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Synaptic, transcriptional and chromatin genes disrupted in autism
Open accessAbstract
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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“including that, prima facie , most proteins encoded by ASD risk genes are involved either in synaptic structure and function or chromatin modification and regulation of gene expression 38,46,47,58 (Fig. 3).”
From Autism spectrum disorder (2020) · cites this paper as [47]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In ASD, a single de novo more risk than the cumulative effect of the top decile of polygenic risk for schizophrenia 47,50”
From Autism spectrum disorder (2020) · cites this paper as [47]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“we observe a 2-fold enrichment of de novo PTVs in highly constrained genes in affected females (n = 1,097) versus affected males (n = 5,333) (p = 3 3 10 6”
From Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism (2020) · cites this paper as De Rubeis et al., 2014
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“ASD affects 1-1.5% of individuals and is highly heritable, with both common and rare variants contributing to its etiology 1-4 .”
From Identification of common genetic risk variants for autism spectrum disorder (2019) · cites this paper as [1]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“By contrast, de novo mutations, mostly copy number variants (CNVs) and gene disrupting point mutations, have larger individual effects, but collectively explain <5% of the overall liability 1-3 and far less of the heritability.”
From Identification of common genetic risk variants for autism spectrum disorder (2019) · cites this paper as [1]
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“Many ASD risk genes associated with transcriptional regulation and chromatin remodelling are crucial for cortical development21,22.”
From Single-cell brain organoid screening identifies developmental defects in autism (2023) · cites this paper as [21]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“where variants in the underlying genes are associated with epilepsy, autism, schizophrenia, or intellectual disability (De Rubeis et al., 2014; Russell et al., 2014; Sadybekov et al., 2017; Shoubridge et al., 2010; Yang et al., 2014”
From Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies (2018) · cites this paper as De Rubeis et al., 2014
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“Rare inherited and de novo variants are major contributors to individual risk for autism spectrum disorder (ASD)”
From Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism (2020) · cites this paper as De Rubeis et al., 2014
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“Notably, 12 of the genes DAWN previously predicted as plausibly contributing to risk (De Rubeis et al., 2014) were identified as new TADA genes here (enrichment p = 8.4 3 10 11 ; OR = 16.4).”
From Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism (2020) · cites this paper as De Rubeis et al., 2014
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“Past analyses have identified two major functional groups of ASD genes: those involved in gene expression regulation (GER), including chromatin regulators and transcription factors, and those involved in neuronal communication (NC), including synaptic function (De Rubeis et al., 2014).”
From Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism (2020) · cites this paper as De Rubeis et al., 2014
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In the citing paper
“Past analyses have identified two major groups of ASD-associated genes: those involved in gene expression regulation (GER) and those involved in neuronal communication (NC) (De Rubeis et al., 2014; Sanders et al., 2015).”
From Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism (2020) · cites this paper as De Rubeis et al., 2014
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In the citing paper
“De novo missense variants occur more frequently than de novo PTVs. Collectively, they show only marginal enrichment over the rate expected by chance”
From Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism (2020) · cites this paper as De Rubeis et al., 2014
Experimental — accuracy not yet measuredIn the citing paper
“Large scale genetic screenings have revealed that many of the identified top-ranking autism risk factors are genes implicated in synaptic homeostasis, transcriptional regulation and chromatin remodeling pathways 140–142.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [141]
In the citing paper
“Another identified high-risk factor for autism is the Cullin 3 (Cul3) gene 141”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [141]
In the citing paper
“In humans, mutations in MAPK3 [92] and TAOK2 [93, 94] but not in KCTD13 [85, 95] have been found in ASD cases.”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [85]
In the citing paper
“Missense variants in MAPK3 are identified in ASD probands [85, 92], but no loss of function (LoF) MAPK3 mutations have been reported in ASD, leaving the direct link to ASD uncertain.”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [85]
In the citing paper
“LoF variants in TAOK2 are identified in ASD probands [93, 94], however it is not a top-ranking ASD risk factor by large genetic screening [85].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [85]
In the citing paper
“This hypothesis is supported by previous studies showing that females with ASD have a greater burden of rare CNVs1,11,12 and gene mutations13,14.”
