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- PMID: 25363760
- UKPMCID: 25363760
- DOI: 10.1038/nature13772
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Synaptic, transcriptional and chromatin genes disrupted in autism.
De Rubeis, Silvia; He, Xin; Goldberg, Arthur P; Poultney, Christopher S; Samocha, Kaitlin; Ercument Cicek, A; Kou, Yan; Liu, Li; Fromer, Menachem; Walker, Susan; Singh, Tarjinder; Klei, Lambertus; Kosmicki, Jack; Fu, Shih-Chen; Aleksic, Branko; Biscaldi, Monica; Bolton, Patrick F; Brownfeld, Jessica M; Cai, Jinlu; Campbell, Nicholas G; Carracedo, Angel; Chahrour, Maria H; Chiocchetti, Andreas G; Coon, Hilary; Crawford, Emily L; Crooks, Lucy; Curran, Sarah R; Dawson, Geraldine; Duketis, Eftichia; Fernandez, Bridget A; Gallagher, Louise; Geller, Evan; Guter, Stephen J; Sean Hill, R; Ionita-Laza, Iuliana; Jimenez Gonzalez, Patricia; Kilpinen, Helena; Klauck, Sabine M; Kolevzon, Alexander; Lee, Irene; Lei, Jing; Lehtimäki, Terho; Lin, Chiao-Feng; Ma'ayan, Avi; Marshall, Christian R; McInnes, Alison L; Neale, Benjamin; Owen, Michael J; Ozaki, Norio; Parellada, Mara; Parr, Jeremy R; Purcell, Shaun; Puura, Kaija; Rajagopalan, Deepthi; Rehnström, Karola; Reichenberg, Abraham; Sabo, Aniko; Sachse, Michael; Sanders, Stephan J; Schafer, Chad; Schulte-Rüther, Martin; Skuse, David; Stevens, Christine; Szatmari, Peter; Tammimies, Kristiina; Valladares, Otto; Voran, Annette; Wang, Li-San; Weiss, Lauren A; Jeremy Willsey, A; Yu, Timothy W; Yuen, Ryan K C; ; ; ; ; Cook, Edwin H; Freitag, Christine M; Gill, Michael; Hultman, Christina M; Lehner, Thomas; Palotie, Aarno; Schellenberg, Gerard D; Sklar, Pamela; State, Matthew W; Sutcliffe, James S; Walsh, Christopher A; Scherer, Stephen W; Zwick, Michael E; Barrett, Jeffrey C; Cutler, David J; Roeder, Kathryn; Devlin, Bernie; Daly, Mark J; Buxbaum, Joseph D
Nature. 2014;515(7526):209-15.
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Full-text held externally
- PMID: 25363760
- UKPMCID: 25363760
- DOI: 10.1038/nature13772
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 <Â 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.
Bibliographic metadata
- De Rubeis, Silvia
- He, Xin
- Goldberg, Arthur P
- Poultney, Christopher S
- Samocha, Kaitlin
- Ercument Cicek, A
- Kou, Yan
- Liu, Li
- Fromer, Menachem
- Walker, Susan
- Singh, Tarjinder
- Klei, Lambertus
- Kosmicki, Jack
- Fu, Shih-Chen
- Aleksic, Branko
- Biscaldi, Monica
- Bolton, Patrick F
- Brownfeld, Jessica M
- Cai, Jinlu
- Campbell, Nicholas G
- Carracedo, Angel
- Chahrour, Maria H
- Chiocchetti, Andreas G
- Coon, Hilary
- Crawford, Emily L
- Crooks, Lucy
- Curran, Sarah R
- Dawson, Geraldine
- Duketis, Eftichia
- Fernandez, Bridget A
- Gallagher, Louise
- Geller, Evan
- Guter, Stephen J
- Sean Hill, R
- Ionita-Laza, Iuliana
- Jimenez Gonzalez, Patricia
- Kilpinen, Helena
- Klauck, Sabine M
- Kolevzon, Alexander
- Lee, Irene
- Lei, Jing
- Lehtimäki, Terho
- Lin, Chiao-Feng
- Ma'ayan, Avi
- Marshall, Christian R
- McInnes, Alison L
- Neale, Benjamin
- Owen, Michael J
- Ozaki, Norio
- Parellada, Mara
