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Nature. 2014 Nov 13;515(7526):209-15. doi: 10.1038/nature13772. Epub 2014 Oct 29.

Synaptic, transcriptional and chromatin genes disrupted in autism.

Collaborators (142)

Akawi N, Al-Turki S, Ambridge K, Barrett J, Barrett D, Bayzetinova T, Carter N, Clayton S, Coomber E, Firth H, Fitzgerald T, Fitzpatrick D, Gererty S, Gribble S, Hurles M, Jones P, Jones W, King D, Krishnappa N, Mason L, McRae J, Michael P, Middleton A, Miller R, Morley K, Parthiban V, Prigmore E, Rajan D, Sifrim A, Tivery A, van Kogelenberg M, Wright C, Adli M, Al-Awadi S, Al-Gazali L, Allub Z, Al-Saad S, Al-Saffar M, Ataman B, Balkhy S, Barkovich AJ, Barry BJ, Bastaki L, Bauman M, Ben-Omran T, Braverman NE, Chahrour MH, Chang BS, Chaudhry HR, Coulter M, D'Gama Am, Daoud A, Eapen V, Felie JM, Gabriel SB, Gascon GG, Greenberg ME, Hanson E, Harmin DA, Hashmi A, Herguner S, Hill RS, Hisama FM, Jiralerspong S, Joseph RM, Khalil S, Khuri-Bulos N, Kwaja O, Kwan BY, LeClair E, Lim ET, Markianos K, Martin M, Masri A, Meyer B, Mochida GH, Morrow EM, Mukaddes NM, Nasir RH, Niaz S, Okarmura-Ikeda K, Oner O, Parlow JN, Poduri A, Rajab A, Rappaport L, Rodriguez J, Schmitz-Abe K, Shen Y, Stevens CR, Stoler JM, Sunu CM, Tan WH, Taniguchi H, Teebi A, Walsh CA, Ware J, Wu BL, Yoo SY, Yu T, Anney R, Ayub M, Bailey A, Baird G, Barrett J, Blackwood D, Bolton P, Breen G, Collier D, Cormican P, Craddock N, Crooks L, Curran S, Danecek P, Durbin R, Gallagher L, Green J, Gurling H, Holt R, Joyce C, LeCouteur A, Lee I, Lönnqvist J, McCarthy S, McGuffin P, McIntosh A, McQuillen A, Merkangas A, Monaco A, Muddyman D, O'Donovan M, Owen M, Palotie A, Parr J, Paunio T, Pietilainen O, Rehnström K, Skuse D, Stalker J, St Clair D, Suvisaari J, Williams H.


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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