From A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex (2022) · cites this paper as [14]
In the citing paper
“We also demonstrated that the genetic architecture in this self-reported cohort is similar to published, clinically confirmed ASD cohorts.3,4,7”
From Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes (2019) · cites this paper as [7]
In the citing paper
“in ASC case-control samples,7 LGD variants in ITSN1 were also identified in the controls (three in 5397 ASC controls and comparable with the cumulative AF of 2.5e−4 in gnomAD v2.1), although they were still overrepresented in cases (two in 1601 cases).”
From Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes (2019) · cites this paper as [7]
In the citing paper
“individuals with ASD have a two- to three-fold increase in the number of rare copy number variations (CNVs) and de novo loss-of-function (nonsense, frameshift, and splice site) variants compared to their unaffected siblings11–14.”
From Genome-wide detection of tandem DNA repeats that are expanded in autism (2020) · cites this paper as [11]
In the citing paper
“Finally, exome sequencing of simplex libraries has repeatedly pointed to CACNA1D, the pore-forming subunit of another L-type channel, as another ASD-associated gene (De Rubeis et al., 2014).”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as De Rubeis et al., 2014
In the citing paper
“Changes in the levels of DNA methylation, histone modifications and changes in non-coding RNA (ncRNA) function are common in disease, as are mutations in epigenetic components 57,125 .”
From Advances in epigenetics link genetics to the environment and disease (2019) · cites this paper as [125]
In the citing paper
“The application of this approach to exomes or whole genomes in large family samples has since become the most effective strategy for identifying ASD susceptibility genes (De Rubeis et al., 2014; Iossifov et al., 2014; Sanders et al., 2015; Satterstrom et al., 2018).”
From Getting to the cores of autism (2019) · cites this paper as De Rubeis et al., 2014
In the citing paper
“However, for the majority of large CNVs, studies have not found evidence for the existence of a single driver gene (De Rubeis et al., 2014; Iossifov et al., 2014).”
From Getting to the cores of autism (2019) · cites this paper as De Rubeis et al., 2014
In the citing paper
“There are 39 such targets (10,18), and we previously estimated that ∼90% of these targets are true causal targets.”
From Low load for disruptive mutations in autism genes and their biased transmission (2015) · cites this paper as [18]
In the citing paper
“Here, we found widespread enrichments across central nervous system neurons with limited to no signal in glial cells and peripheral nervous system neurons (Table S10, Figure S17).”
From Rare coding variants in ten genes confer substantial risk for schizophrenia (2022) · cites this paper as [34]
In the citing paper
“These findings are consistent with a model whereby inherited variation, both common (11) and rare (26,28), defines a substrate of susceptibility, and additional high-risk genetic (including de novo, recessive and X-linked variation) and/or non-genetic factors then act on this substrate to surpass the liability threshold that results in ASD (Fig. 1).”
From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [26]
In the citing paper
“Transmitted variants that disrupt protein function can also have a strong influence on risk when inherited and acting dominantly (odds ratios ∼3) (26) or if resulting in biallelic disruption and acting in a recessive (34,35) or X-linked (34) manner (odds ratio above 2).”
From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [26]
In the citing paper
“Rare variants can be inherited from unaffected parents (26,28,34,35) or arise as de novo mutations during the meiotic divisions of gametogenesis (21)(22)(23)(24)(25)(26)(27)(30)(31)(32)36,37).”
From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [26]
In the citing paper
“Autosomal de novo loss-of-function SNV has been identified that acts in a dominant manner and carries a large burden for individual risk, with odds ratios of 20 or above for genes identified to date (24,26).”
From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [26]
In the citing paper
“ANK2 has been consistently associated with ASD (22,26,80) and also with cardiac arrhythmia (OMIM no.600919) (78).”
From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [26]
In the citing paper
“Simulations based on the observed number of recurrently disrupted genes have estimated that there are some 600-1200 ASD risk genes (21,24,26,51).”
From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [26]
In the citing paper
“In fact, recent discoveries indicate shared genes and pathways between ASD and congenital heart disease (CHD) (26,93,94).”
