086/301624 · Cited by 207 · see citing works
Swillen, A., Vogels, A., Devriendt, K., & Fryns, J. P. (2000) · American Journal of Medical Genetics · doi:10.1002/1096-8628(200022)97:2 · Cited by 188 · see citing works
Soni, S., Whittington, J. E., Holland, A. J., Webb, T., Maina, E. N., Boer, H., & Clarke, D. (2006) · Journal of Intellectual Disability Research · doi:10.1111/j.1365-2788.2006.00895.x · Cited by 179 · see citing works
Doornbos, M., Sikkema-Raddatz, B., Ruijvenkamp, C. A. L., Dijkhuizen, T., Bijlsma, E. K., Gijsbers, A. C. J., Hilhorst-Hofstee, Y., Hordijk, R., Verbruggen, K. T., Kerstjens-Frederikse, W. S. (., et al. (2009) · European Journal of Medical Genetics · doi:10.1016/j.ejmg.2009.03.010 · Cited by 165 · see citing works
The phenomenology and diagnosis of psychiatric illness in people with Prader–Willi syndrome
Soni, S., Whittington, J. E., Holland, A. J., Webb, T., Maina, E. N., Boer, H., & Clarke, D. (2008) · Psychological Medicine · doi:10.1017/s0033291707002504 · Cited by 148 · see citing works
Prader-Willi syndrome: the psychopathological phenotype in uniparental disomy
Verhoeven, W. M. A., Tuinier, S., & Curfs, L. M. G. (2003) · Journal of Medical Genetics · doi:10.1136/jmg.40.10.e112 · Cited by 130 · see citing works
Chromosome 15 maternal uniparental disomy and psychosis in Prader-Willi syndrome
Vogels, A., MATTHIJS, G. L., Legius, E., et al. (2003) · Journal of Medical Genetics · doi:10.1136/jmg.40.1.72 · Cited by 121 · see citing works
Molecular Cytogenetics of Autism
Xu, J., Zwaigenbaum, L., Szatmari, P., & Scherer, S. (2004) · Current Genomics · doi:10.2174/1389202043349246 · Cited by 95 · see citing works
Communication, cognition, and social interaction in the Angelman syndrome
Penner, K. A., Johnston, J., Faircloth, B. H., Irish, P., & Williams, C. A. (1993) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320460108 · Cited by 93 · see citing works
Thomas, J. A., Johnson, J. P., Kraai, T. L. P., Wilson, R., Tartaglia, N. R., LeRoux, J., Beischel, L. S., McGavran, L., & Hagerman, R. J. (2003) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.10176 · Cited by 92 · see citing works
Prader–Willi syndrome and cycloid psychoses
Bouras, N., Verhoeven, W. M. A., Curfs, L. M. G., et al. (1998) · Journal of Intellectual Disability Research · doi:10.1046/j.1365-2788.1998.4260455.x · Cited by 78 · see citing works
Gender influences monoallelic expression of ATP10A in human brain
Hogart, A., Patzel, K. A., & LaSalle, J. M. (2008) · Human Genetics · doi:10.1007/s00439-008-0546-0 · Cited by 46 · see citing works
DuBose, A. J., Johnstone, K. A., Smith, E. Y., Hallett, R. A. E., & Resnick, J. L. (2009) · Neurogenetics · doi:10.1007/s10048-009-0226-9 · Cited by 42 · see citing works
The Angelman Syndrome Protein Ube3A Regulates Synapse Development by Ubiquitinating Arc
Greer, P. L., Hanayama, R., Bloodgood, B. L., Mardinly, A. R., Lipton, D. M., Flavell, S. W., Kim, T.-K., Griffith, E. C., Waldon, Z., Maehr, R., et al. (2010) · Cell · doi:10.1016/j.cell.2010.01.026 · Cited by 30 · see citing works
Estimate of prevalence of proximal 15q duplication syndrome
Moeschler, J. B., Mohandas, T., Hawk, A. B., et al. (2002) · American Journal of Medical Genetics · doi:10.1002/ajmg.10419 · Cited by 18 · see citing works
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Malhotra, D., & Sebat, J. (2012) · Cell · doi:10.1016/j.cell.2012.02.039 · Cited by 854 · see citing works
Kirov, G., Pocklington, A. J., Holmans, P., Ivanov, D., Ikeda, M., Ruderfer, D., Moran, J., Chambert, K., Toncheva, D., Georgieva, L., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2011.154 · Cited by 844 · see citing works
