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Analysis of Rare,Exonic Variation amongst Subjects with Autism Spectrum Disorders and Population Controls
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نویسنده
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liu l. ,sabo a. ,neale b.m. ,nagaswamy u. ,stevens c. ,lim e. ,bodea c.a. ,muzny d. ,reid j.g. ,banks e. ,coon h. ,depristo m. ,dinh h. ,fennel t. ,flannick j. ,gabriel s. ,garimella k. ,gross s. ,hawes a. ,lewis l. ,makarov v. ,maguire j. ,newsham i. ,poplin r. ,ripke s. ,shakir k. ,samocha k.e. ,wu y. ,boerwinkle e. ,buxbaum j.d. ,cook jr. e.h. ,devlin b. ,schellenberg g.d. ,sutcliffe j.s. ,daly m.j. ,gibbs r.a. ,roeder k.
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منبع
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plos genetics - 2013 - دوره : 9 - شماره : 4
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چکیده
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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. © 2013 liu et al.
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آدرس
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department of statistics,carnegie mellon university,pittsburgh,pa, United States, human genome sequencing center,baylor college of medicine,houston,tx, United States, analytic and translational genetics unit,department of medicine,massachusetts general hospital and harvard medical school,boston,ma,united states,program in medical and population genetics,broad institute of harvard and mit,cambridge,ma, United States, human genome sequencing center,baylor college of medicine,houston,tx, United States, program in medical and population genetics,broad institute of harvard and mit,cambridge,ma, United States, analytic and translational genetics unit,department of medicine,massachusetts general hospital and harvard medical school,boston,ma,united states,program in medical and population genetics,broad institute of harvard and mit,cambridge,ma, United States, department of statistics,carnegie mellon university,pittsburgh,pa, United States, human genome sequencing center,baylor college of medicine,houston,tx, United States, human genome sequencing center,baylor college of medicine,houston,tx, United States, program in medical and population genetics,broad institute of harvard and mit,cambridge,ma, United States, department of psychiatry,university of utah,salt lake city,ut, United States, program in medical and population genetics,broad institute of harvard and mit,cambridge,ma, United States, human genome sequencing center,baylor college of medicine,houston,tx, United States, program in medical and population genetics,broad institute of harvard and mit,cambridge,ma, United States, program in medical and population genetics,broad institute of harvard and mit,cambridge,ma, United States, program in medical and population genetics,broad institute of harvard and mit,cambridge,ma, United States, program in medical and population genetics,broad institute of harvard and mit,cambridge,ma, United States, human genome sequencing center,baylor college of medicine,houston,tx, United States, human genome sequencing center,baylor college of medicine,houston,tx, United States, human genome sequencing center,baylor college of medicine,houston,tx, United States, seaver autism center for research and treatment,mount sinai school of medicine,new york,ny,united states,department of psychiatry,mount sinai school of medicine,new york,ny, United States, program in medical and population genetics,broad institute of harvard and mit,cambridge,ma, United States, university of texas md anderson cancer center,houston,tx, United States, program in medical and population genetics,broad institute of harvard and mit,cambridge,ma, United States, analytic and translational genetics unit,department of medicine,massachusetts general hospital and harvard medical school,boston,ma,united states,program in medical and population genetics,broad institute of harvard and mit,cambridge,ma, United States, program in medical and population genetics,broad institute of harvard and mit,cambridge,ma, United States, analytic and translational genetics unit,department of medicine,massachusetts general hospital and harvard medical school,boston,ma,united states,program in medical and population genetics,broad institute of harvard and mit,cambridge,ma, United States, university of texas md anderson cancer center,houston,tx, United States, human genome sequencing center,baylor college of medicine,houston,tx,united states,human genetics center,university of texas health science center at houston,houston,tx, United States, seaver autism center for research and treatment,mount sinai school of medicine,new york,ny,united states,department of psychiatry,mount sinai school of medicine,new york,ny,united states,department of genetics and genomic sciences,mount sinai school of medicine,new york,ny,united states,friedman brain institute,mount sinai school of medicine,new york,ny, United States, department of psychiatry,university of illinois at chicago,chicago,il, United States, department of psychiatry,university of pittsburgh school of medicine,pittsburgh,pa, United States, pathology and laboratory medicine,perelman school of medicine,university of pennsylvania,philadelphia,pa, United States, vanderbilt brain institute,department of molecular physiology and biophysics and department of psychiatry,vanderbilt university,nashville,tn, United States, analytic and translational genetics unit,department of medicine,massachusetts general hospital and harvard medical school,boston,ma,united states,program in medical and population genetics,broad institute of harvard and mit,cambridge,ma, United States, human genome sequencing center,baylor college of medicine,houston,tx, United States, department of statistics,carnegie mellon university,pittsburgh,pa,united states,ray and stephanie lane center for computational biology,carnegie mellon university,pittsburgh,pa, United States
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Authors
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