Synaptic, transcriptional and chromatin genes disrupted in autism

Silvia De Rubeis; Xin He; Arthur P. Goldberg; Christopher S. Poultney; Kaitlin Samocha; A. Ercument Cicek; Yan Kou; Li Liu; Menachem Fromer; Susan Walker; Tarjinder Singh; Lambertus Klei; Jack Kosmicki; Shih Chen Fu; Branko Aleksic; Monica Biscaldi; Patrick F. Bolton; Jessica M. Brownfeld; Jinlu Cai; Nicholas G. Campbell; Angel Carracedo; Maria H. Chahrour; Andreas G. Chiocchetti; Hilary Coon; Emily L. Crawford; Lucy Crooks; Sarah R. Curran; Geraldine Dawson; Eftichia Duketis; Bridget A. Fernandez; Louise Gallagher; Evan Geller; Stephen J. Guter; R. Sean Hill; Iuliana Ionita-Laza; Patricia Jimenez Gonzalez; 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 Neale; Michael J. Owen; Norio Ozaki; Mara Parellada; Jeremy R. Parr; Shaun Purcell; Kaija Puura; Deepthi Rajagopalan; Karola Rehnström; Abraham Reichenberg; Aniko Sabo; Michael Sachse; Stephan J. Sanders; Chad Schafer; Martin Schulte-Rüther; David Skuse; Christine Stevens; Peter Szatmari; Kristiina Tammimies; Otto Valladares; Annette Voran; Li San Wang; Lauren A. Weiss; A. Jeremy Willsey; Timothy W. Yu; Ryan K.C. Yuen; Edwin H. Cook; Christine M. Freitag; Michael Gill; Christina M. Hultman; Thomas Lehner; Aarno Palotie; Gerard D. Schellenberg; Pamela Sklar; Matthew W. State; James S. Sutcliffe; Christopher A. Walsh; Stephen W. Scherer; Michael E. Zwick; Jeffrey C. Barrett; David J. Cutler; Kathryn Roeder; Bernie Devlin; Mark J. Daly; Joseph D. Buxbaum

doi:10.1038/nature13772

Synaptic, transcriptional and chromatin genes disrupted in autism

Silvia De Rubeis, Xin He, Arthur P. Goldberg, Christopher S. Poultney, Kaitlin Samocha, A. Ercument Cicek, Yan Kou, Li Liu, Menachem Fromer, Susan Walker, Tarjinder Singh, Lambertus Klei, Jack Kosmicki, Shih Chen Fu, Branko Aleksic, Monica Biscaldi, Patrick F. Bolton, Jessica M. Brownfeld, Jinlu Cai, Nicholas G. CampbellAngel Carracedo, Maria H. Chahrour, Andreas G. Chiocchetti, Hilary Coon, Emily L. Crawford, Lucy Crooks, Sarah R. Curran, Geraldine Dawson, Eftichia Duketis, Bridget A. Fernandez, Louise Gallagher, Evan Geller, Stephen J. Guter, R. Sean Hill, Iuliana Ionita-Laza, Patricia Jimenez Gonzalez, 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 Neale, Michael J. Owen, Norio Ozaki, Mara Parellada, Jeremy R. Parr, Shaun Purcell, Kaija Puura, Deepthi Rajagopalan, Karola Rehnström, Abraham Reichenberg, Aniko Sabo, Michael Sachse, Stephan J. Sanders, Chad Schafer, Martin Schulte-Rüther, David Skuse, Christine Stevens, Peter Szatmari, Kristiina Tammimies, Otto Valladares, Annette Voran, Li San Wang, Lauren A. Weiss, A. Jeremy Willsey, Timothy W. Yu, Ryan K.C. Yuen, Edwin H. Cook, Christine M. Freitag, Michael Gill, Christina M. Hultman, Thomas Lehner, Aarno Palotie, Gerard D. Schellenberg, Pamela Sklar, Matthew W. State, James S. Sutcliffe, Christopher A. Walsh, Stephen W. Scherer, Michael E. Zwick, Jeffrey C. Barrett, David J. Cutler, Kathryn Roeder, Bernie Devlin, Mark J. Daly, Joseph D. Buxbaum

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Abstract

The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show 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 (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers - most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.

