Analysis of rare, exonic variation amongst subjects with autism spectrum disorders and population controls.
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 va...
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2013-04-01
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doaj-9939beeb8dd24c64a4ec4cb26f0d76e22020-11-24T22:05:32ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042013-04-0194e100344310.1371/journal.pgen.1003443Analysis of rare, exonic variation amongst subjects with autism spectrum disorders and population controls.Li LiuAniko SaboBenjamin M NealeUma NagaswamyChristine StevensElaine LimCorneliu A BodeaDonna MuznyJeffrey G ReidEric BanksHillary CoonMark DepristoHuyen DinhTim FennelJason FlannickStacey GabrielKiran GarimellaShannon GrossAlicia HawesLora LewisVladimir MakarovJared MaguireIrene NewshamRyan PoplinStephan RipkeKhalid ShakirKaitlin E SamochaYuanqing WuEric BoerwinkleJoseph D BuxbaumEdwin H CookBernie DevlinGerard D SchellenbergJames S SutcliffeMark J DalyRichard A GibbsKathryn RoederWe 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.http://europepmc.org/articles/PMC3623759?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Li Liu Aniko Sabo Benjamin M Neale Uma Nagaswamy Christine Stevens Elaine Lim Corneliu A Bodea Donna Muzny Jeffrey G Reid Eric Banks Hillary Coon Mark Depristo Huyen Dinh Tim Fennel Jason Flannick Stacey Gabriel Kiran Garimella Shannon Gross Alicia Hawes Lora Lewis Vladimir Makarov Jared Maguire Irene Newsham Ryan Poplin Stephan Ripke Khalid Shakir Kaitlin E Samocha Yuanqing Wu Eric Boerwinkle Joseph D Buxbaum Edwin H Cook Bernie Devlin Gerard D Schellenberg James S Sutcliffe Mark J Daly Richard A Gibbs Kathryn Roeder |
spellingShingle |
Li Liu Aniko Sabo Benjamin M Neale Uma Nagaswamy Christine Stevens Elaine Lim Corneliu A Bodea Donna Muzny Jeffrey G Reid Eric Banks Hillary Coon Mark Depristo Huyen Dinh Tim Fennel Jason Flannick Stacey Gabriel Kiran Garimella Shannon Gross Alicia Hawes Lora Lewis Vladimir Makarov Jared Maguire Irene Newsham Ryan Poplin Stephan Ripke Khalid Shakir Kaitlin E Samocha Yuanqing Wu Eric Boerwinkle Joseph D Buxbaum Edwin H Cook Bernie Devlin Gerard D Schellenberg James S Sutcliffe Mark J Daly Richard A Gibbs Kathryn Roeder Analysis of rare, exonic variation amongst subjects with autism spectrum disorders and population controls. PLoS Genetics |
author_facet |
Li Liu Aniko Sabo Benjamin M Neale Uma Nagaswamy Christine Stevens Elaine Lim Corneliu A Bodea Donna Muzny Jeffrey G Reid Eric Banks Hillary Coon Mark Depristo Huyen Dinh Tim Fennel Jason Flannick Stacey Gabriel Kiran Garimella Shannon Gross Alicia Hawes Lora Lewis Vladimir Makarov Jared Maguire Irene Newsham Ryan Poplin Stephan Ripke Khalid Shakir Kaitlin E Samocha Yuanqing Wu Eric Boerwinkle Joseph D Buxbaum Edwin H Cook Bernie Devlin Gerard D Schellenberg James S Sutcliffe Mark J Daly Richard A Gibbs Kathryn Roeder |
author_sort |
Li Liu |
title |
Analysis of rare, exonic variation amongst subjects with autism spectrum disorders and population controls. |
title_short |
Analysis of rare, exonic variation amongst subjects with autism spectrum disorders and population controls. |
title_full |
Analysis of rare, exonic variation amongst subjects with autism spectrum disorders and population controls. |
title_fullStr |
Analysis of rare, exonic variation amongst subjects with autism spectrum disorders and population controls. |
title_full_unstemmed |
Analysis of rare, exonic variation amongst subjects with autism spectrum disorders and population controls. |
title_sort |
analysis of rare, exonic variation amongst subjects with autism spectrum disorders and population controls. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2013-04-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC3623759?pdf=render |
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