Most genetic risk for autism resides with common variation
Trent Gaugler,Lambertus Klei,Stephen Sanders,Corneliu A. Bodea,Arthur P. Goldberg,Ann B. Lee,Milind Mahajan,Dina Manaa,Yudi Pawitan,Jennifer Reichert,Stephan Ripke,Sven Sandin,Pamela Sklar,Oscar Svantesson,Abraham Reichenberg,Christina M. Hultman,Bernie Devlin,Kathryn Roeder,Joseph D. Buxbaum +18 more
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TLDR
Autism's genetic architecture is reached: its narrow-sense heritability is ∼52.4%, with most due to common variation, and rare de novo mutations contribute substantially to individual liability, yet their contribution to variance in liability, 2.6%, is modest compared to that for heritable variation.Abstract:
Joseph Buxbaum and colleagues use an epidemiological sample from Sweden to investigate the genetic architecture of autism spectrum disorders. They conclude that most inherited risk for autism is determined by common variation and that rare variation explains a smaller fraction of total heritability.read more
Citations
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Journal ArticleDOI
Synaptic, transcriptional and chromatin genes disrupted in autism
Silvia De Rubeis,Xin-Xin He,Arthur P. Goldberg,Christopher S. Poultney,Kaitlin E. Samocha,A. Ercument Cicek,Yan Kou,Li Liu,Menachem Fromer,Menachem Fromer,R. Susan Walker,Tarjinder Singh,Lambertus Klei,Jack A. Kosmicki,Shih-Chen Fu,Branko Aleksic,Monica Biscaldi,Patrick Bolton,Jessica M. Brownfeld,Jinlu Cai,Nicholas G. Campbell,Angel Carracedo,Angel Carracedo,Maria H. Chahrour,Andreas G. Chiocchetti,Hilary Coon,Emily L. Crawford,Lucy Crooks,Sarah Curran,Geraldine Dawson,Eftichia Duketis,Bridget A. Fernandez,Louise Gallagher,Evan T. Geller,Stephen J. Guter,R. Sean Hill,R. Sean Hill,Iuliana Ionita-Laza,Patricia Jiménez González,Helena Kilpinen,Sabine M. Klauck,Alexander Kolevzon,Irene Lee,Jing Lei,Terho Lehtimäki,Chiao-Feng Lin,Avi Ma'ayan,Christian R. Marshall,Alison L. McInnes,Benjamin M. Neale,Michael John Owen,Norio Ozaki,Mara Parellada,Jeremy R. Parr,Shaun Purcell,Kaija Puura,Deepthi Rajagopalan,Karola Rehnström,Abraham Reichenberg,Aniko Sabo,Michael Sachse,Stephen Sanders,Chad M. Schafer,Martin Schulte-Rüther,David Skuse,David Skuse,Christine Stevens,Peter Szatmari,Kristiina Tammimies,Otto Valladares,Annette Voran,Li-San Wang,Lauren A. Weiss,A. Jeremy Willsey,Timothy W. Yu,Timothy W. Yu,Ryan K. C. Yuen,Edwin H. Cook,Christine M. Freitag,Michael Gill,Christina M. Hultman,Thomas Lehner,Aarno Palotie,Aarno Palotie,Aarno Palotie,Gerard D. Schellenberg,Pamela Sklar,Matthew W. State,James S. Sutcliffe,Christopher A. Walsh,Christopher A. Walsh,Stephen W. Scherer,Michael E. Zwick,Jeffrey C. Barrett,David J. Cutler,Kathryn Roeder,Bernie Devlin,Mark J. Daly,Mark J. Daly,Joseph D. Buxbaum +99 more
TL;DR: Using exome sequencing, it is shown that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate of < 0.05, plus a set of 107 genes strongly enriched for those likely to affect risk (FDR < 0.30).
Journal ArticleDOI
Identification of common genetic risk variants for autism spectrum disorder
TL;DR: A genome-wide association meta-analysis of 18,381 austim spectrum disorder cases and 27,969 controls identifies five risk loci and the authors find quantitative and qualitative polygenic heterogeneity across ASD subtypes.