Original language	English (US)
Pages (from-to)	209-215
Number of pages	7
Journal	Nature
Volume	515
Issue number	7526
DOIs	https://doi.org/10.1038/nature13772
State	Published - Nov 13 2014

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De Rubeis, S., He, X., Goldberg, A. P., Poultney, C. S., Samocha, K., Cicek, A. E., Kou, Y., Liu, L., Fromer, M., Walker, S., Singh, T., Klei, L., Kosmicki, J., Fu, S. C., Aleksic, B., Biscaldi, M., Bolton, P. F., Brownfeld, J. M., Cai, J., ... Buxbaum, J. D. (2014). Synaptic, transcriptional and chromatin genes disrupted in autism. Nature, 515(7526), 209-215. https://doi.org/10.1038/nature13772

De Rubeis, S, He, X, Goldberg, AP, Poultney, CS, Samocha, K, Cicek, AE, Kou, Y, Liu, L, Fromer, M, Walker, S, Singh, T, Klei, L, Kosmicki, J, Fu, SC, Aleksic, B, Biscaldi, M, Bolton, PF, Brownfeld, JM, Cai, J, Campbell, NG, Carracedo, A, Chahrour, MH, Chiocchetti, AG, Coon, H, Crawford, EL, Crooks, L, Curran, SR, Dawson, G, Duketis, E, Fernandez, BA, Gallagher, L, Geller, E, Guter, SJ, Hill, RS, Ionita-Laza, I, Gonzalez, PJ, Kilpinen, H, Klauck, SM, Kolevzon, A, Lee, I, Lei, J, Lehtimäki, T, Lin, CF, Ma'ayan, A, Marshall, CR, McInnes, AL, Neale, B, Owen, MJ, Ozaki, N, Parellada, M, Parr, JR, Purcell, S, Puura, K, Rajagopalan, D, Rehnström, K, Reichenberg, A, Sabo, A, Sachse, M, Sanders, SJ, Schafer, C, Schulte-Rüther, M, Skuse, D, Stevens, C, Szatmari, P, Tammimies, K, Valladares, O, Voran, A, Wang, LS, Weiss, LA, Willsey, AJ, Yu, TW, Yuen, RKC, Cook, EH, Freitag, CM, Gill, M, Hultman, CM, Lehner, T, Palotie, A, Schellenberg, GD, Sklar, P, State, MW, Sutcliffe, JS, Walsh, CA, Scherer, SW, Zwick, ME, Barrett, JC, Cutler, DJ, Roeder, K, Devlin, B, Daly, MJ & Buxbaum, JD 2014, 'Synaptic, transcriptional and chromatin genes disrupted in autism', Nature, vol. 515, no. 7526, pp. 209-215. https://doi.org/10.1038/nature13772

@article{4aec27e7506c4a1ebf93015bbb4178ad,

title = "Synaptic, transcriptional and chromatin genes disrupted in autism",

abstract = "The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show 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 (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers - most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.",

author = "{De Rubeis}, Silvia and Xin He and Goldberg, {Arthur P.} and Poultney, {Christopher S.} and Kaitlin Samocha and Cicek, {A. Ercument} and Yan Kou and Li Liu and Menachem Fromer and Susan Walker and Tarjinder Singh and Lambertus Klei and Jack Kosmicki and Fu, {Shih Chen} and Branko Aleksic and Monica Biscaldi and Bolton, {Patrick F.} and Brownfeld, {Jessica M.} and Jinlu Cai and Campbell, {Nicholas G.} and Angel Carracedo and Chahrour, {Maria H.} and Chiocchetti, {Andreas G.} and Hilary Coon and Crawford, {Emily L.} and Lucy Crooks and Curran, {Sarah R.} and Geraldine Dawson and Eftichia Duketis and Fernandez, {Bridget A.} and Louise Gallagher and Evan Geller and Guter, {Stephen J.} and Hill, {R. Sean} and Iuliana Ionita-Laza and Gonzalez, {Patricia Jimenez} and Helena Kilpinen and Klauck, {Sabine M.} and Alexander Kolevzon and Irene Lee and Jing Lei and Terho Lehtim{\"a}ki and Lin, {Chiao Feng} and Avi Ma'ayan and Marshall, {Christian R.} and McInnes, {Alison L.} and Benjamin Neale and Owen, {Michael J.} and Norio Ozaki and Mara Parellada and Parr, {Jeremy R.} and Shaun Purcell and Kaija Puura and Deepthi Rajagopalan and Karola Rehnstr{\"o}m and Abraham Reichenberg and Aniko Sabo and Michael Sachse and Sanders, {Stephan J.} and Chad Schafer and Martin Schulte-R{\"u}ther and David Skuse and Christine Stevens and Peter Szatmari and Kristiina Tammimies and Otto Valladares and Annette Voran and Wang, {Li San} and Weiss, {Lauren A.} and Willsey, {A. Jeremy} and Yu, {Timothy W.} and Yuen, {Ryan K.C.} and Cook, {Edwin H.} and Freitag, {Christine M.} and Michael Gill and Hultman, {Christina M.} and Thomas Lehner and Aarno Palotie and Schellenberg, {Gerard D.} and Pamela Sklar and State, {Matthew W.} and Sutcliffe, {James S.} and Walsh, {Christopher A.} and Scherer, {Stephen W.} and Zwick, {Michael E.} and Barrett, {Jeffrey C.} and Cutler, {David J.} and Kathryn Roeder and Bernie Devlin and Daly, {Mark J.} and Buxbaum, {Joseph D.}",

