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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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Frequency of variants by genderFrequency of de novo (DN) and transmitted (TR) variants per sample in males (black) and females (white) for genes with q < 0.1 (upper panel), q < 0.3 (central panel), or all TADA genes (lower panel). The P values were determined by a one-tailed permutation test (*P < 0.5; **P < 0.01; ***P < 0.01).
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Figure 10: Frequency of variants by genderFrequency of de novo (DN) and transmitted (TR) variants per sample in males (black) and females (white) for genes with q < 0.1 (upper panel), q < 0.3 (central panel), or all TADA genes (lower panel). The P values were determined by a one-tailed permutation test (*P < 0.5; **P < 0.01; ***P < 0.01).

Mentions: Genes with FDR < 0.1 show profound female enrichment for de novo events (P=0.005 for LoF, P=0.004 for Mis3), consistent with de novo events having large impact on liability (OR ≥ 20; Extended Data Fig. 5). Genes with FDR between 0.1 and 0.3, however, show substantially less enrichment for female events, consistent with a modest impact for LoF variants (OR range 2-4, whether transmitted or de novo) and little to no effect from Mis3 variants. The results are consistent with inheritance patterns, LoF mutations in FDR < 0.1 genes are rarely inherited from unaffected parents while those in the 0.1 < FDR < 0.3 group are far more often inherited than de novo.


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)

Frequency of variants by genderFrequency of de novo (DN) and transmitted (TR) variants per sample in males (black) and females (white) for genes with q < 0.1 (upper panel), q < 0.3 (central panel), or all TADA genes (lower panel). The P values were determined by a one-tailed permutation test (*P < 0.5; **P < 0.01; ***P < 0.01).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 10: Frequency of variants by genderFrequency of de novo (DN) and transmitted (TR) variants per sample in males (black) and females (white) for genes with q < 0.1 (upper panel), q < 0.3 (central panel), or all TADA genes (lower panel). The P values were determined by a one-tailed permutation test (*P < 0.5; **P < 0.01; ***P < 0.01).
Mentions: Genes with FDR < 0.1 show profound female enrichment for de novo events (P=0.005 for LoF, P=0.004 for Mis3), consistent with de novo events having large impact on liability (OR ≥ 20; Extended Data Fig. 5). Genes with FDR between 0.1 and 0.3, however, show substantially less enrichment for female events, consistent with a modest impact for LoF variants (OR range 2-4, whether transmitted or de novo) and little to no effect from Mis3 variants. The results are consistent with inheritance patterns, LoF mutations in FDR < 0.1 genes are rarely inherited from unaffected parents while those in the 0.1 < FDR < 0.3 group are far more often inherited than de novo.

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