Abstract
| Original language | English |
|---|---|
| Journal | Nature |
| Volume | 515 |
| Issue number | 7526 |
| DOIs | |
| Publication status | Published - 13 Nov 2014 |
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In: Nature, Vol. 515, No. 7526, 13.11.2014.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Synaptic, transcriptional and chromatin genes disrupted in autism.
AU - Samocha, Kaitlin
AU - Ercument Cicek, A
AU - Liu, Li
AU - Klei, Lambertus
AU - Kosmicki, Jack
AU - Biscaldi, Monica
AU - Brownfeld, Jessica M
AU - Cai, Jinlu
AU - Campbell, Nicholas G
AU - Crawford, Emily L
AU - Dawson, Geraldine
AU - Duketis, Eftichia
AU - Fernandez, Bridget A
AU - Geller, Evan
AU - Guter, Stephen J
AU - Jimenez Gonzalez, Patricia
AU - Kilpinen, Helena
AU - Klauck, Sabine M
AU - Kolevzon, Alexander
AU - Lei, Jing
AU - Lehtimäki, Terho
AU - Lin, Chiao-Feng
AU - Marshall, Christian R
AU - McInnes, Alison L
AU - Puura, Kaija
AU - Rajagopalan, Deepthi
AU - Reichenberg, Abraham
AU - Sachse, Michael
AU - Schulte-Rüther, Martin
AU - Stevens, Christine
AU - Valladares, Otto
AU - Voran, Annette
AU - Jeremy Willsey, A
AU - Schellenberg, Gerard D
AU - Sklar, Pamela
A2 - Akawi, Nadia
A2 - Al-Turki, Saeed
A2 - Ambridge, Kirsty
A2 - Barrett, Daniel
A2 - Bayzetinova, Tanya
A2 - Carter, Nigel
A2 - Clayton, Stephen
A2 - Coomber, Eve
A2 - Firth, Helen
A2 - Fitzgerald, Tomas
A2 - FitzPatrick, David
A2 - Gerety, Sebastian
A2 - Gribble, Susan
A2 - Hurles, Matthew
A2 - Jones, Philip
A2 - Jones, Wendy
A2 - King, Daniel
A2 - Krishnappa, Netravathi
A2 - Mason, Laura
A2 - McRae, Jeremy
A2 - Michael, Parker
A2 - Middleton, Anna
A2 - Miller, Ray
A2 - Morley, Katherine
A2 - Parthiban, Vijaya
A2 - Prigmore, Elena
A2 - Rajan, Diana
A2 - Sifrim, Alejandro
A2 - Tivery, Adrian
A2 - van Kogelenberg, Margriet
A2 - Wright, Caroline
A2 - Adli, Mazhar
A2 - Al-Awadi, Sadika
A2 - Al-Gazali, Lihadh
A2 - Alloub, Zeinab I
A2 - Al-Saad, Samira
A2 - Al-Saffar, Muna
A2 - Ataman, Bulent
A2 - Balkhy, Soher
A2 - Barkovich, A James
A2 - Barry, Brenda J
A2 - Bastaki, Laila
A2 - Bauman, Margaret
A2 - Ben-Omran, Tawfeg
A2 - Braverman, Nancy E
A2 - Chang, Bernard S
A2 - Chaudhry, Haroon R
A2 - Coulter, Michael
A2 - D'Gama, Alissa M
A2 - Daoud, Azhar
A2 - Eapen, Valsamma
A2 - Felie, Jillian M
A2 - Gabriel, Stacey B
A2 - Gascon, Generoso G
A2 - Greenberg, Micheal E
A2 - Hanson, Ellen
A2 - Harmin, David A
A2 - Hashmi, Asif
A2 - Herguner, Sabri
A2 - Hill, R Sean
A2 - Hisama, Fuki M
A2 - Jiralerspong, Sarn
A2 - Joseph, Robert M
A2 - Khalil, Samir
A2 - Khuri-Bulos, Najwa
A2 - Kwaja, Omar
A2 - Kwan, Benjamin Y
A2 - LeClair, Elaine
A2 - Lim, Elaine T
A2 - Markianos, Kyriakos
A2 - Martin, Madelena
A2 - Masri, Amira
A2 - Meyer, Brian
A2 - Mochida, Ganeshwaran H
A2 - Mukaddes, Nahit M
A2 - Nasir, Ramzi H
A2 - Niaz, Saima
A2 - Okamura-Ikeda, Kazuko
A2 - Oner, Ozgur
A2 - Partlow, Jennifer N
A2 - Poduri, Annapurna
A2 - Rajab, Anna
A2 - Rappaport, Leonard
A2 - Rodriguez, Jacqueline
A2 - Schmitz-Abe, Klaus
A2 - Shen, Yiping
A2 - Stevens, Christine R
A2 - Stoler, Joan M
A2 - Sunu, Christine M
A2 - Tan, Wen-Hann
A2 - Taniguchi, Hisaaki
A2 - Teebi, Ahmad
A2 - Ware, Janice
A2 - Wu, Bai-Lin
A2 - Yoo, Seung-Yun
A2 - Anney, Richard
A2 - Ayub, Mohammad
A2 - Bailey, Anthony
A2 - Baird, Gillian
A2 - Barrett, Jeff
A2 - Blackwood, Douglas
A2 - Bolton, Patrick
A2 - Breen, Gerome
A2 - Collier, David
A2 - Cormican, Paul
A2 - Craddock, Nick
A2 - Crooks, Lucy
A2 - Curran, Sarah
A2 - Danecek, Petr
A2 - Durbin, Richard
A2 - Gallagher, Louise
A2 - Green, Jonathan
A2 - Gurling, Hugh
A2 - Holt, Richard
A2 - Joyce, Chris
