Individual common variants exert weak effects on the risk for autism spectrum disorders.
Richard Anney,Lambertus Klei,Dalila Pinto,Dalila Pinto,Joana Almeida,Elena Bacchelli,Gillian Baird,Nadia Bolshakova,Sven Bölte,Patrick Bolton,Thomas Bourgeron,Thomas Bourgeron,Sean Brennan,Jessica Brian,Jillian P. Casey,Judith Conroy,Catarina Correia,Catarina Correia,Christina Corsello,Emily L. Crawford,Maretha de Jonge,Richard Delorme,Eftichia Duketis,Frederico Duque,Annette Estes,Penny Farrar,Bridget A. Fernandez,Susan E. Folstein,Eric Fombonne,John R. Gilbert,Christopher Gillberg,Joseph T. Glessner,Andrew Green,Jonathan Green,Stephen J. Guter,Elizabeth A. Heron,Richard Holt,Jennifer L. Howe,Gillian Hughes,Vanessa Hus,Roberta Igliozzi,Suma Jacob,Graham Kenny,Cecilia Kim,Alexander Kolevzon,Vlad Kustanovich,Clara Lajonchere,Janine A. Lamb,Miriam Law-Smith,Marion Leboyer,Ann Le Couteur,Bennett L. Leventhal,Bennett L. Leventhal,Xiao-Qing Liu,Frances Lombard,Catherine Lord,Linda Lotspeich,Sabata C. Lund,Tiago R. Magalhaes,Tiago R. Magalhaes,Carine Mantoulan,Christopher J. McDougle,Christopher J. McDougle,Nadine M. Melhem,Alison K. Merikangas,Nancy J. Minshew,Ghazala Mirza,Jeff Munson,Carolyn Noakes,Gudrun Nygren,Katerina Papanikolaou,Alistair T. Pagnamenta,Barbara Parrini,Tara Paton,Andrew Pickles,David J. Posey,Fritz Poustka,Jiannis Ragoussis,Regina Regan,Wendy Roberts,Kathryn Roeder,Bernadette Rogé,Michael Rutter,Sabine Schlitt,Naisha Shah,Val C. Sheffield,Latha Soorya,Inês Sousa,Vera Stoppioni,Nuala Sykes,Raffaella Tancredi,Ann P. Thompson,Susanne Thomson,Ana Tryfon,John Tsiantis,Herman van Engeland,John B. Vincent,Fred R. Volkmar,Jacob A. S. Vorstman,Simon Wallace,Kirsty Wing,Kerstin Wittemeyer,Shawn Wood,Danielle Zurawiecki,Lonnie Zwaigenbaum,Anthony J. Bailey,Agatino Battaglia,Rita M. Cantor,Hilary Coon,Michael L. Cuccaro,Geraldine Dawson,Geraldine Dawson,Sean Ennis,Christine M. Freitag,Daniel H. Geschwind,Jonathan L. Haines,Sabine M. Klauck,William M. McMahon,Elena Maestrini,Judith Miller,Judith Miller,Anthony P. Monaco,Anthony P. Monaco,Stanley F. Nelson,John I. Nurnberger,Guiomar Oliveira,Jeremy R. Parr,Margaret A. Pericak-Vance,Joseph Piven,Gerard D. Schellenberg,Stephen W. Scherer,Astrid M. Vicente,Astrid M. Vicente,Thomas H. Wassink,Ellen M. Wijsman,Catalina Betancur,Catalina Betancur,Catalina Betancur,Joseph D. Buxbaum,Edwin H. Cook,Louise Gallagher,Michael Gill,Joachim Hallmayer,Andrew D. Paterson,James S. Sutcliffe,Peter Szatmari,Veronica J. Vieland,Hakon Hakonarson,Bernie Devlin +148 more
TLDR
Stage 2 of the Autism Genome Project genome-wide association study is reported, adding 1301 ASD families and bringing the total to 2705 families analysed, and it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.Abstract:
While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.read more
Citations
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Recurrent 15q11.2 BP1-BP2 microdeletions and microduplications in the etiology of neurodevelopmental disorders.
Chiara Picinelli,Carla Lintas,Ignazio S. Piras,Stefano Gabriele,Roberto Sacco,Claudia Brogna,Antonio M. Persico +6 more
TL;DR: Evaluated the expression levels of the four genes in peripheral blood RNA and found the expected reduction in the deleted case, while duplicated carriers displayed high interindividual variability, suggesting that differential expression of these genes could partially account for differences in clinical phenotypes, especially among duplication carriers.
Journal ArticleDOI
Identification of Human Neuronal Protein Complexes Reveals Biochemical Activities and Convergent Mechanisms of Action in Autism Spectrum Disorders
Jingjing Li,Zhihai Ma,Minyi Shi,Ramy H. Malty,Hiroyuki Aoki,Zoran Minic,Sadhna Phanse,Ke Jin,Dennis P. Wall,Zhaolei Zhang,Alexander E. Urban,Joachim Hallmayer,Mohan Babu,Michael Snyder +13 more
TL;DR: The study reveals molecular components in ASD, suggests a shared mechanism between the syndromic and idiopathic forms of ASDs, and provides a systems framework for analyzing complex human diseases.
Journal ArticleDOI
From De Novo Mutations to Personalized Therapeutic Interventions in Autism
TL;DR: Mutation detection by microarray analysis and DNA sequencing has confirmed that de novo copy-number variants or point mutations in protein-coding regions of genes contribute to risk, and some of the underlying causal variants and genes have been identified.
Journal ArticleDOI
Genetic diagnosis of autism spectrum disorders: the opportunity and challenge in the genomics era.