Journal ArticleDOI
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
F. Kyle Satterstrom,F. Kyle Satterstrom,Jack A. Kosmicki,Jiebiao Wang,Michael S. Breen,Silvia De Rubeis,Joon Yong An,Joon Yong An,Minshi Peng,Ryan Collins,Jakob Grove,Jakob Grove,Lambertus Klei,Christine Stevens,Jennifer Reichert,Maureen Mulhern,Mykyta Artomov,Sherif Gerges,Brooke Sheppard,Xinyi Xu,Aparna Bhaduri,Utku Norman,Harrison Brand,Grace Schwartz,Rachel Nguyen,Elizabeth E. Guerrero,Caroline Dias,Branko Aleksic,Richard Anney,Mafalda Barbosa,Somer L. Bishop,Alfredo Brusco,Jonas Bybjerg-Grauholm,Angel Carracedo,Marcus C.Y. Chan,Andreas G. Chiocchetti,Brian H.Y. Chung,Hilary Coon,Michael L. Cuccaro,Aurora Currò,Bernardo Dalla Bernardina,Ryan N. Doan,Enrico Domenici,Shan Dong,Chiara Fallerini,Montserrat Fernández-Prieto,Giovanni Battista Ferrero,Christine M. Freitag,Menachem Fromer,J. Jay Gargus,Daniel H. Geschwind,Elisa Giorgio,Javier González-Peñas,Stephen J. Guter,Danielle Halpern,Emily Hansen-Kiss,Xin He,Gail E. Herman,Irva Hertz-Picciotto,David M. Hougaard,Christina M. Hultman,Iuliana Ionita-Laza,Suma Jacob,Jesslyn Jamison,Astanand Jugessur,Miia Kaartinen,Gun Peggy Knudsen,Alexander Kolevzon,Itaru Kushima,So Lun Lee,Terho Lehtimäki,Elaine T. Lim,Carla Lintas,W. Ian Lipkin,Diego Lopergolo,Fátima Lopes,Yunin Ludena,Patrícia Maciel,Per Magnus,Behrang Mahjani,Nell Maltman,Dara S. Manoach,Gal Meiri,Idan Menashe,Judith Miller,Nancy J. Minshew,Eduarda Montenegro M. de Souza,Danielle de Paula Moreira,Eric M. Morrow,Ole Mors,Preben Bo Mortensen,Matthew W. Mosconi,Pierandrea Muglia,Benjamin M. Neale,Merete Nordentoft,Norio Ozaki,Aarno Palotie,Mara Parellada,Maria Rita Passos-Bueno,Margaret A. Pericak-Vance,Antonio M. Persico,Isaac N. Pessah,Kaija Puura,Abraham Reichenberg,Alessandra Renieri,Evelise Riberi,Elise B. Robinson,Elise B. Robinson,Kaitlin E. Samocha,Sven Sandin,Sven Sandin,Susan L. Santangelo,Susan L. Santangelo,Gerry Schellenberg,Stephen W. Scherer,Sabine Schlitt,Rebecca J. Schmidt,Lauren M. Schmitt,Isabela Maya Wahys Silva,Tarjinder Singh,Tarjinder Singh,Paige M. Siper,Moyra Smith,Gabriela Soares,Camilla Stoltenberg,Pål Surén,Ezra Susser,John A. Sweeney,Peter Szatmari,Lara Tang,Flora Tassone,Karoline Teufel,Elisabetta Trabetti,Maria del Pilar Trelles,Christopher A. Walsh,Lauren A. Weiss,Thomas Werge,Donna M. Werling,Emilie M. Wigdor,Emilie M. Wigdor,Emma Wilkinson,A. Jeremy Willsey,Timothy W. Yu,Mullin H.C. Yu,Ryan Yuen,Elaine Cristina Zachi,Esben Agerbo,Thomas Damm Als,Vivek Appadurai,Marie Bækvad-Hansen,Rich Belliveau,Alfonso Buil,Caitlin E. Carey,Felecia Cerrato,Kimberly Chambert,Claire Churchhouse,Claire Churchhouse,Søren Dalsgaard,Ditte Demontis,Ashley Dumont,Jacqueline I. Goldstein,Christine Søholm Hansen,Mads E. Hauberg,Mads E. Hauberg,Mads E. Hauberg,Mads V. Hollegaard,Daniel P. Howrigan,Hailiang Huang,Julian Maller,Alicia R. Martin,Joanna Martin,Manuel Mattheisen,Jennifer L. Moran,Jonatan Pallesen,Duncan S. Palmer,Carsten Bøcker Pedersen,Marianne Giørtz Pedersen,Timothy Poterba,Jesper Buchhave Poulsen,Stephan Ripke,Andrew J. Schork,Wesley K. Thompson,Patrick Turley,Raymond K. Walters,Catalina Betancur,Edwin H. Cook,Louise Gallagher,Michael Gill,James S. Sutcliffe,Audrey Thurm,Michael E. Zwick,Anders D. Børglum,Matthew W. State,A. Ercument Cicek,A. Ercument Cicek,Michael E. Talkowski,David J. Cutler,Bernie Devlin,Stephen Sanders,Kathryn Roeder,Mark J. Daly,Joseph D. Buxbaum +201 more
TL;DR: The largest exome sequencing study of autism spectrum disorder (ASD) to date, using an enhanced analytical framework to integrate de novo and case-control rare variation, identifies 102 risk genes at a false discovery rate of 0.1 or less, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.