- Parr, Jeremy R
- Purcell, Shaun
- Puura, Kaija
- Rajagopalan, Deepthi
- Rehnström, Karola
- Reichenberg, Abraham
- Sabo, Aniko
- Sachse, Michael
- Sanders, Stephan J
- Schafer, Chad
- Schulte-RĂĽther, Martin
- Skuse, David
- Stevens, Christine
- Szatmari, Peter
- Tammimies, Kristiina
- Valladares, Otto
- Voran, Annette
- Wang, Li-San
- Weiss, Lauren A
- Jeremy Willsey, A
- Yu, Timothy W
- Yuen, Ryan K C
- Cook, Edwin H
- Freitag, Christine M
- Gill, Michael
- Hultman, Christina M
- Lehner, Thomas
- Palotie, Aarno
- Schellenberg, Gerard D
- Sklar, Pamela
- State, Matthew W
- Sutcliffe, James S
- Walsh, Christopher A
- Scherer, Stephen W
- Zwick, Michael E
- Barrett, Jeffrey C
- Cutler, David J
- Roeder, Kathryn
- Devlin, Bernie
- Daly, Mark J
- Buxbaum, Joseph D
- Akawi, Nadia
- Al-Turki, Saeed
- Ambridge, Kirsty
- Barrett, Jeffrey
- Barrett, Daniel
- Bayzetinova, Tanya
- Carter, Nigel
- Clayton, Stephen
- Coomber, Eve
- Firth, Helen
- Fitzgerald, Tomas
- FitzPatrick, David
- Gerety, Sebastian
- Gribble, Susan
- Hurles, Matthew
- Jones, Philip
- Jones, Wendy
- King, Daniel
- Krishnappa, Netravathi
- Mason, Laura
- McRae, Jeremy
- Michael, Parker
- Middleton, Anna
- Miller, Ray
- Morley, Katherine
- Parthiban, Vijaya
- Prigmore, Elena
- Rajan, Diana
- Sifrim, Alejandro
- Tivery, Adrian
- van Kogelenberg, Margriet
- Wright, Caroline
- Adli, Mazhar
- Al-Awadi, Sadika
- Al-Gazali, Lihadh
- Alloub, Zeinab I
- Al-Saad, Samira
- Al-Saffar, Muna
- Ataman, Bulent
- Balkhy, Soher
- Barkovich, A James
- Barry, Brenda J
- Bastaki, Laila
- Bauman, Margaret
- Ben-Omran, Tawfeg
- Braverman, Nancy E
- Chahrour, Maria H
- Chang, Bernard S
- Chaudhry, Haroon R
- Coulter, Michael
- D'Gama, Alissa M
- Daoud, Azhar
- Eapen, Valsamma
- Felie, Jillian M
- Gabriel, Stacey B
- Gascon, Generoso G
- Greenberg, Micheal E
- Hanson, Ellen
- Harmin, David A
- Hashmi, Asif
- Herguner, Sabri
- Hill, R Sean
- Hisama, Fuki M
- Jiralerspong, Sarn
- Joseph, Robert M
- Khalil, Samir
- Khuri-Bulos, Najwa
- Kwaja, Omar
- Kwan, Benjamin Y
- LeClair, Elaine
- Lim, Elaine T
- Markianos, Kyriakos
- Martin, Madelena
- Masri, Amira
- Meyer, Brian
- Mochida, Ganeshwaran H
- Morrow, Eric M
- Mukaddes, Nahit M
- Nasir, Ramzi H
- Niaz, Saima
- Okamura-Ikeda, Kazuko
- Oner, Ozgur
- Partlow, Jennifer N
- Poduri, Annapurna
- Rajab, Anna
- Rappaport, Leonard
- Rodriguez, Jacqueline
- Schmitz-Abe, Klaus
- Shen, Yiping
- Stevens, Christine R
- Stoler, Joan M
- Sunu, Christine M
- Tan, Wen-Hann
- Taniguchi, Hisaaki
- Teebi, Ahmad
- Walsh, Christopher A
- Ware, Janice
- Wu, Bai-Lin
- Yoo, Seung-Yun
- Yu, Timothy
- Anney, Richard
- Ayub, Mohammad
- Bailey, Anthony
- Baird, Gillian
- Barrett, Jeff
- Blackwood, Douglas
- Bolton, Patrick
- Breen, Gerome
- Collier, David
- Cormican, Paul
- Craddock, Nick
- Crooks, Lucy
- Curran, Sarah
- Danecek, Petr
- Durbin, Richard
- Gallagher, Louise
- Green, Jonathan
- Gurling, Hugh
- Holt, Richard
- Joyce, Chris
- LeCouteur, Ann
- Lee, Irene
- Lönnqvist, Jouko
- McCarthy, Shane
- McGuffin, Peter
- McIntosh, Andrew
- McQuillin, Andrew
- Merikangas, Alison
