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Synaptic, transcriptional and chromatin genes disrupted in autism.

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, Shih-Chen F, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza J, Jimenz Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei 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, Li-San W, Weiss LA, Willsey AJ, Yu TW, Yuen RK, DDD StudyHomozygosity Mapping Collaborative for AutismUK10K ConsortiumCook 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, Barett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD - Nature (2014)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

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.

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ASD genes in synaptic networka. Enrichment of 107 TADA genes in: FMRP targets from two independent datasets and their overlap; RBFOX targets; RBFOX targets with predicted alterations in splicing; RBFOX and H3K4me3 overlapping targets; genes with de novo mutations in schizophrenia; human orthologues of Genes2Cognition mouse synaptosome or PSD genes; constrained genes; and, genes encoding mitochondrial proteins (as a control). Red bars indicate empirical P-values. b. Synaptic proteins encoded by TADA genes. c.De novo Mis3 variants in Nav1.2 (SCN2A). The four repeats (I-IV) with P-loops, the EF-hand, and the IQ domain are shown, as are the four amino acids (DEKA) forming the inner ring of the ion selectivity filter. d. Relevant variants in Cav1.3 (CACNA1D). Part of the channel is shown, including helices one and six (S1 and S6) for the I-IV domains, NSCaTE motif, EF-hand domain, pre-IQ, IQ, PCRD, DCRD, proline-rich region, and PDZ-binding motif.
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Figure 1: ASD genes in synaptic networka. Enrichment of 107 TADA genes in: FMRP targets from two independent datasets and their overlap; RBFOX targets; RBFOX targets with predicted alterations in splicing; RBFOX and H3K4me3 overlapping targets; genes with de novo mutations in schizophrenia; human orthologues of Genes2Cognition mouse synaptosome or PSD genes; constrained genes; and, genes encoding mitochondrial proteins (as a control). Red bars indicate empirical P-values. b. Synaptic proteins encoded by TADA genes. c.De novo Mis3 variants in Nav1.2 (SCN2A). The four repeats (I-IV) with P-loops, the EF-hand, and the IQ domain are shown, as are the four amino acids (DEKA) forming the inner ring of the ion selectivity filter. d. Relevant variants in Cav1.3 (CACNA1D). Part of the channel is shown, including helices one and six (S1 and S6) for the I-IV domains, NSCaTE motif, EF-hand domain, pre-IQ, IQ, PCRD, DCRD, proline-rich region, and PDZ-binding motif.

Mentions: FDR < 0.3 gene sets are strongly enriched for genes under evolutionary constraint18 (P=3.0×10−11, Fig. 1a, Supplementary Table 4), consistent with the hypothesis that heterozygous LoF mutations in these genes are ASD risk factors. Indeed over 5% of ASD subjects carry de novo LoF mutations in our FDR < 0.3 list. We also observed that genes in the FDR < 0.3 list had a significant excess of de novo LoF events detected by the largest schizophrenia WES study to date29 (P=0.0085, Fig. 1a), providing further evidence for overlapping risk loci between these disorders and independent confirmation of the signal in the gene sets presented here.


Synaptic, transcriptional and chromatin genes disrupted in autism.

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, Shih-Chen F, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza J, Jimenz Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei 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, Li-San W, Weiss LA, Willsey AJ, Yu TW, Yuen RK, DDD StudyHomozygosity Mapping Collaborative for AutismUK10K ConsortiumCook 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, Barett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD - Nature (2014)

ASD genes in synaptic networka. Enrichment of 107 TADA genes in: FMRP targets from two independent datasets and their overlap; RBFOX targets; RBFOX targets with predicted alterations in splicing; RBFOX and H3K4me3 overlapping targets; genes with de novo mutations in schizophrenia; human orthologues of Genes2Cognition mouse synaptosome or PSD genes; constrained genes; and, genes encoding mitochondrial proteins (as a control). Red bars indicate empirical P-values. b. Synaptic proteins encoded by TADA genes. c.De novo Mis3 variants in Nav1.2 (SCN2A). The four repeats (I-IV) with P-loops, the EF-hand, and the IQ domain are shown, as are the four amino acids (DEKA) forming the inner ring of the ion selectivity filter. d. Relevant variants in Cav1.3 (CACNA1D). Part of the channel is shown, including helices one and six (S1 and S6) for the I-IV domains, NSCaTE motif, EF-hand domain, pre-IQ, IQ, PCRD, DCRD, proline-rich region, and PDZ-binding motif.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4402723&req=5

Figure 1: ASD genes in synaptic networka. Enrichment of 107 TADA genes in: FMRP targets from two independent datasets and their overlap; RBFOX targets; RBFOX targets with predicted alterations in splicing; RBFOX and H3K4me3 overlapping targets; genes with de novo mutations in schizophrenia; human orthologues of Genes2Cognition mouse synaptosome or PSD genes; constrained genes; and, genes encoding mitochondrial proteins (as a control). Red bars indicate empirical P-values. b. Synaptic proteins encoded by TADA genes. c.De novo Mis3 variants in Nav1.2 (SCN2A). The four repeats (I-IV) with P-loops, the EF-hand, and the IQ domain are shown, as are the four amino acids (DEKA) forming the inner ring of the ion selectivity filter. d. Relevant variants in Cav1.3 (CACNA1D). Part of the channel is shown, including helices one and six (S1 and S6) for the I-IV domains, NSCaTE motif, EF-hand domain, pre-IQ, IQ, PCRD, DCRD, proline-rich region, and PDZ-binding motif.
Mentions: FDR < 0.3 gene sets are strongly enriched for genes under evolutionary constraint18 (P=3.0×10−11, Fig. 1a, Supplementary Table 4), consistent with the hypothesis that heterozygous LoF mutations in these genes are ASD risk factors. Indeed over 5% of ASD subjects carry de novo LoF mutations in our FDR < 0.3 list. We also observed that genes in the FDR < 0.3 list had a significant excess of de novo LoF events detected by the largest schizophrenia WES study to date29 (P=0.0085, Fig. 1a), providing further evidence for overlapping risk loci between these disorders and independent confirmation of the signal in the gene sets presented here.

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

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.

Show MeSH
Related in: MedlinePlus