De Novo Rates and Selection of Schizophrenia-Associated Copy Number Variants
Abstract
Background At least 10 large and rare recurrent DNA copy number variants (CNVs) have been identified as risk factors for schizophrenia and other neurodevelopmental disorders. Because such conditions are associated with reduced fecundity, these pathogenic CNVs should be filtered out from the population by selection and must be replenished by de novo events.Methods To estimate the mutation rate (μ) for these CNVs and the selection pressure (s) against them, we first conducted a literature review on the rate of each of these CNVs in the population and the rate of their de novo occurrence. In each generation, the number of CNVs lost because of reduced fertility must be replenished by the same number of de novo CNVs. Therefore, the observed ratio of de novo versus all (inherited + de novo) CNVs approximates the selection coefficient (s) of that CNV. The mutation rate approximates to μ = s × q, where q is the frequency of the CNV in the population.Results High selection pressure operates at all these loci (s = .12 - .88), suggesting that following de novo occurrence, each of these CNVs persists in the population in only a few generations. The mutation rate for each CNV is high, affecting between 1:3500 and 1:30,000 individuals. The rarest CNVs have the highest selection coefficients.Conclusions The CNVs that increase risk to develop schizophrenia are caused by recent de novo mutations and are under strong selection pressure. They persist in the population because of high mutation rates.
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Such CNVs must frequently occur as recurrent de novo mutations.
“Accordingly, such CNVs must frequently occur as recurrent de novo mutations.”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [22]
Those mutations that occur in multiple unrelated individuals are likely to do so through independent de novo mutations.
“those that occur in multiple unrelated individuals are likely to do so through independent de novo mutations.7, 22, 23, 24”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [22]
Cites
The incidence of congenital heart disease.
Hoffman, J. I. E., & Kaplan, S. (2002) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(02)01886-7 · Cited by 6,099 · see citing works
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
Epilepsy: A Comprehensive Textbook
(2008) · JAMA · doi:10.1001/jama.300.4.443-a · Cited by 2,355 · see citing works
Baird, G., Simonoff, E., Pickles, A., Chandler, S., Loucas, T., Meldrum, D., & Charman, T. (2006) · The Lancet · doi:10.1016/s0140-6736(06)69041-7 · Cited by 2,104 · 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
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
Sanders, S. J., Ercan-Sencicek, A. G., Hus, V., Luo, R., Murtha, M. T., Moreno-De-Luca, D., Chu, S. H., Moreau, M. P., Gupta, A. R., Thomson, S. A., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.05.002 · Cited by 1,263 · see citing works
Ryan, A. K., Goodship, J. A., Wilson, D. I., Philip, N., Levy, A., Seidel, H., Schuffenhauer, S., Oechsler, H., Belohradsky, B. H., Prieur, M., et al. (1997) · Journal of Medical Genetics · doi:10.1136/jmg.34.10.798 · Cited by 1,192 · see citing works
Prevalence of autism-spectrum conditions: UK school-based population study
Baron-Cohen, S., Scott, F. J., Allison, C., Williams, J., Bolton, P., Matthews, F. E., & Brayne, C. (2009) · British Journal of Psychiatry · doi:10.1192/bjp.bp.108.059345 · Cited by 918 · see citing works
Schizophrenia genesis: the origins of madness
(1991) · Choice Reviews Online · doi:10.5860/choice.28-6500 · Cited by 832 · see citing works
Strong association of de novo copy number mutations with sporadic schizophrenia
Xu, B., Roos, J. L., Levy, S., van Rensburg, E. J., Gogos, J. A., & Karayiorgou, M. (2008) · Nature Genetics · doi:10.1038/ng.162 · Cited by 813 · see citing works
Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes
Mefford, H. C., Sharp, A. J., Baker, C., Itsara, A., Jiang, Z., Buysse, K., Huang, S., Maloney, V. K., Crolla, J. A., Baralle, D., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0805384 · Cited by 804 · see citing works
Rate, molecular spectrum, and consequences of human mutation
Lynch, M. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912629107 · Cited by 792 · see citing works
Rare de novo and transmitted copy-number variation in autistic spectrum disorders
Levy, D., Ronemus, M., Yamrom, B., Lee, Y.-H., Leotta, A., Kendall, J., Marks, S., Lakshmi, B., Pai, D., Ye, K., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.05.015 · Cited by 712 · 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-citationHj, M. (1950) · PubMed · Cited by 672 · see citing works
Brunetti-Pierri, N., Berg, J. S., Scaglia, F., Belmont, J., Bacino, C. A., Sahoo, T., Lalani, S. R., Graham, B., Lee, B., Shinawi, M., et al. (2008) · Nature Genetics · doi:10.1038/ng.279 · Cited by 625 · see citing works
Williams, N. M., Zaharieva, I., Martin, A., Langley, K., Mantripragada, K., Fossdal, R., Stefansson, H., Stefansson, K., Magnusson, P., Gudmundsson, O. O., et al. (2010) · The Lancet · doi:10.1016/s0140-6736(10)61109-9 · Cited by 572 · see citing works
Self-citation15q13.3 microdeletions increase risk of idiopathic generalized epilepsy.