TL;DR: Findings from research studies in the genetics of ASD now support an important role for molecular diagnostics in the clinical genetics evaluation of ASDs and the challenge that remains is to determine the causal role of genetic variants identified through molecular testing.
Journal ArticleDOI
A CTNNA3 compound heterozygous deletion implicates a role for αT-catenin in susceptibility to autism spectrum disorder
Elena Bacchelli,Fabiola Ceroni,Dalila Pinto,Silvia Lomartire,Maila Giannandrea,Patrizia D'Adamo,Elena Bonora,Piero Parchi,Raffaella Tancredi,Agatino Battaglia,Elena Maestrini +10 more
TL;DR: The finding of a rare compound heterozygous CTNNA3 exonic deletion segregating with ASD, the absence of CTNna3 homozygous exonic deletions in controls and the high expression of Ctnna3 in both brain areas analysed implicate CTnNA3 in ASD susceptibility.
References
More filters
Journal ArticleDOI
PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses
Shaun Purcell,Shaun Purcell,Benjamin M. Neale,Benjamin M. Neale,Kathe Todd-Brown,Lori Thomas,Manuel A. R. Ferreira,David Bender,David Bender,Julian Maller,Julian Maller,Pamela Sklar,Pamela Sklar,Paul I.W. de Bakker,Paul I.W. de Bakker,Mark J. Daly,Mark J. Daly,Pak C. Sham +17 more
TL;DR: This work introduces PLINK, an open-source C/C++ WGAS tool set, and describes the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation, which focuses on the estimation and use of identity- by-state and identity/descent information in the context of population-based whole-genome studies.
Journal ArticleDOI
Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders
TL;DR: The revised interview has been reorganized, shortened, modified to be appropriate for children with mental ages from about 18 months into adulthood and linked to ICD-10 and DSM-IV criteria.
Journal ArticleDOI
Common polygenic variation contributes to risk of schizophrenia and bipolar disorder
Shaun Purcell,Shaun Purcell,Naomi R. Wray,Jennifer Stone,Jennifer Stone,Peter M. Visscher,Michael Conlon O'Donovan,Patrick F. Sullivan,Pamela Sklar,Pamela Sklar,Douglas M. Ruderfer,Andrew McQuillin,Derek W. Morris,Colm O'Dushlaine,Aiden Corvin,Peter Holmans,Stuart MacGregor,Hugh Gurling,Douglas Blackwood,Nicholas John Craddock,Michael Gill,Christina M. Hultman,Christina M. Hultman,George Kirov,Paul Lichtenstein,Walter J. Muir,Michael John Owen,Carlos N. Pato,Edward M. Scolnick,Edward M. Scolnick,David St Clair,Nigel Williams,Lyudmila Georgieva,Ivan Nikolov,Nadine Norton,Hywel Williams,Draga Toncheva,Vihra Milanova,Emma Flordal Thelander,Patrick Sullivan,Elaine Kenny,Emma M. Quinn,Khalid Choudhury,Susmita Datta,Jonathan Pimm,Srinivasa Thirumalai,Vinay Puri,Robert Krasucki,Jacob Lawrence,Digby Quested,Nicholas Bass,Caroline Crombie,Gillian Fraser,Soh Leh Kuan,Nicholas Walker,Kevin A. McGhee,Ben S. Pickard,P. Malloy,Alan W Maclean,Margaret Van Beck,Michele T. Pato,Helena Medeiros,Frank A. Middleton,Célia Barreto Carvalho,Christopher P. Morley,Ayman H. Fanous,David V. Conti,James A. Knowles,Carlos Ferreira,António Macedo,M. Helena Azevedo,Andrew Kirby,Andrew Kirby,Manuel A. R. Ferreira,Manuel A. R. Ferreira,Mark J. Daly,Mark J. Daly,Kimberly Chambert,Finny G Kuruvilla,Stacey Gabriel,Kristin G. Ardlie,Jennifer L. Moran +81 more
TL;DR: The extent to which common genetic variation underlies the risk of schizophrenia is shown, using two analytic approaches, and the major histocompatibility complex is implicate, which is shown to involve thousands of common alleles of very small effect.
Journal ArticleDOI
Strong Association of De Novo Copy Number Mutations with Autism
Jonathan Sebat,B. Lakshmi,Dheeraj Malhotra,Jennifer Troge,Christa Lese-Martin,Tom Walsh,Boris Yamrom,Seungtai Yoon,Alexander Krasnitz,Jude Kendall,Anthony Leotta,Deepa Pai,Ray Zhang,Yoon-ha Lee,James W. Hicks,Sarah J. Spence,Annette Lee,Kaija Puura,Terho Lehtimäki,David H. Ledbetter,Peter K. Gregersen,Joel D. Bregman,James S. Sutcliffe,Vaidehi Jobanputra,Wendy K. Chung,Dorothy Warburton,Mary Claire King,David Skuse,Daniel H. Geschwind,T. Conrad Gilliam,Kenny Ye,Michael Wigler +31 more
TL;DR: Findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.
Journal ArticleDOI
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations
Brian J. O'Roak,Laura Vives,Santhosh Girirajan,Emre Karakoc,Niklas Krumm,Bradley P. Coe,Roie Levy,Arthur Ko,Choli Lee,Joshua D. Smith,Emily H. Turner,Ian B. Stanaway,Benjamin Vernot,Maika Malig,Carl Baker,Beau Reilly,Joshua M. Akey,Elhanan Borenstein,Elhanan Borenstein,Mark J. Rieder,Deborah A. Nickerson,Raphael Bernier,Jay Shendure,Evan E. Eichler,Evan E. Eichler +24 more
TL;DR: It is shown that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD.
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