Cited by 97Genetic Associations and EpidemiologyGenomics and Rare DiseasesAutism Spectrum Disorder Research

A Population Genetic Approach to Mapping Neurological Disorder Genes Using Deep Resequencing

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Myers, Rachel A., Casals, Ferran, Gauthier, Julie, Hamdan, Fadi F., Keebler, Jon, Boyko, Adam R., Bustamante, Carlos D., Piton, Amelie M. +11 more·2011·PLoS Genetics

Abstract

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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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
Venue
PLoS Genetics
Published
2011-02-24
Volume
7
Issue
2
Pages
e1001318
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
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
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

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