Helbig, I., Mefford, H. C., Sharp, A. J., Guipponi, M., Fichera, M., Franke, A., Muhle, H., de Kovel, C., Baker, C., von Spiczak, S., et al. (2009) · Nature Genetics · doi:10.1038/ng.292 · Cited by 551 · see citing works
Keller, M. C., & Miller, G. F. (2006) · Behavioral and Brain Sciences · doi:10.1017/s0140525x06009095 · Cited by 545 · see citing works
Incidence of autism spectrum disorders: Changes over time and their meaning*
Rutter, M. L. (2005) · Acta Paediatrica · doi:10.1111/j.1651-2227.2005.tb01779.x · Cited by 516 · see citing works
The rate of spontaneous mutation of a human gene
Haldane, J. B. S. (1935) · Journal of Genetics · doi:10.1007/bf02982403 · Cited by 515 · see citing works
Driscoll, D. A., Salvin, J., Sellinger, B., Budarf, M. L., McDonald‐McGinn, D. M., Zackai, E. H., & Emanuel, B. S. (1993) · Journal of Medical Genetics · doi:10.1136/jmg.30.10.813 · Cited by 487 · see citing works
The rate of spontaneous mutation of a human gene
Haldane, J. B. S. (2004) · Journal of Genetics · doi:10.1007/bf02717892 · Cited by 472 · see citing works
Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies
de Kovel, C. G. F., Trucks, H., Helbig, I., Mefford, H. C., Baker, C., Leu, C., Kluck, C., Muhle, H., von Spiczak, S., Ostertag, P., et al. (2010) · Brain · doi:10.1093/brain/awp262 · Cited by 445 · see citing works
Levinson, D. F., Duan, J., Oh, S., Wang, K., Sanders, A. R., Shi, J., Zhang, N., Mowry, B. J., Olincy, A., Amin, F., et al. (2011) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2010.10060876 · Cited by 434 · see citing works
Genomic rearrangements and sporadic disease
Lupski, J. R. (2007) · Nature Genetics · doi:10.1038/ng2084 · Cited by 424 · see citing works
Support 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-citationThe annual incidence of DiGeorge/velocardiofacial syndrome
Devriendt, K., Fryns, J. P., Mortier, G., van Thienen, M. N., & Keymolen, K. (1998) · Journal of Medical Genetics · doi:10.1136/jmg.35.9.789-a · Cited by 330 · see citing works
Schizophrenia Genesis: The Origins of Madness
Forman, S. D., & van Kammen, D. P. (1992) · American Journal of Psychiatry · doi:10.1176/ajp.149.10.1401-a · Cited by 329 · see citing works
De novo rates and selection of large copy number variation
Itsara, A., Wu, H., Smith, J. D., Nickerson, D. A., Romieu, I., London, S. J., & Eichler, E. E. (2010) · Genome Research · doi:10.1101/gr.107680.110 · Cited by 328 · cited 1× · see citing works
“To calculate the variances of q and s for each schizophrenia locus we used the equation p(1-p)/n as described in Itsara et al. (2010) (58).”
Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia
Moreno-De-Luca, D., Mulle, J. G., Kaminsky, E. B., Sanders, S. J., Myers, S. M., Adam, M. P., Pakula, A. T., Eisenhauer, N. J., Uhas, K., Weik, L., et al. (2010) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2010.10.004 · Cited by 324 · see citing works
Ballif, B. C., Theisen, A. P., Coppinger, J., Gowans, G. C., Hersh, J. H., Madan‐Khetarpal, S., Schmidt, K. R., Tervo, R. C., Escobar, L., Friedrich, C. A., et al. (2008) · Molecular Cytogenetics · doi:10.1186/1755-8166-1-8 · Cited by 297 · see citing works
Dibbens, L. M., Mullen, S. A., Helbig, K. L., Mefford, H. C., Bayly, M. A., Bellows, S. T., Leu, C., Trucks, H., Obermeier, T., Wittig, M., et al. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp311 · Cited by 263 · 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
Neurexin 1 (NRXN1) Deletions in Schizophrenia
Kirov, G., Rujescu, D., Ingason, A., Collier, D. A., O'Donovan, M. C., & Owen, M. J. (2009) · Schizophrenia Bulletin · doi:10.1093/schbul/sbp079 · Cited by 235 · see citing works
Self-citationMicrodeletions of 3q29 confer high risk for schizophrenia
Mulle, J. G., Dodd, A. F., McGrath, J. A., Wolyniec, P. S., Mitchell, A. A., Shetty, A. C., Sobreira, N. L., Valle, D., Rudd, M. K., Satten, G., et al. (2010) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2010.07.013 · Cited by 223 · see citing works
The 100-year epidemiology of schizophrenia
Jablensky, A. V. (1997) · Schizophrenia Research · doi:10.1016/s0920-9964(97)85354-6 · Cited by 178 · 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
Kimura, M., & Ohta, T. (1969) · Genetics · doi:10.1093/genetics/63.3.701 · Cited by 162 · see citing works
Chromosome 1q21.1 Contiguous Gene Deletion Is Associated With Congenital Heart Disease
Christiansen, J., Dyck, J. D., Elyas, B. G., Lilley, M., Bamforth, J. S., Hicks, M., Sprysak, K. A., Tomaszewski, R., Haase, S. M., Vicen-Wyhony, L. M., et al. (2004) · Circulation Research · doi:10.1161/01.res.0000130528.72330.5c · Cited by 156 · see citing works
Bundy, H., Stahl, D., & MacCabe, J. H. (2011) · Acta Psychiatrica Scandinavica · doi:10.1111/j.1600-0447.2010.01623.x · Cited by 150 · see citing works
Murphy, K. C., & Owen, M. J. (2001) · The British Journal of Psychiatry · doi:10.1192/bjp.179.5.397 · Cited by 148 · see citing works
Self-citationTHE PREVALENCE OF MENTAL RETARDATION1
Kiely, M. (1987) · Epidemiologic Reviews · doi:10.1093/oxfordjournals.epirev.a036302 · Cited by 114 · see citing works
Ingason, A., Kirov, G., Giegling, I., Hansen, T., Isles, A. R., Jakobsen, K. D., Kristinsson, K. T., le Roux, L., Gustafsson, O., Craddock, N., et al. (2011) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2010.09111660 · Cited by 114 · see citing works
Self-citationMinimum prevalence of chromosome 22q11 deletions.
Wilson, D. I., Cross, I. E., & Burn, J. (1994) · UCL Discovery (University College London) · Cited by 82 · see citing works
Phenotypic variations on the theme of CNVs
O’Donovan, M. C., Kirov, G., & Owen, M. J. (2008) · Nature Genetics · doi:10.1038/ng1208-1392 · Cited by 65 · see citing works
Self-citationSiervi, A. D., Rossetti, M. V., Parera, V. E., Astrin, K. H., Aizencang, G. I., Glass, I. A., Batlle, A. M. D. C., & Desnick, R. J. (1999) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(19991008)86:4 · Cited by 42 · see citing works
The genetic basis for mental retardation
Raynham, H., Gibbons, R. J., Jonathan Flint, C., & Higgs, D. R. (1996) · QJM · doi:10.1093/qjmed/89.3.169 · Cited by 40 · see citing works
ON THE PERSISTENCE AND PERVASIVENESS OF A NEW MUTATION
García‐Dorado, A., Caballero, A., & Crow, J. F. (2003) · Evolution · doi:10.1111/j.0014-3820.2003.tb01507.x · Cited by 24 · see citing works
[Congenital cardiopathy in a data-based population].
