Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder

Ryan K C Yuen; Daniele Merico; Matt Bookman; Jennifer L. Howe; Bhooma Thiruvahindrapuram; Rohan V. Patel; Joe Whitney; Nicole Deflaux; Jonathan Bingham; Zhuozhi Wang; Giovanna Pellecchia; Janet A. Buchanan; Susan Walker; Christian R. Marshall; Mohammed Uddin; Mehdi Zarrei; Eric Deneault; Lia D'Abate; Ada J S Chan; Stephanie Koyanagi; Tara Paton; Sergio L. Pereira; Ny Hoang; Worrawat Engchuan; Edward J. Higginbotham; Karen Ho; Sylvia Lamoureux; Weili Li; Jeffrey R. MacDonald; Thomas Nalpathamkalam; Wilson W L Sung; Fiona J. Tsoi; John Wei; Lizhen Xu; Anne Marie Tasse; Emily Kirby; William Van Etten; Simon Twigger; Wendy Roberts; Irene Drmic; Sanne Jilderda; Bonnie Mackinnon Modi; Barbara Kellam; Michael Szego; Cheryl Cytrynbaum; Rosanna Weksberg; Lonnie Zwaigenbaum; Marc Woodbury-Smith; Jessica Brian; Lili Senman; Alana Iaboni; Krissy Doyle-Thomas; Ann Thompson; Christina Chrysler; Jonathan Leef; Tal Savion-Lemieux; Isabel M. Smith; Xudong Liu; Rob Nicolson; Vicki Seifer; Angie Fedele; Edwin H. Cook; Stephen Dager; Annette Estes; Louise Gallagher; Beth A. Malow; Jeremy R. Parr; Sarah J. Spence; Jacob Vorstman; Brendan J. Frey; James T. Robinson; Lisa J. Strug; Bridget A. Fernandez; Mayada Elsabbagh; Melissa T. Carter; Joachim Hallmayer; Bartha M. Knoppers; Evdokia Anagnostou; Peter Szatmari; Robert H. Ring; David Glazer; Mathew T. Pletcher; Stephen W. Scherer

doi:10.1038/nn.4524

Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder

Ryan K C Yuen, Daniele Merico, Matt Bookman, Jennifer L. Howe, Bhooma Thiruvahindrapuram, Rohan V. Patel, Joe Whitney, Nicole Deflaux, Jonathan Bingham, Zhuozhi Wang, Giovanna Pellecchia, Janet A. Buchanan, Susan Walker, Christian R. Marshall, Mohammed Uddin, Mehdi Zarrei, Eric Deneault, Lia D'Abate, Ada J S Chan, Stephanie KoyanagiTara Paton, Sergio L. Pereira, Ny Hoang, Worrawat Engchuan, Edward J. Higginbotham, Karen Ho, Sylvia Lamoureux, Weili Li, Jeffrey R. MacDonald, Thomas Nalpathamkalam, Wilson W L Sung, Fiona J. Tsoi, John Wei, Lizhen Xu, Anne Marie Tasse, Emily Kirby, William Van Etten, Simon Twigger, Wendy Roberts, Irene Drmic, Sanne Jilderda, Bonnie Mackinnon Modi, Barbara Kellam, Michael Szego, Cheryl Cytrynbaum, Rosanna Weksberg, Lonnie Zwaigenbaum, Marc Woodbury-Smith, Jessica Brian, Lili Senman, Alana Iaboni, Krissy Doyle-Thomas, Ann Thompson, Christina Chrysler, Jonathan Leef, Tal Savion-Lemieux, Isabel M. Smith, Xudong Liu, Rob Nicolson, Vicki Seifer, Angie Fedele, Edwin H. Cook, Stephen Dager, Annette Estes, Louise Gallagher, Beth A. Malow, Jeremy R. Parr, Sarah J. Spence, Jacob Vorstman, Brendan J. Frey, James T. Robinson, Lisa J. Strug, Bridget A. Fernandez, Mayada Elsabbagh, Melissa T. Carter, Joachim Hallmayer, Bartha M. Knoppers, Evdokia Anagnostou, Peter Szatmari, Robert H. Ring, David Glazer, Mathew T. Pletcher, Stephen W. Scherer^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

We are performing whole-genome sequencing of families with autism spectrum disorder (ASD) to build a resource (MSSNG) for subcategorizing the phenotypes and underlying genetic factors involved. Here we report sequencing of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible on a cloud platform and through a controlled-access internet portal. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertions and deletions or copy number variations per ASD subject. We identified 18 new candidate ASD-risk genes and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (P = 6 × 10^-4). In 294 of 2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried copy number variations and/or chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.