From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [26]
In the citing paper
“such rare high-confidence mutations tend to be significantly enriched in genes involved in synaptic functions, transcriptional regulation, and chromatin remodeling functions, and/or are downstream targets of the fragile X syndrome protein (FMRP) complex.1, 3”
From Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder (2018) · cites this paper as [1]
In the citing paper
“We recently demonstrated that genes frequently found mutated in ASD1 may regulate the downstream expression of genes directly relevant to brain size as well as other regulatory genes with cell cycle functions, particularly those involved in the regulation of the G1–S phase transition.67”
From Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder (2018) · cites this paper as [1]
In the citing paper
“Albeit rare, de novo mutations have emerged as substantial contributors to ASD risk [83, 165, 166, 254, 261, 309].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [83]
In the citing paper
“Chromodomain helicase DNA-binding protein 8 (CHD8), encoding a chromatin modifying gene on chromosome 14q11.2, is one of the high-penetrance ASD risk genes recently identified by sequencing studies [83, 165, 261, 347].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [83]
In the citing paper
“RBFOX targets are also frequently dysregulated in autism, highlighting the critical role of alternative splicing in brain development and function (De Rubeis et al., 2014; Voineagu et al., 2011; Weyn-Vanhentenryck et al., 2014).”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as De Rubeis et al., 2014
In the citing paper
“Alterations in other genes implicated in E/T coupling have been observed before in ASD individuals and include Ca2+ signaling components such as the voltage-dependent channels Cav1.2 (CACNA1C), Cav1.3 (CACNA1D) and the α-δ auxiliary subunit of L-type voltage-gated Ca2+ channels (CACNA2D3) [102, 103].”
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Self-citation
Metadata
- Authors
- Study, T. D., De Rubeis, S., Autism, H. M. C. F., UK10K Consortium, The Autism Sequencing Consortium, He, X., Goldberg, A. P., Poultney, C. S., Samocha, K., Ercument Cicek, A., Kou, Y., Liu, L., Fromer, M., Walker, S., Singh, T., Klei, L., Kosmicki, J., Fu, S.-C., Aleksic, B., Biscaldi, M., Bolton, P. F., Brownfeld, J. M., Cai, J., Campbell, N. G., Carracedo, A., Chahrour, M. H., Chiocchetti, A. G., Coon, H., Crawford, E. L., Crooks, L., Curran, S. R., Dawson, G., Duketis, E., Fernandez, B. A., Gallagher, L., Geller, E., Guter, S. J., Sean Hill, R., Ionita-Laza, I., Jimenez Gonzalez, P., Kilpinen, H., Klauck, S. M., Kolevzon, A., Lee, I., Lei, J., Lehtimäki, T., Lin, C.-F., Ma’ayan, A., Marshall, C. R., McInnes, A. L., Neale, B., Owen, M. J., Ozaki, N., Parellada, M., Parr, J. R., Purcell, S., Puura, K., Rajagopalan, D., Rehnström, K., Reichenberg, A., Sabo, A., Sachse, M., Sanders, S. J., Schafer, C., Schulte-Rüther, M., Skuse, D., Stevens, C., Szatmari, P., Tammimies, K., Valladares, O., Voran, A., Wang, L.-S., Weiss, L. A., Jeremy Willsey, A., Yu, T. W., Yuen, R. K. C., Cook, E. H., Freitag, C. M., Gill, M., Hultman, C. M., Lehner, T., Palotie, A., Schellenberg, G. D., Sklar, P., State, M. W., Sutcliffe, J. S., Walsh, C. A., Scherer, S. W., Zwick, M. E., Barrett, J. C., Cutler, D. J., Roeder, K., Devlin, B., Daly, M. J., & Buxbaum, J. D.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Carnegie Mellon University (US)
- Massachusetts General Hospital (US)
- Hospital for Sick Children (CA)
- Wellcome Sanger Institute (GB)
- University of Pittsburgh (US)
- University of Freiburg (DE)
- King's College London (GB)
- Vanderbilt University (US)
- Universidade de Santiago de Compostela (ES)
- Harvard University (US)
- Boston Children's Hospital (US)
- Goethe University Frankfurt (DE)
- University of Utah (US)
- Duke University (US)
- Memorial University of Newfoundland (CA)
- Trinity College Dublin (IE)
- University of Illinois Chicago (US)
- European Bioinformatics Institute (GB)
- German Cancer Research Center (DE)
- Fimlab (Finland) (FI)
- Kaiser Permanente (US)
- Broad Institute (US)
- Universidad Complutense de Madrid (ES)
- Nagoya University (JP)
- Tampere University Hospital (FI)
- Baylor College of Medicine (US)
- University of California, San Francisco (US)
- University College London (GB)
- National Health Service (GB)
- University of Pennsylvania (US)
- National Institutes of Health (US)
- University of Toronto (CA)
- Emory University (US)
- Corresponding author
- Daly, Mark J.