Magnani, C., Bussolati, G., Gambini, L., et al. (2000) · PubMed · Cited by 2 · see citing works
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Cited by
Sorted by citations
Owen, M. J., Sawa, A., & Mortensen, P. B. (2016) · The Lancet · doi:10.1016/s0140-6736(15)01121-6 · Cited by 1,870 · see citing works
Self-citationDe novo mutations in schizophrenia implicate synaptic networks
Fromer, M., Pocklington, A. J., Kavanagh, D. H., Williams, H. J., Dwyer, S., Gormley, P., Georgieva, L., Rees, E., Palta, P., Ruderfer, D. M., et al. (2014) · Nature · doi:10.1038/nature12929 · Cited by 1,617 · see citing works
Self-citationKirov, 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-citationNeurodevelopmental model of schizophrenia: update 2012
Rapoport, J. L., Giedd, J. N., & Gogtay, N. (2012) · Molecular Psychiatry · doi:10.1038/mp.2012.23 · Cited by 790 · see citing works
Analysis of copy number variations at 15 schizophrenia-associated loci
Rees, E., Walters, J. T. R., Georgieva, L., Isles, A. R., Chambert, K. D., Richards, A. L., Mahoney-Davies, G., Legge, S. E., Moran, J. L., McCarroll, S. A., et al. (2014) · British Journal of Psychiatry · doi:10.1192/bjp.bp.113.131052 · Cited by 443 · see citing works
Self-citationThe Penetrance of Copy Number Variations for Schizophrenia and Developmental Delay
Kirov, G., Rees, E., Walters, J. T. R., Escott-Price, V., Georgieva, L., Richards, A. L., Chambert, K. D., Davies, G., Legge, S. E., Moran, J. L., et al. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.07.022 · Cited by 368 · see citing works
Self-citationPower, R. A., Kyaga, S., Uher, R., MacCabe, J. H., Långström, N., Landen, M., McGuffin, P., Lewis, C. M., Lichtenstein, P., & Svensson, A. C. (2013) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2013.268 · Cited by 336 · see citing works
Medical consequences of pathogenic CNVs in adults: analysis of the UK Biobank
Crawford, K., Bracher-Smith, M., Owen, D., Kendall, K. M., Rees, E., Pardiñas, A. F., Einon, M., Escott-Price, V., Walters, J. T. R., O’Donovan, M. C., et al. (2019) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2018-105477 · Cited by 175 · see citing works
Self-citationCNVs in neuropsychiatric disorders
Kirov, G. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv253 · Cited by 159 · see citing works
Self-citationGROUP Investigators, Rees, E., Han, J., Morgan, J., Carrera, N., Escott-Price, V., Pocklington, A. J., Duffield, M., Hall, L. S., Legge, S. E., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-019-0565-2 · Cited by 129 · see citing works
Self-citationBéna, F., Bruno, D. L., Eriksson, M., van Ravenswaaij‐Arts, C., Stark, Z., Dijkhuizen, T., Gerkes, E., Gimelli, S., Ganesamoorthy, D., Thuresson, A. C., et al. (2013) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32148 · Cited by 109 · see citing works
- Authors
- Rees, E., Moskvina, V., Owen, M. J., O'Donovan, M. C., & Kirov, G.
- Affiliations
- Cardiff University (GB)
- Corresponding author
- Kirov, George
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 70
- Issue
- 12
- Pages
- 1109-1114
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W2068817758
- Cited by
- 94
- References
- 52
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 7 · 2018: 2 · 2017: 4 · 2016: 8 · 2015: 7 · 2014: 14 · 2013: 15 · 2012: 17
- FWCI
- 9.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- schizophrenia, copy number variation, de novo mutations, mutation rate, selection pressure, selection coefficients, recurrent CNVs, neurodevelopmental disorders, fecundity, population genetics
- MeSH terms
- Algorithms, Gene Frequency, Humans, Models, Biological, Risk Factors, Schizophrenia, Selection, Genetic, DNA Copy Number Variations, Mutation Rate
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