Journal ArticleDOI
Autism spectrum disorder.
TL;DR: Clinicians can make a difference by providing timely and individualised help to families navigating referrals and access to community support systems, by providing accurate information despite often unfiltered media input, and by anticipating transitions such as family changes and school entry and leaving.
References
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Book
Genetics and Analysis of Quantitative Traits
Michael Lynch,Bruce Walsh +1 more
TL;DR: This book discusses the genetic Basis of Quantitative Variation, Properties of Distributions, Covariance, Regression, and Correlation, and Properties of Single Loci, and Sources of Genetic Variation for Multilocus Traits.
Journal ArticleDOI
GCTA: a tool for genome-wide complex trait analysis.
TL;DR: The GCTA software is a versatile tool to estimate and partition complex trait variation with large GWAS data sets and focuses on the function of estimating the variance explained by all the SNPs on the X chromosome and testing the hypotheses of dosage compensation.
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.
Related Papers (5)
The contribution of de novo coding mutations to autism spectrum disorder
Ivan Iossifov,Brian J. O'Roak,Stephen Sanders,Stephen Sanders,Michael Ronemus,Niklas Krumm,Dan Levy,Holly A.F. Stessman,Kali Witherspoon,Laura Vives,Karynne E. Patterson,Joshua D. Smith,Bryan W. Paeper,Deborah A. Nickerson,Jeanselle Dea,Shan Dong,Shan Dong,Luis E. Gonzalez,Jeffrey D. Mandell,Shrikant Mane,Michael T. Murtha,Catherine A.W. Sullivan,Michael F. Walker,Zainulabedin Waqar,Liping Wei,A. Jeremy Willsey,A. Jeremy Willsey,Boris Yamrom,Yoon-ha Lee,Ewa A. Grabowska,Ertugrul Dalkic,Ertugrul Dalkic,Zihua Wang,Steven Marks,Peter Andrews,Anthony Leotta,Jude Kendall,Inessa Hakker,Julie Rosenbaum,Beicong Ma,Linda Rodgers,Jennifer Troge,Giuseppe Narzisi,Seungtai Yoon,Michael C. Schatz,Kenny Ye,W. Richard McCombie,Jay Shendure,Evan E. Eichler,Evan E. Eichler,Matthew W. State,Matthew W. State,Michael Wigler +52 more
Synaptic, transcriptional and chromatin genes disrupted in autism
Silvia De Rubeis,Xin-Xin He,Arthur P. Goldberg,Christopher S. Poultney,Kaitlin E. Samocha,A. Ercument Cicek,Yan Kou,Li Liu,Menachem Fromer,Menachem Fromer,R. Susan Walker,Tarjinder Singh,Lambertus Klei,Jack A. Kosmicki,Shih-Chen Fu,Branko Aleksic,Monica Biscaldi,Patrick Bolton,Jessica M. Brownfeld,Jinlu Cai,Nicholas G. Campbell,Angel Carracedo,Angel Carracedo,Maria H. Chahrour,Andreas G. Chiocchetti,Hilary Coon,Emily L. Crawford,Lucy Crooks,Sarah Curran,Geraldine Dawson,Eftichia Duketis,Bridget A. Fernandez,Louise Gallagher,Evan T. Geller,Stephen J. Guter,R. Sean Hill,R. Sean Hill,Iuliana Ionita-Laza,Patricia Jiménez