Strong association of de novo copy number mutations with sporadic schizophrenia
Abstract
Schizophrenia is an etiologically heterogeneous psychiatric disease, which exists in familial and nonfamilial (sporadic) forms. Here, we examine the possibility that rare de novo copy number (CN) mutations with relatively high penetrance contribute to the genetic component of schizophrenia. We carried out a whole-genome scan and implemented a number of steps for finding and confirming CN mutations. Confirmed de novo mutations were significantly associated with schizophrenia (P = 0.00078) and were collectively approximately 8 times more frequent in sporadic (but not familial) cases with schizophrenia than in unaffected controls. In comparison, rare inherited CN mutations were only modestly enriched in sporadic cases. Our results suggest that rare de novo germline mutations contribute to schizophrenia vulnerability in sporadic cases and that rare genetic lesions at many different loci can account, at least in part, for the genetic heterogeneity of this disease.
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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 [24]
The de novo rate in those with a history of psychosis in a parent was lower (1.6%) than in those without such history (5.5%), although this was not statistically significant.
“As in an earlier study,24 the de novo rate in those with a history of psychosis in a parent was lower (1.6%) than in those without such history (5.5%), although this was not statistically significant.”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [24]
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 [24]
One study showed that the rate of de novo CNV mutation in probands with no family history was 8 times higher in cases than in controls.
“One study on de novo CNV mutation in schizophrenia24 showed that the rate of de novo CNV mutation in probands with no family history was 8 times higher in cases than in controls.”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [24]
The control rates were similar to those in our experimental group with an affected parent, suggesting that technical variation between our own and other studies does not make a major impact on our conclusions.
“Finally, we note that the control rates were similar to those in our experimental group with an affected parent (who according to an earlier work24 do not have elevated rates of de novo mutation), suggesting that technical variation between our own and other studies does not make a major impact on our conclusions.”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [24]
Our estimate of the de novo rate is lower than initial reports in autism and schizophrenia.
“Our estimate of the de novo rate is lower than initial reports in autism23 and schizophrenia24”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [24]
CNVs, both deletions and duplications, have been implicated in SZ.
“CNVs, both deletions and duplications, have been implicated in SZ [132-134]”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [132]
Increased SV burden in SCZ cases has been reported by multiple groups.
“Increased SV burden in SCZ cases has been reported by multiple groups. 47,48,50”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [50]
For SCZ, the available data are insufficient to resolve the issue of whether simplex/multiplex differences exist in de novo mutation rates.
“For SCZ, the available data are insufficient to resolve this issue. 45,50”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [50]
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- Authors
- Xu, B., Roos, J. L., Levy, S., van Rensburg, E. J., Gogos, J. A., & Karayiorgou, M.
- Affiliations
- Columbia University (US)
- Vanderbilt University (US)
- Corresponding author
- Gogos, Joseph A
- Karayiorgou, Maria
- Venue
- Nature Genetics
- Published
- 2008-05-30
- Volume
- 40
- Issue
- 7
- Pages
- 880-885
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1973502710
- Cited by
- 813
- References
- 30
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 18 · 2023: 15 · 2022: 19 · 2021: 21 · 2020: 26 · 2019: 35 · 2018: 31 · 2017: 40 · 2016: 37 · 2015: 41 · 2014: 51 · 2013: 64 · 2012: 82
- FWCI
- 60.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH061399, R01MH061399, R01MH077235, MH077235)
- National Eye Institute (P30-EY08126, P30EY008126)
- National Cancer Institute (P30 CA 68485, P30CA068485)
- 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, sporadic schizophrenia, familial schizophrenia, genetic heterogeneity, germline mutations, rare variants, whole genome scan, genetic susceptibility
- MeSH terms
- Algorithms, Chromosome Mapping, Chromosomes, Human, Family, Female, Gene Frequency, Genetic Testing, Genetics, Population, Genotype, Humans, Genetic Linkage, Male, Schizophrenia, Germ-Line Mutation, Gene Dosage, Oligonucleotide Array Sequence Analysis, Inheritance Patterns
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