Original language	English
Pages (from-to)	602-611
Number of pages	10
Journal	Nature Neuroscience
Volume	20
Issue number	4
DOIs	https://doi.org/10.1038/nn.4524
Publication status	Published - Apr 2017

Keywords

Autism spectrum disorders
Next-generation sequencing

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10.1038/nn.4524

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Yuen, R. K. C., Merico, D., Bookman, M., Howe, J. L., Thiruvahindrapuram, B., Patel, R. V., Whitney, J., Deflaux, N., Bingham, J., Wang, Z., Pellecchia, G., Buchanan, J. A., Walker, S., Marshall, C. R., Uddin, M., Zarrei, M., Deneault, E., D'Abate, L., Chan, A. J. S., ... Scherer, S. W. (2017). Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. Nature Neuroscience, 20(4), 602-611. https://doi.org/10.1038/nn.4524

@article{9adbe235e3624fd2a520f50749939d6c,

title = "Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder",

abstract = "We are performing whole-genome sequencing of families with autism spectrum disorder (ASD) to build a resource (MSSNG) for subcategorizing the phenotypes and underlying genetic factors involved. Here we report sequencing of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible on a cloud platform and through a controlled-access internet portal. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertions and deletions or copy number variations per ASD subject. We identified 18 new candidate ASD-risk genes and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (P = 6 × 10-4). In 294 of 2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried copy number variations and/or chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.",

keywords = "Autism spectrum disorders, Next-generation sequencing",

author = "Yuen, {Ryan K C} and Daniele Merico and Matt Bookman and Howe, {Jennifer L.} and Bhooma Thiruvahindrapuram and Patel, {Rohan V.} and Joe Whitney and Nicole Deflaux and Jonathan Bingham and Zhuozhi Wang and Giovanna Pellecchia and Buchanan, {Janet A.} and Susan Walker and Marshall, {Christian R.} and Mohammed Uddin and Mehdi Zarrei and Eric Deneault and Lia D'Abate and Chan, {Ada J S} and Stephanie Koyanagi and Tara Paton and Pereira, {Sergio L.} and Ny Hoang and Worrawat Engchuan and Higginbotham, {Edward J.} and Karen Ho and Sylvia Lamoureux and Weili Li and MacDonald, {Jeffrey R.} and Thomas Nalpathamkalam and Sung, {Wilson W L} and Tsoi, {Fiona J.} and John Wei and Lizhen Xu and Tasse, {Anne Marie} and Emily Kirby and {Van Etten}, William and Simon Twigger and Wendy Roberts and Irene Drmic and Sanne Jilderda and Modi, {Bonnie Mackinnon} and Barbara Kellam and Michael Szego and Cheryl Cytrynbaum and Rosanna Weksberg and Lonnie Zwaigenbaum and Marc Woodbury-Smith and Jessica Brian and Lili Senman and Alana Iaboni and Krissy Doyle-Thomas and Ann Thompson and Christina Chrysler and Jonathan Leef and Tal Savion-Lemieux and Smith, {Isabel M.} and Xudong Liu and Rob Nicolson and Vicki Seifer and Angie Fedele and Cook, {Edwin H.} and Stephen Dager and Annette Estes and Louise Gallagher and Malow, {Beth A.} and Parr, {Jeremy R.} and Spence, {Sarah J.} and Jacob Vorstman and Frey, {Brendan J.} and Robinson, {James T.} and Strug, {Lisa J.} and Fernandez, {Bridget A.} and Mayada Elsabbagh and Carter, {Melissa T.} and Joachim Hallmayer and Knoppers, {Bartha M.} and Evdokia Anagnostou and Peter Szatmari and Ring, {Robert H.} and David Glazer and Pletcher, {Mathew T.} and Scherer, {Stephen W.}",

