title: Analysis of rare, exonic variation amongst subjects with autism spectrum disorders and population controls.
abstract: We report on results from whole-exome sequencing (WES) of 1,039 subjects diagnosed with autism spectrum disorders (ASD) and 870 controls selected from the NIMH repository to be of similar ancestry to cases. The WES data came from two centers using different methods to produce sequence and to call variants from it. Therefore, an initial goal was to ensure the distribution of rare variation was similar for data from different centers. This proved straightforward by filtering called variants by fraction of missing data, read depth, and balance of alternative to reference reads. Results were evaluated using seven samples sequenced at both centers and by results from the association study. Next we addressed how the data and/or results from the centers should be combined. Gene-based analyses of association was an obvious choice, but should statistics for association be combined across centers (meta-analysis) or should data be combined and then analyzed (mega-analysis)? Because of the nature of many gene-based tests, we showed by theory and simulations that mega-analysis has better power than meta-analysis. Finally, before analyzing the data for association, we explored the impact of population structure on rare variant analysis in these data. Like other recent studies, we found evidence that population structure can confound case-control studies by the clustering of rare variants in ancestry space; yet, unlike some recent studies, for these data we found that principal component-based analyses were sufficient to control for ancestry and produce test statistics with appropriate distributions. After using a variety of gene-based tests and both meta- and mega-analysis, we found no new risk genes for ASD in this sample. Our results suggest that standard gene-based tests will require much larger samples of cases and controls before being effective for gene discovery, even for a disorder like ASD.
authors.affiliation: Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Aniko
authors.initials: A
authors.lastname: Sabo
authors.forename: Benjamin M
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authors.lastname: Neale
authors.forename: Uma
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authors.lastname: Nagaswamy
authors.forename: Christine
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authors.lastname: Stevens
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authors.forename: Corneliu A
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authors.forename: Hillary
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authors.forename: Mark
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authors.lastname: Depristo
authors.forename: Huyen
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authors.lastname: Dinh
authors.forename: Tim
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authors.lastname: Fennel
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authors.lastname: Flannick
authors.forename: Stacey
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authors.forename: Kiran
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authors.lastname: Garimella
authors.forename: Shannon
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authors.lastname: Gross
authors.forename: Alicia
authors.initials: A
authors.lastname: Hawes
authors.forename: Lora
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authors.lastname: Lewis
authors.forename: Vladimir
authors.initials: V
authors.lastname: Makarov
authors.forename: Jared
authors.initials: J
authors.lastname: Maguire
authors.forename: Irene
authors.initials: I
authors.lastname: Newsham
authors.forename: Ryan
authors.initials: R
authors.lastname: Poplin
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.forename: Khalid
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authors.lastname: Shakir
authors.forename: Kaitlin E
authors.initials: KE
authors.lastname: Samocha
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Wu
authors.forename: Eric
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authors.lastname: Boerwinkle
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Cook
authors.forename: Bernie
authors.initials: B
authors.lastname: Devlin
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.forename: James S
authors.initials: JS
authors.lastname: Sutcliffe
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: Kathryn
authors.initials: K
authors.lastname: Roeder
mesh_terms: D016022:Case-Control Studies; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000503:physiopathology; D059472:Exome; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D011155:Population Control; D017422:Sequence Analysis, DNA; D012984:Software