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Rare Copy Number Variants<subtitle>A Point of Rarity in Genetic Risk for Bipolar Disorder and Schizophrenia</subtitle><alt-title>Rare Copy Number Variants</alt-title>
Open accessAbstract
CONTEXT: Recent studies suggest that copy number variation in the human genome is extensive and may play an important role in susceptibility to disease, including neuropsychiatric disorders such as schizophrenia and autism. The possible involvement of copy number variants (CNVs) in bipolar disorder has received little attention to date. OBJECTIVES: To determine whether large (>100,000 base pairs) and rare (found in <1% of the population) CNVs are associated with susceptibility to bipolar disorder and to compare with findings in schizophrenia. DESIGN: A genome-wide survey of large, rare CNVs in a case-control sample using a high-density microarray. SETTING: The Wellcome Trust Case Control Consortium. PARTICIPANTS: There were 1697 cases of bipolar disorder and 2806 nonpsychiatric controls. All participants were white UK residents. MAIN OUTCOME MEASURES: Overall load of CNVs and presence of rare CNVs. RESULTS: The burden of CNVs in bipolar disorder was not increased compared with controls and was significantly less than in schizophrenia cases. The CNVs previously implicated in the etiology of schizophrenia were not more common in cases with bipolar disorder. CONCLUSIONS: Schizophrenia and bipolar disorder differ with respect to CNV burden in general and association with specific CNVs in particular. Our data are consistent with the possibility that possession of large, rare deletions may modify the phenotype in those at risk of psychosis: those possessing such events are more likely to be diagnosed as having schizophrenia, and those without them are more likely to be diagnosed as having bipolar disorder.
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In the citing paper
“For BIP, there are reports of increased 51–53 and similar SV burden in cases versus controls 54,55”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [54]
In the citing paper
“Current evidence suggests that CNVs have a role to play (Malhotra et al., 2011), but some, particularly large deletions appear to play a very limited role (Grozeva et al., 2010; Malhotra et al., 2011).”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Grozeva et al., 2010
In the citing paper
“However, the observed effects were still quite small (OR~1.5), and results from two other studies (Grozeva et al., 2010; McQuillin et al., 2011) did not support these findings.”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Grozeva et al., 2010
In the citing paper
“Pleiotropic effects are common, the same CNV often conferring risk for a range of neurodevelopmental phenotypes including autism, mental retardation, attention deficit hyperactivity disorder and epilepsy”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [14]
In the citing paper
“there is little evidence that schizophrenia-associated CNVs confer risk for bipolar disorder.14”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [14]
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“1).(18,19) The estimatedeffectsizes for theseCNVsaresubstantiallygreater than those conferred by the SNPs discussed earlier.”
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“There have been reports of specific CNVs in individuals with bipolar disorder, but none has addressed the question of whether CNVs show significant overrepresentation in cases compared with controls.(21,22) The aim of the present study was to investigate CNVs in a large sample of patients with bipolar disorder (n=1697…”
MethodSingleton deletions throughout the genome increase risk of bipolar disorder
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“The only systematic study to date for bipolar disorder did not find anyincrease inoverallCNVload,althoughtherewasanominally significant increase in “singleton” CNVs in cases compared with controls.(20) There have been reports of specific CNVs in individuals with bipolar disorder, but none has addressed the question of…”
BackgroundCraddock, N. J., Jones, L. A., Jones, I. R., Kirov, G., Green, E., Grozeva, D., Moskvina, V., Nikolov, I., Hamshere, M. L., Vukcevic, D., et al. (2008) · Molecular Psychiatry · doi:10.1038/mp.2008.66 · Cited by 134
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“1).(18,19) The estimatedeffectsizes for theseCNVsaresubstantiallygreater than those conferred by the SNPs discussed earlier.”
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“Current evidence suggests that, consistent with findings in GWASs of nonpsychiatric disorders, a large number of susceptibility loci will be identified as larger samples are studied.(7) The focus of GWASs is identification of common polymorphisms that influence susceptibility to illness.”
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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
Genetic architectures of psychiatric disorders: the emerging picture and its implications
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CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics
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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
“14 All of the currently known risk CNVs are rare (control frequencies typically 0.001) and confer substantial effects on risk (odds ratios 3–30).”
BackgroundInfluentialSelf-citationPractitioner Review: What have we learnt about the causes of ADHD?
Thapar, A., Cooper, M., Eyre, O., & Langley, K. (2013) · Journal of Child Psychology and Psychiatry · doi:10.1111/j.1469-7610.2012.02611.x · Cited by 701
“It is of interest that association between CNVs and mood disorders has not been consistently found suggesting that such variants might be especially important in neurodevelopmental disorders (Grozeva et al., 2010).”
Background
Metadata
- Authors
- Grozeva, D.
- Affiliations
- Cardiff University (GB)
- Corresponding author
- Grozeva, Detelina
- ORCID
- Grozeva, Detelina
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2010-04-01
- Volume
- 67
- Issue
- 4
- Pages
- 318
- ISSN
- 0003-990X (ISSN-L)
- PMC
- PMC4476027
- OpenAlex
- W2165070791
- Cited by
- 192
- References
- 44
- Citations by year
- 2025: 1 · 2024: 2 · 2022: 8 · 2021: 6 · 2020: 7 · 2019: 5 · 2018: 6 · 2017: 7 · 2016: 13 · 2015: 14 · 2014: 24 · 2013: 16 · 2012: 38
- FWCI
- 17.43
- Type
- journal article
- Language
- en
- Open access
- green
- kclpure.kcl.ac.uk
- Licence
- other-oa
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Figshare (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Wellcome Trust (079643, 061858, 090532)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- copy number variation, bipolar disorder, schizophrenia, genetic susceptibility, CNV burden, psychosis, neuropsychiatric disorders, Wellcome Trust Case Control Consortium
- MeSH terms
- Bipolar Disorder, Genotype, Humans, Risk Factors, Schizophrenia, Genetic Predisposition to Disease, Oligonucleotide Array Sequence Analysis, Genome-Wide Association Study, DNA Copy Number Variations
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