note = "Funding Information: This work was funded by Autism Speaks, Autism Speaks Canada, the Canadian Institute for Advanced Research, the University of Toronto McLaughlin Centre, Genome Canada/Ontario Genomics Institute, the Government of Ontario, the Canadian Institutes of Health Research (CIHR), NeuroDevNet, Ontario Brain Institute, the Catherine and Maxwell Meighen Foundation and The Hospital for Sick Children Foundation. Special thanks to B. and (the late) S. Wright for their vision in helping to conceptualize and develop this project and to foundational philanthropic supporters C. Dolan, G. Gund, B. Marcus, V. and J. Morgan and S. Wise. R.K.C.Y. is funded by the CIHR Postdoctoral Fellowship, NARSAD Young Investigator award and Thrasher Early Career Award. R.W. is funded by the Ontario Brain Institute and NeuroDevNet. M.U. is funded by the Banting Postdoctoral Fellowship. M.W. is funded by a CIHR (Institute of Genetics) Clinical Investigatorship Award. L.Z. is funded by the Stollery Children's Hospital Foundation Chair in Autism Research. P.S. is funded by the Patsy and Jamie Anderson Chair in Child and Youth Mental Health. B.M.K. is funded by the Canada Research Chair in Law and Medicine. S.W.S. is funded by the GlaxoSmithKline-CIHR Chair in Genome Sciences at the University of Toronto and The Hospital for Sick Children. Publisher Copyright: {\textcopyright} 2017 Nature America, Inc., part of Springer Nature. All rights reserved.",

year = "2017",

month = apr,

doi = "10.1038/nn.4524",

language = "English",

volume = "20",

pages = "602--611",

journal = "Nature Neuroscience",

issn = "1097-6256",

publisher = "Nature Publishing Group",

number = "4",

}

Yuen, RKC, Merico, D, Bookman, M, Howe, JL, Thiruvahindrapuram, B, Patel, RV, Whitney, J, Deflaux, N, Bingham, J, Wang, Z, Pellecchia, G, Buchanan, JA, Walker, S, Marshall, CR, Uddin, M, Zarrei, M, Deneault, E, D'Abate, L, Chan, AJS, Koyanagi, S, Paton, T, Pereira, SL, Hoang, N, Engchuan, W, Higginbotham, EJ, Ho, K, Lamoureux, S, Li, W, MacDonald, JR, Nalpathamkalam, T, Sung, WWL, Tsoi, FJ, Wei, J, Xu, L, Tasse, AM, Kirby, E, Van Etten, W, Twigger, S, Roberts, W, Drmic, I, Jilderda, S, Modi, BM, Kellam, B, Szego, M, Cytrynbaum, C, Weksberg, R, Zwaigenbaum, L, Woodbury-Smith, M, Brian, J, Senman, L, Iaboni, A, Doyle-Thomas, K, Thompson, A, Chrysler, C, Leef, J, Savion-Lemieux, T, Smith, IM, Liu, X, Nicolson, R, Seifer, V, Fedele, A, Cook, EH, Dager, S, Estes, A, Gallagher, L, Malow, BA, Parr, JR, Spence, SJ, Vorstman, J, Frey, BJ, Robinson, JT, Strug, LJ, Fernandez, BA, Elsabbagh, M, Carter, MT, Hallmayer, J, Knoppers, BM, Anagnostou, E, Szatmari, P, Ring, RH, Glazer, D, Pletcher, MT & Scherer, SW 2017, 'Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder', Nature Neuroscience, vol. 20, no. 4, pp. 602-611. https://doi.org/10.1038/nn.4524

TY - JOUR

T1 - Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder

AU - Yuen, Ryan K C

AU - Merico, Daniele

AU - Bookman, Matt

AU - Howe, Jennifer L.

AU - Thiruvahindrapuram, Bhooma

AU - Patel, Rohan V.

AU - Whitney, Joe

AU - Deflaux, Nicole

AU - Bingham, Jonathan

AU - Wang, Zhuozhi

AU - Pellecchia, Giovanna

AU - Buchanan, Janet A.

AU - Walker, Susan

AU - Marshall, Christian R.

AU - Uddin, Mohammed

AU - Zarrei, Mehdi

AU - Deneault, Eric

AU - D'Abate, Lia

AU - Chan, Ada J S

AU - Koyanagi, Stephanie

AU - Paton, Tara

AU - Pereira, Sergio L.

AU - Hoang, Ny

AU - Engchuan, Worrawat

AU - Higginbotham, Edward J.

AU - Ho, Karen

AU - Lamoureux, Sylvia

AU - Li, Weili

AU - MacDonald, Jeffrey R.

AU - Nalpathamkalam, Thomas

AU - Sung, Wilson W L

AU - Tsoi, Fiona J.