year = "2014",

month = nov,

day = "13",

doi = "10.1038/nature13772",

language = "English (US)",

volume = "515",

pages = "209--215",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7526",

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TY - JOUR

T1 - Synaptic, transcriptional and chromatin genes disrupted in autism

AU - De Rubeis, Silvia

AU - He, Xin

AU - Goldberg, Arthur P.

AU - Poultney, Christopher S.

AU - Samocha, Kaitlin

AU - Cicek, A. Ercument

AU - Kou, Yan

AU - Liu, Li

AU - Fromer, Menachem

AU - Walker, Susan

AU - Singh, Tarjinder

AU - Klei, Lambertus

AU - Kosmicki, Jack

AU - Fu, Shih Chen

AU - Aleksic, Branko

AU - Biscaldi, Monica

AU - Bolton, Patrick F.

AU - Brownfeld, Jessica M.

AU - Cai, Jinlu

AU - Campbell, Nicholas G.

AU - Carracedo, Angel

AU - Chahrour, Maria H.

AU - Chiocchetti, Andreas G.

AU - Coon, Hilary

AU - Crawford, Emily L.

AU - Crooks, Lucy

AU - Curran, Sarah R.

AU - Dawson, Geraldine

AU - Duketis, Eftichia

AU - Fernandez, Bridget A.

AU - Gallagher, Louise

AU - Geller, Evan

AU - Guter, Stephen J.

AU - Hill, R. Sean

AU - Ionita-Laza, Iuliana

AU - Gonzalez, Patricia Jimenez

AU - Kilpinen, Helena

AU - Klauck, Sabine M.

AU - Kolevzon, Alexander

AU - Lee, Irene

AU - Lei, Jing

AU - Lehtimäki, Terho

AU - Lin, Chiao Feng

AU - Ma'ayan, Avi

AU - Marshall, Christian R.

AU - McInnes, Alison L.

AU - Neale, Benjamin

AU - Owen, Michael J.

AU - Ozaki, Norio

AU - Parellada, Mara

AU - Parr, Jeremy R.

AU - Purcell, Shaun

AU - Puura, Kaija

AU - Rajagopalan, Deepthi

AU - Rehnström, Karola

AU - Reichenberg, Abraham

AU - Sabo, Aniko

AU - Sachse, Michael

AU - Sanders, Stephan J.

AU - Schafer, Chad

AU - Schulte-Rüther, Martin

AU - Skuse, David

AU - Stevens, Christine

AU - Szatmari, Peter

AU - Tammimies, Kristiina

AU - Valladares, Otto

AU - Voran, Annette

AU - Wang, Li San

AU - Weiss, Lauren A.

AU - Willsey, A. Jeremy

AU - Yu, Timothy W.

AU - Yuen, Ryan K.C.

AU - Cook, Edwin H.

AU - Freitag, Christine M.

AU - Gill, Michael

AU - Hultman, Christina M.

AU - Lehner, Thomas

AU - Palotie, Aarno

AU - Schellenberg, Gerard D.

AU - Sklar, Pamela

AU - State, Matthew W.

AU - Sutcliffe, James S.

AU - Walsh, Christopher A.

AU - Scherer, Stephen W.

AU - Zwick, Michael E.

AU - Barrett, Jeffrey C.

AU - Cutler, David J.

AU - Roeder, Kathryn

AU - Devlin, Bernie

AU - Daly, Mark J.

AU - Buxbaum, Joseph D.

PY - 2014/11/13

Y1 - 2014/11/13

N2 - The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show 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 (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers - most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.

AB - The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show 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 (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers - most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.

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UR - http://www.scopus.com/inward/citedby.url?scp=84912144889&partnerID=8YFLogxK

U2 - 10.1038/nature13772

DO - 10.1038/nature13772

M3 - Article

C2 - 25363760

AN - SCOPUS:84912144889

SN - 0028-0836

VL - 515

SP - 209

EP - 215

JO - Nature

JF - Nature

IS - 7526

ER -

Synaptic, transcriptional and chromatin genes disrupted in autism

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