González,Helena Kilpinen,Sabine M. Klauck,Alexander Kolevzon,Irene Lee,Jing Lei,Terho Lehtimäki,Chiao-Feng Lin,Avi Ma'ayan,Christian R. Marshall,Alison L. McInnes,Benjamin M. Neale,Michael John Owen,Norio Ozaki,Mara Parellada,Jeremy R. Parr,Shaun Purcell,Kaija Puura,Deepthi Rajagopalan,Karola Rehnström,Abraham Reichenberg,Aniko Sabo,Michael Sachse,Stephen Sanders,Chad M. Schafer,Martin Schulte-Rüther,David Skuse,David Skuse,Christine Stevens,Peter Szatmari,Kristiina Tammimies,Otto Valladares,Annette Voran,Li-San Wang,Lauren A. Weiss,A. Jeremy Willsey,Timothy W. Yu,Timothy W. Yu,Ryan K. C. Yuen,Edwin H. Cook,Christine M. Freitag,Michael Gill,Christina M. Hultman,Thomas Lehner,Aarno Palotie,Aarno Palotie,Aarno Palotie,Gerard D. Schellenberg,Pamela Sklar,Matthew W. State,James S. Sutcliffe,Christopher A. Walsh,Christopher A. Walsh,Stephen W. Scherer,Michael E. Zwick,Jeffrey C. Barrett,David J. Cutler,Kathryn Roeder,Bernie Devlin,Mark J. Daly,Mark J. Daly,Joseph D. Buxbaum +99 more
De novo mutations revealed by whole-exome sequencing are strongly associated with autism
Stephen Sanders,Michael T. Murtha,Abha R. Gupta,John D. Murdoch,Melanie J. Raubeson,A. Jeremy Willsey,A. Gulhan Ercan-Sencicek,Nicholas M. DiLullo,Neelroop N. Parikshak,Jason L. Stein,Michael F. Walker,Gordon T. Ober,Nicole A. Teran,Youeun Song,Paul El-Fishawy,Ryan C. Murtha,Murim Choi,John D. Overton,Robert D. Bjornson,Nicholas Carriero,Kyle A. Meyer,Kaya Bilguvar,Shrikant Mane,Nenad Sestan,Richard P. Lifton,Murat Gunel,Kathryn Roeder,Daniel H. Geschwind,Bernie Devlin,Matthew W. State +29 more
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
Patterns and rates of exonic de novo mutations in autism spectrum disorders
Benjamin M. Neale,Yan Kou,Li Liu,Avi Ma'ayan,Kaitlin E. Samocha,Kaitlin E. Samocha,Aniko Sabo,Chiao-Feng Lin,Christine Stevens,Li-San Wang,Vladimir Makarov,Paz Polak,Paz Polak,Seungtai Yoon,Jared Maguire,Emily L. Crawford,Nicholas G. Campbell,Evan T. Geller,Otto Valladares,Chad M. Schafer,Han Liu,Tuo Zhao,Guiqing Cai,Jayon Lihm,Ruth Dannenfelser,Omar Jabado,Zuleyma Peralta,Uma Nagaswamy,Donna M. Muzny,Jeffrey G. Reid,Irene Newsham,Yuanqing Wu,Lora Lewis,Yi Han,Benjamin F. Voight,Benjamin F. Voight,Elaine T. Lim,Elaine T. Lim,Elizabeth J. Rossin,Elizabeth J. Rossin,Andrew Kirby,Andrew Kirby,Jason Flannick,Menachem Fromer,Menachem Fromer,Khalid Shakir,Timothy Fennell,Kiran V. Garimella,Eric Banks,Ryan Poplin,Stacey Gabriel,Mark A. DePristo,Jack R. Wimbish,Braden E. Boone,Shawn Levy,Catalina Betancur,Shamil R. Sunyaev,Shamil R. Sunyaev,Eric Boerwinkle,Eric Boerwinkle,Joseph D. Buxbaum,Edwin H. Cook,Bernie Devlin,Richard A. Gibbs,Kathryn Roeder,Gerard D. Schellenberg,James S. Sutcliffe,Mark J. Daly,Mark J. Daly +68 more