A2 - LeCouteur, Ann
A2 - Lee, Irene
A2 - Lönnqvist, Jouko
A2 - McCarthy, Shane
A2 - McGuffin, Peter
A2 - McIntosh, Andrew
A2 - McQuillin, Andrew
A2 - Merikangas, Alison
A2 - Monaco, Anthony
A2 - Muddyman, Dawn
A2 - O'Donovan, Michael
A2 - Owen, Michael
A2 - Palotie, Aarno
A2 - Parr, Jeremy
A2 - Paunio, Tiina
A2 - Pietilainen, Olli
A2 - Rehnström, Karola
A2 - Skuse, David
A2 - Stalker, Jim
A2 - St Clair, David
A2 - Suvisaari, Jaana
A2 - Williams, Hywel
A2 - Aleksic, Branko
A2 - Bailey-Wilson, Joan
A2 - Betancur, Catalina
A2 - Bilder, Deborah
A2 - Boerwinkle, Eric
A2 - Brudno, Michael
A2 - Burbach, Peter
A2 - Buxbaum, Joseph
A2 - Camp, Nicola
A2 - Carracedo, Angel
A2 - Chahrour, Maria
A2 - Chiocchetti, Andreas
A2 - Cicek, Ercument
A2 - Cook, Ed
A2 - Coon, Hilary
A2 - Coppola, Giovanni
A2 - Cutler, David
A2 - Daly, Mark
A2 - De Rubeis, Silvia
A2 - dePristo, Mark
A2 - Devlin, Bernie
A2 - Doan, Ryan
A2 - Eichler, Evan
A2 - Felsenfeld, Adam
A2 - Freitag, Christine
A2 - Fromer, Menachem
A2 - Fu, Shih-Chen
A2 - Gabriels, Robin
A2 - Geschwind, Dan
A2 - Gibbs, Richard
A2 - Gill, Michael
A2 - Goldberg, Arthur P
A2 - Haines, Jonathan
A2 - Hakonarson, Hakon
A2 - Hansen, Nancy
A2 - He, Xin
A2 - Hill, Sean
A2 - Hultman, Christina
A2 - Ionita-Laza, Iuliana
A2 - Jugessur, Anil
A2 - Justice, Cristina
A2 - Kaplan, Desmond
A2 - Kim, Yoonhee
A2 - Knudsen, Gun Peggy
A2 - Koeleman, Bobby
A2 - Kou, Yan
A2 - Krumm, Niklas
A2 - Lehner, Thomas
A2 - Leppa, Virpi
A2 - Lese Martin, Christa
A2 - Lowe, Jennifer
A2 - Ma'ayan, Avi
A2 - Magnus, Per
A2 - Markianos, Kyriacos
A2 - Minshew, Nancy
A2 - Morris, Derek
A2 - Morrow, Eric
A2 - Mulle, Jennifer
A2 - Mullikin, Jim
A2 - Neale, Benjamin
A2 - Ozaki, Norio
A2 - Parellada, Mara
A2 - Perez, Laura
A2 - Pericak-Vance, Margaret
A2 - Porter, Forbes D
A2 - Poultney, Chris
A2 - Purcell, Shaun
A2 - Reichenberg, Avi
A2 - Robinson, Elise
A2 - Roeder, Kathryn
A2 - Ruzzo, Elizabeth
A2 - Sabo, Aniko
A2 - Sanders, Stephan
A2 - Santangelo, Susan L
A2 - Schafer, Chad
A2 - Schellenberg, Gerry
A2 - Scherer, Stephen
A2 - Shendure, Jay
A2 - Siegel, Matthew
A2 - Simpson, Claire
A2 - Singh, Tarjinder
A2 - State, Matthew
A2 - Stoltenberg, Camilla
A2 - Surén, Pål
A2 - Sutcliffe, James
A2 - Szatmari, Peter
A2 - Tammimies, Kristiina
A2 - Tierney, Elaine
A2 - Turner, Tychele
A2 - Verdi, Mary
A2 - Vorstman, Jacob
A2 - Walker, Susan
A2 - Walsh, Christopher
A2 - Wang, Li-San
A2 - Wei, Liping
A2 - Weiss, Lauren
A2 - Wigler, Michael
A2 - Willsley, Jeremy
A2 - Wink, Logan
A2 - Yousaf, Afsheen
A2 - Yu, Tim
A2 - Yuen, Ryan
A2 - Zwick, Michael
N1 - 5UL1 RR024975, NCRR NIH HHS, United StatesMH077139, NIMH NIH HHS, United StatesMH089482, NIMH NIH HHS, United StatesMH095034, NIMH NIH HHS, United StatesP30 HD15052, NICHD NIH HHS, United StatesP50 HD055751, NICHD NIH HHS, United StatesR01 MH061009, NIMH NIH HHS, United StatesR01 MH089482, NIMH NIH HHS, United StatesR01MH083565, NIMH NIH HHS, United StatesR01MH089208, NIMH NIH HHS, United StatesR37 MH057881, NIMH NIH HHS, United StatesRC2MH089952, NIMH NIH HHS, United StatesU01MH100209, NIMH NIH HHS, United StatesU01MH100229, NIMH NIH HHS, United StatesU01MH100233, NIMH NIH HHS, United StatesU01MH100239, NIMH NIH HHS, United StatesU54 HG003067, NHGRI NIH HHS, United StatesUL1TR000445, NCATS NIH HHS, United StatesWT091310, Wellcome Trust, United KingdomWT098051, Wellcome Trust, United Kingdom, Howard Hughes Medical Institute, United States
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.
U2 - 10.1038/nature13772
DO - 10.1038/nature13772
M3 - Article
C2 - 25363760
SN - 1476-4687
VL - 515
JO - Nature
JF - Nature
IS - 7526
ER -