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Schizophrenia: a common disease caused by multiple rare alleles
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Summary: Schizophrenia is widely held to stem from the combined effects of multiple common polymorphisms, each with a small impact on disease risk. We suggest an alternative view: that schizophrenia is highly heterogeneous genetically and that many predisposing mutations are highly penetrant and individually rare, even specific to single cases or families. This ‘common disease – rare alleles' hypothesis is supported by recent findings in human genomics and by allelic and locus heterogeneity for other complex traits. We review the implications of this model for gene discovery research in schizophrenia.
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“The notion is that a disease such as schizophrenia is actually a collection of hundreds, or possibly even thousands, of similar conditions attributable to rare variants at individual loci18.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [18]
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Metadata
- Authors
- McClellan, J. M., Susser, E., & King, M.-C.
- Affiliations
- University of Washington (US)
- New York State Psychiatric Institute (US)
- Corresponding author
- McClellan, Jon M.
- Venue
- British Journal of Psychiatry
- Publisher
- Royal College of Psychiatrists
- Published
- 2007-03
- Volume
- 190
- Issue
- 3
- Pages
- 194-199
- ISSN
- 0007-1250 (ISSN-L)
- 1472-1465
- OpenAlex
- W2114381854
- Cited by
- 296
- References
- 85
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 5 · 2023: 2 · 2022: 6 · 2021: 7 · 2020: 10 · 2019: 7 · 2018: 1 · 2017: 7 · 2016: 13 · 2015: 14 · 2014: 16 · 2013: 24 · 2012: 23
- FWCI
- 5.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The British Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5k20mh001120-05)
- National Institute of Mental Health (MH 01120)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- schizophrenia, genetic heterogeneity, locus heterogeneity, allelic heterogeneity, rare mutations, penetrance, genetic susceptibility, gene discovery, complex traits
- MeSH terms
- Alleles, Humans, Genetic Linkage, Mutation, Nerve Tissue Proteins, Polymorphism, Genetic, RNA, Messenger, Schizophrenia, Genome, Human, Genetic Predisposition to Disease, Biomedical Research, RNA, Long Noncoding
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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