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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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De novo variants in SET lysine methyltransferases and JmjC lysine demethylasesMis3 are in black, LoF in red, and variants identified in other disorders in grey (Fig. 5). JmjC, Jumonji C domain; JmjN, Jumonji N domain; JmjC, PHD, plant homeodomain; ARID, AT-rich interacting domain; SET, Su(var)3-9, Enhancer-of-zeste, Trithorax domain; FYR N, FY-rich N-terminal domain; FYR C, FY-rich C-terminal domain; PWWP, Pro-Trp-Trp-Pro domain; HMG, high mobility group box; AWS, associated with SET domain; Bromo, bromodomain; BAH, bromo adjacent homology.
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Figure 12: De novo variants in SET lysine methyltransferases and JmjC lysine demethylasesMis3 are in black, LoF in red, and variants identified in other disorders in grey (Fig. 5). JmjC, Jumonji C domain; JmjN, Jumonji N domain; JmjC, PHD, plant homeodomain; ARID, AT-rich interacting domain; SET, Su(var)3-9, Enhancer-of-zeste, Trithorax domain; FYR N, FY-rich N-terminal domain; FYR C, FY-rich C-terminal domain; PWWP, Pro-Trp-Trp-Pro domain; HMG, high mobility group box; AWS, associated with SET domain; Bromo, bromodomain; BAH, bromo adjacent homology.

Mentions: Lysines on histones 3 and 4 can be mono-, di-, or tri-methylated, providing a versatile mechanism for either activation or repression of transcription. Of 107 TADA genes, five are SET lysine methyltransferases, four are Jumonji (JmjC) lysine demethylases, and two are readers (Fig. 3a). RBFOX1 co-isolates with H3K4me341, and our dataset is enriched in targets shared by RBFOX1 and H3K4me3 (P=0.0166, Fig. 1a, Supplementary Table 4). Some de novo missense variants targeting these genes map to functional domains (Extended Data Fig. 7).


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)

De novo variants in SET lysine methyltransferases and JmjC lysine demethylasesMis3 are in black, LoF in red, and variants identified in other disorders in grey (Fig. 5). JmjC, Jumonji C domain; JmjN, Jumonji N domain; JmjC, PHD, plant homeodomain; ARID, AT-rich interacting domain; SET, Su(var)3-9, Enhancer-of-zeste, Trithorax domain; FYR N, FY-rich N-terminal domain; FYR C, FY-rich C-terminal domain; PWWP, Pro-Trp-Trp-Pro domain; HMG, high mobility group box; AWS, associated with SET domain; Bromo, bromodomain; BAH, bromo adjacent homology.
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Related In: Results  -  Collection

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Figure 12: De novo variants in SET lysine methyltransferases and JmjC lysine demethylasesMis3 are in black, LoF in red, and variants identified in other disorders in grey (Fig. 5). JmjC, Jumonji C domain; JmjN, Jumonji N domain; JmjC, PHD, plant homeodomain; ARID, AT-rich interacting domain; SET, Su(var)3-9, Enhancer-of-zeste, Trithorax domain; FYR N, FY-rich N-terminal domain; FYR C, FY-rich C-terminal domain; PWWP, Pro-Trp-Trp-Pro domain; HMG, high mobility group box; AWS, associated with SET domain; Bromo, bromodomain; BAH, bromo adjacent homology.
Mentions: Lysines on histones 3 and 4 can be mono-, di-, or tri-methylated, providing a versatile mechanism for either activation or repression of transcription. Of 107 TADA genes, five are SET lysine methyltransferases, four are Jumonji (JmjC) lysine demethylases, and two are readers (Fig. 3a). RBFOX1 co-isolates with H3K4me341, and our dataset is enriched in targets shared by RBFOX1 and H3K4me3 (P=0.0166, Fig. 1a, Supplementary Table 4). Some de novo missense variants targeting these genes map to functional domains (Extended Data Fig. 7).

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