A Population Genetic Approach to Mapping Neurological Disorder Genes Using Deep Resequencing
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Deep resequencing of functional regions in human genomes is key to identifying potentially causal rare variants for complex disorders. Here, we present the results from a large-sample resequencing (n = 285 patients) study of candidate genes coupled with population genetics and statistical methods to identify rare variants associated with Autism Spectrum Disorder and Schizophrenia. Three genes, MAP1A, GRIN2B, and CACNA1F, were consistently identified by different methods as having significant excess of rare missense mutations in either one or both disease cohorts. In a broader context, we also found that the overall site frequency spectrum of variation in these cases is best explained by population models of both selection and complex demography rather than neutral models or models accounting for complex demography alone. Mutations in the three disease-associated genes explained much of the difference in the overall site frequency spectrum among the cases versus controls. This study demonstrates that genes associated with complex disorders can be mapped using resequencing and analytical methods with sample sizes far smaller than those required by genome-wide association studies. Additionally, our findings support the hypothesis that rare mutations account for a proportion of the phenotypic variance of these complex disorders.
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Exome sequencing revealed schizophrenia-linked de novo mutations in GRIN2A and GRIN2B.
“Exome sequencing has revealed schizophrenia-linked de novo mutations in GRIN2A and GRIN2B [Tarabeux, 2011 #3386;Myers, 2011 #3486]”
From Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis (2016) · cites this paper as Myers, 2011 #3486
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- Authors
- Myers, R. A., Casals, F., Gauthier, J., Hamdan, F. F., Keebler, J., Boyko, A. R., Bustamante, C. D., Piton, A. M., Spiegelman, D., Henrion, E., Zilversmit, M., Hussin, J., Quinlan, J., Yang, Y., Lafrenière, R. G., Griffing, A. R., Stone, E. A., Rouleau, G. A., & Awadalla, P.
- Affiliations
- North Carolina State University (US)
- Centre Hospitalier de l’Université de Montréal (CA)
- Stanford Medicine (US)
- Université de Montréal (CA)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Corresponding author
- Rouleau, Guy A.
- Awadalla, Philip
- ORCID
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-02-24
- Volume
- 7
- Issue
- 2
- Pages
- e1001318
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3044677
- OpenAlex
- W1965970535
- Cited by
- 97
- References
- 76
- Citations by year
- 2026: 5 · 2025: 1 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 5 · 2019: 7 · 2018: 4 · 2017: 6 · 2016: 5 · 2015: 10 · 2014: 11 · 2013: 9 · 2012: 16
- FWCI
- 7.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, other-oa)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship@McGill (McGill) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- eScholarship@McGill (McGill) (submittedVersion, other-oa)
- ANU Open Research (Australian National University) (submittedVersion)
- Funders
- Genome Canada
- Ministère du Développement Économique, de l’Innovation et de l’Exportation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- autism spectrum disorder, schizophrenia, candidate genes, MAP1A, NR2B subunit, CACNA1F, site frequency spectrum, natural selection, population genetics, neurological disorders, gene mapping
- MeSH terms
- Child, Child Development Disorders, Pervasive, Chromosome Mapping, Female, Genetics, Population, Humans, Male, Mutation, Schizophrenia, Selection, Genetic, Cohort Studies, Sequence Analysis, DNA, Polymorphism, Single Nucleotide, Genetic Loci
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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