AU - Wei, John

AU - Xu, Lizhen

AU - Tasse, Anne Marie

AU - Kirby, Emily

AU - Van Etten, William

AU - Twigger, Simon

AU - Roberts, Wendy

AU - Drmic, Irene

AU - Jilderda, Sanne

AU - Modi, Bonnie Mackinnon

AU - Kellam, Barbara

AU - Szego, Michael

AU - Cytrynbaum, Cheryl

AU - Weksberg, Rosanna

AU - Zwaigenbaum, Lonnie

AU - Woodbury-Smith, Marc

AU - Brian, Jessica

AU - Senman, Lili

AU - Iaboni, Alana

AU - Doyle-Thomas, Krissy

AU - Thompson, Ann

AU - Chrysler, Christina

AU - Leef, Jonathan

AU - Savion-Lemieux, Tal

AU - Smith, Isabel M.

AU - Liu, Xudong

AU - Nicolson, Rob

AU - Seifer, Vicki

AU - Fedele, Angie

AU - Cook, Edwin H.

AU - Dager, Stephen

AU - Estes, Annette

AU - Gallagher, Louise

AU - Malow, Beth A.

AU - Parr, Jeremy R.

AU - Spence, Sarah J.

AU - Vorstman, Jacob

AU - Frey, Brendan J.

AU - Robinson, James T.

AU - Strug, Lisa J.

AU - Fernandez, Bridget A.

AU - Elsabbagh, Mayada

AU - Carter, Melissa T.

AU - Hallmayer, Joachim

AU - Knoppers, Bartha M.

AU - Anagnostou, Evdokia

AU - Szatmari, Peter

AU - Ring, Robert H.

AU - Glazer, David

AU - Pletcher, Mathew T.

AU - Scherer, Stephen W.

N1 - Funding Information: This work was funded by Autism Speaks, Autism Speaks Canada, the Canadian Institute for Advanced Research, the University of Toronto McLaughlin Centre, Genome Canada/Ontario Genomics Institute, the Government of Ontario, the Canadian Institutes of Health Research (CIHR), NeuroDevNet, Ontario Brain Institute, the Catherine and Maxwell Meighen Foundation and The Hospital for Sick Children Foundation. Special thanks to B. and (the late) S. Wright for their vision in helping to conceptualize and develop this project and to foundational philanthropic supporters C. Dolan, G. Gund, B. Marcus, V. and J. Morgan and S. Wise. R.K.C.Y. is funded by the CIHR Postdoctoral Fellowship, NARSAD Young Investigator award and Thrasher Early Career Award. R.W. is funded by the Ontario Brain Institute and NeuroDevNet. M.U. is funded by the Banting Postdoctoral Fellowship. M.W. is funded by a CIHR (Institute of Genetics) Clinical Investigatorship Award. L.Z. is funded by the Stollery Children's Hospital Foundation Chair in Autism Research. P.S. is funded by the Patsy and Jamie Anderson Chair in Child and Youth Mental Health. B.M.K. is funded by the Canada Research Chair in Law and Medicine. S.W.S. is funded by the GlaxoSmithKline-CIHR Chair in Genome Sciences at the University of Toronto and The Hospital for Sick Children. Publisher Copyright: © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.

PY - 2017/4

Y1 - 2017/4

N2 - We are performing whole-genome sequencing of families with autism spectrum disorder (ASD) to build a resource (MSSNG) for subcategorizing the phenotypes and underlying genetic factors involved. Here we report sequencing of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible on a cloud platform and through a controlled-access internet portal. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertions and deletions or copy number variations per ASD subject. We identified 18 new candidate ASD-risk genes and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (P = 6 × 10-4). In 294 of 2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried copy number variations and/or chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.

AB - We are performing whole-genome sequencing of families with autism spectrum disorder (ASD) to build a resource (MSSNG) for subcategorizing the phenotypes and underlying genetic factors involved. Here we report sequencing of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible on a cloud platform and through a controlled-access internet portal. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertions and deletions or copy number variations per ASD subject. We identified 18 new candidate ASD-risk genes and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (P = 6 × 10-4). In 294 of 2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried copy number variations and/or chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.

KW - Autism spectrum disorders

KW - Next-generation sequencing

UR - http://www.scopus.com/inward/record.url?scp=85014531804&partnerID=8YFLogxK

U2 - 10.1038/nn.4524

DO - 10.1038/nn.4524

M3 - Article

C2 - 28263302

AN - SCOPUS:85014531804

SN - 1097-6256

VL - 20

SP - 602

EP - 611

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 4

ER -

Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder

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