Self-citationAnalysis of copy number variations at 15 schizophrenia-associated loci
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CYFIP family proteins between autism and intellectual disability: links with Fragile X syndrome
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- Authors
- Ingason, A., Kirov, G., Giegling, I., Hansen, T., Isles, A. R., Jakobsen, K. D., Kristinsson, K. T., le Roux, L., Gustafsson, O., Craddock, N., Möller, H.-J., McQuillin, A., Muglia, P., Cichon, S., Rietschel, M., Ophoff, R. A., Djurovic, S., Andreassen, O. A., Pietiläinen, O. P. H., Peltonen, L., Dempster, E., Collier, D. A., St. Clair, D., Rasmussen, H. B., Glenthøj, B. Y., Kiemeney, L. A., Franke, B., Tosato, S., Bonetto, C., Saemundsen, E., Hreidarsson, S. J., GROUP Investigators, Nöthen, M. M., Gurling, H., O'Donovan, M. C., Owen, M. J., Sigurdsson, E., Petursson, H., Stefansson, H., Rujescu, D., Stefansson, K., & Werge, T.
- Affiliations
- deCODE Genetics (Iceland) (IS)
- From the Research Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark; deCODE Genetics, Reykjavik, Iceland; the Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, U.K.; the Department of Psychiatry and the Division of Molecular and Clinical Neurobiology, Ludwig-Maximilians-University, Munich; the Centre for...
- ORCID
- Ingason, Andrés
- Kirov, George
- Giegling, Ina
- Hansen, Thomas
- Isles, Anthony R.
- Craddock, Nick
- Möller, Hans-Jürgen
- McQuillin, Andrew
- Muglia, Pierandrea
- Cichon, Sven
- Rietschel, Marcella
- Ophoff, Roel A.
- Djurovic, Srdjan
- Andreassen, Ole A.
- Pietiläinen, Olli P.H.
- Peltonen, Leena
- Dempster, Emma
- Collier, David A.
- Kiemeney, Lambertus A.
- Franke, Barbara
- Tosato, Sarah
- Bonetto, Chiara
- Nöthen, Markus M.
- Owen, Michael J.
- Rujescu, Dan
- Werge, Thomas
- Venue
- American Journal of Psychiatry
- Published
- 2011-04
- Volume
- 168
- Issue
- 4
- Pages
- 408-417
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC3428917
- OpenAlex
- W2090823243
- Cited by
- 114
- References
- 42
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 2 · 2023: 5 · 2022: 5 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 6 · 2017: 5 · 2016: 4 · 2015: 11 · 2014: 13 · 2013: 12 · 2012: 20
- FWCI
- 10.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- JuSER (Forschungszentrum Jülich) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- Funders
- Bristol-Myers Squibb
- Eli Lilly and Company
- GlaxoSmithKline
- Højteknologifonden
- Wellcome Trust (089061)
- European Commission (LSHM-CT-2006-037761, 218251, 223423)
- Cardiff University
- Bundesministerium für Bildung und Forschung
- Lundbeckfonden
- Danmarks Frie Forskningsfond
- H. Lundbeck A/S
- National Institutes of Health
- Medical Research Council
- National Institute of Mental Health (R01MH071425, MH071425)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- maternal uniparental disomy, copy number variation, schizophrenia, schizoaffective disorder, early-onset psychosis, Prader-Willi syndrome, Angelman syndrome, genomic imprinting, imprinted genes, autism spectrum disorder, shared genetic etiology
- MeSH terms
- Adolescent, Adult, Child, Chromosomes, Human, Pair 15, Denmark, Female, Genotype, United Kingdom, Humans, Male, Mothers, Prader-Willi Syndrome, Psychotic Disorders, Schizophrenia, Blotting, Southern, Age of Onset, Uniparental Disomy, Young Adult, Genetic Association Studies, DNA Copy Number Variations
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