Synaptic, transcriptional and chromatin genes disrupted in autism.

Nature 2014 Nov 29;515(7526):209-15. Epub 2014 Oct 29.

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.

Download full-text PDF

Source
http://www2.massgeneral.org/bbs/gen228/Reading2015/BiPolar/S
Web Search
https://www.gwern.net/docs/algernon/2014-rubeis.pdf
Web Search
http://www.nature.com/doifinder/10.1038/nature13772
Publisher Site
http://dx.doi.org/10.1038/nature13772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402723PMC
November 2014
137 Reads

Publication Analysis

Top Keywords

autosomal genes
8
autism cases
4
3871 autism
4
cases 9937
4
9937 ancestry-matched
4
ancestry-matched parental
4
variation 3871
4
coding variation
4
hundreds genes
4
impact hundreds
4
genes exome
4
exome sequencing
4
analysis rare
4
sequencing analysis
4
parental controls
4
implicates autosomal
4
107 autosomal
4
set 107
4
genes enriched
4
enriched affect
4

References

(Supplied by CrossRef)
Article in Am. J. Med. Genet. B Neuropsychiatr. Genet.
A Ronald et al.
Am. J. Med. Genet. B Neuropsychiatr. Genet. 2011
Article in Science
J Sebat et al.
Science 2007
Article in Nature
D Pinto et al.
Nature 2010
Article in Mol. Autism
L Klei et al.
Mol. Autism 2012
Article in Nature Genet.
T Gaugler et al.
Nature Genet. 2014
Article in Neuron
TW Yu et al.
Neuron 2013
Article in Neuron
ET Lim et al.
Neuron 2013
Article in Am. J. Hum. Genet.
CS Poultney et al.
Am. J. Hum. Genet. 2013
Article in Brain Res.
C Betancur et al.
Brain Res. 2011
Article in Nature
JT Glessner et al.
Nature 2009
Article in Nature
SJ Sanders et al.
Nature 2012

Similar Publications