- Monaco, Anthony
- Muddyman, Dawn
- O'Donovan, Michael
- Owen, Michael
- Palotie, Aarno
- Parr, Jeremy
- Paunio, Tiina
- Pietilainen, Olli
- Rehnström, Karola
- Skuse, David
- Stalker, Jim
- St Clair, David
- Suvisaari, Jaana
- Williams, Hywel
- Aleksic, Branko
- Anney, Richard
- Bailey-Wilson, Joan
- Barrett, Jeffrey
- Betancur, Catalina
- Bilder, Deborah
- Boerwinkle, Eric
- Brudno, Michael
- Burbach, Peter
- Buxbaum, Joseph
- Camp, Nicola
- Carracedo, Angel
- Chahrour, Maria
- Chiocchetti, Andreas
- Cicek, Ercument
- Cook, Ed
- Coon, Hilary
- Coppola, Giovanni
- Cormican, Paul
- Coulter, Michael
- Cutler, David
- Daly, Mark
- De Rubeis, Silvia
- dePristo, Mark
- Devlin, Bernie
- Doan, Ryan
- Eichler, Evan
- Felsenfeld, Adam
- Freitag, Christine
- Fromer, Menachem
- Fu, Shih-Chen
- Gabriels, Robin
- Geschwind, Dan
- Gibbs, Richard
- Gill, Michael
- Goldberg, Arthur P
- Haines, Jonathan
- Hakonarson, Hakon
- Hansen, Nancy
- He, Xin
- Hill, Sean
- Hultman, Christina
- Ionita-Laza, Iuliana
- Jugessur, Anil
- Justice, Cristina
- Kaplan, Desmond
- Kim, Yoonhee
- Knudsen, Gun Peggy
- Koeleman, Bobby
- Kou, Yan
- Krumm, Niklas
- Lehner, Thomas
- Leppa, Virpi
- Lese Martin, Christa
- Lowe, Jennifer
- Ma'ayan, Avi
- Magnus, Per
- Markianos, Kyriacos
- Markianos, Kyriacos
- Minshew, Nancy
- Morris, Derek
- Morrow, Eric
- Mulle, Jennifer
- Mullikin, Jim
- Neale, Benjamin
- Ozaki, Norio
- Palotie, Aarno
- Parellada, Mara
- Perez, Laura
- Pericak-Vance, Margaret
- Porter, Forbes D
- Poultney, Chris
- Purcell, Shaun
- Reichenberg, Avi
- Robinson, Elise
- Roeder, Kathryn
- Ruzzo, Elizabeth
- Sabo, Aniko
- Sanders, Stephan
- Santangelo, Susan L
- Schafer, Chad
- Schellenberg, Gerry
- Scherer, Stephen
- Schmitz-Abe, Klaus
- Shendure, Jay
- Siegel, Matthew
- Simpson, Claire
- Singh, Tarjinder
- State, Matthew
- Stoltenberg, Camilla
- Surén, Pål
- Sutcliffe, James
- Szatmari, Peter
- Tammimies, Kristiina
- Tierney, Elaine
- Turner, Tychele
- Verdi, Mary
- Vorstman, Jacob
- Walker, Susan
- Walsh, Christopher
- Wang, Li-San
- Wei, Liping
- Weiss, Lauren
- Wigler, Michael
- Willsley, Jeremy
- Wink, Logan
- Yousaf, Afsheen
- Yu, Tim
- Yuen, Ryan
- Zwick, Michael
- 5UL1 RR024975, NCRR NIH HHS, United States
- MH077139, NIMH NIH HHS, United States
- MH089482, NIMH NIH HHS, United States
- MH095034, NIMH NIH HHS, United States
- P30 HD15052, NICHD NIH HHS, United States
- P50 HD055751, NICHD NIH HHS, United States
- R01 MH061009, NIMH NIH HHS, United States
- R01 MH089482, NIMH NIH HHS, United States
- R01MH083565, NIMH NIH HHS, United States
- R01MH089208, NIMH NIH HHS, United States
- R37 MH057881, NIMH NIH HHS, United States
- RC2MH089952, NIMH NIH HHS, United States
- U01MH100209, NIMH NIH HHS, United States
- U01MH100229, NIMH NIH HHS, United States
- U01MH100233, NIMH NIH HHS, United States
- U01MH100239, NIMH NIH HHS, United States
- U54 HG003067, NHGRI NIH HHS, United States
- UL1TR000445, NCATS NIH HHS, United States
- WT091310, Wellcome Trust, United Kingdom
- WT098051, Wellcome Trust, United Kingdom
- , Howard Hughes Medical Institute, United States