- Buxbaum, Joseph D.
- ORCID
- He, Xin
- Goldberg, Arthur P.
- Samocha, Kaitlin
- Kou, Yan
- Liu, Li
- Fromer, Menachem
- Singh, Tarjinder
- Klei, Lambertus
- Kosmicki, Jack
- Fu, Shih-Chen
- Bolton, Patrick F.
- Chahrour, Maria H.
- Chiocchetti, Andreas G.
- Coon, Hilary
- Crooks, Lucy
- Curran, Sarah R.
- Fernandez, Bridget A.
- Gallagher, Louise
- Geller, Evan
- Guter, Stephen J.
- Kilpinen, Helena
- Kolevzon, Alexander
- Lee, Irene
- Lei, Jing
- Lehtimäki, Terho
- Lin, Chiao-Feng
- Ma’ayan, Avi
- Marshall, Christian R.
- Neale, Benjamin
- Owen, Michael J.
- Ozaki, Norio
- Parellada, Mara
- Parr, Jeremy R.
- Purcell, Shaun
- Puura, Kaija
- Reichenberg, Abraham
- Sabo, Aniko
- Sanders, Stephan J.
- Skuse, David
- Stevens, Christine
- Tammimies, Kristiina
- Valladares, Otto
- Wang, Li-San
- Weiss, Lauren A.
- Yu, Timothy W.
- Yuen, Ryan K. C.
- Cook, Edwin H.
- Freitag, Christine M.
- Gill, Michael
- Hultman, Christina M.
- Lehner, Thomas
- Palotie, Aarno
- Schellenberg, Gerard D.
- Sklar, Pamela
- State, Matthew W.
- Sutcliffe, James S.
- Walsh, Christopher A.
- Scherer, Stephen W.
- Zwick, Michael E.
- Barrett, Jeffrey C.
- Cutler, David J.
- Roeder, Kathryn
- Devlin, Bernie
- Daly, Mark J.
- Buxbaum, Joseph D.
- Venue
- Nature
- Published
- 2014-10-29
- Volume
- 515
- Issue
- 7526
- Pages
- 209-215
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4402723
- OpenAlex
- W2108994842
- Cited by
- 2,746
- References
- 47
- Citations by year
- 2026: 151 · 2025: 198 · 2024: 224 · 2023: 215 · 2022: 234 · 2021: 273 · 2020: 290 · 2019: 258 · 2018: 213 · 2017: 264 · 2016: 229 · 2015: 183 · 2014: 10
- FWCI
- 127.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- UNSWorks (UNSW Sydney) (submittedVersion, cc-by-nc-nd)
- RePEc: Research Papers in Economics (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- RUNA. Repositorio Institucional del Sergas (Servicio Gallego de Salud (SERGAS)) (submittedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Howard Hughes Medical Institute
- Autism Speaks
- Wellcome Trust (091986, WT 098051, WT091310)
- Health Research Board
- Vanderbilt University Medical Center (UL1TR000445, HD15052)
- Broad Institute
- National Institute for Health and Care Research (NF-SI-0510-10268, HICF-1009-003, PI13/01136, WT098051)
- Meath Foundation
- National Institutes of Health (5rc2mh089952-02, PI13/01136, UL1TR000445, MH057881, HG003067, HD-15052, HD055751, RR024975)
- Medical Research Council (MR/L010305/1)
- National Institute of Mental Health (U01MH100209, R01MH061009, R01MH083565, R01MH077139, U01MH100229, R01MH097849, MH095034, RC2-MH089952, R01MH094400, R37MH057881, R01MH089208, U01MH100239, MH089482, MH057881, R01MH095034, R01MH089482, MH077139, MH061009, R01MH095797, U01MH100233)
- National Human Genome Research Institute (U54HG003067, T32HG002295)
- National Institute of Neurological Disorders and Stroke (R01NS073601)
- National Center for Research Resources (UL1RR024975)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD015052, P50HD055751, P30 HD-15052)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- autism spectrum disorder, rare coding variants, synaptic genes, transcriptional regulation, chromatin remodeling, histone lysine methylation, voltage-gated ion channels, evolutionary constraints, autism risk genes, exome sequencing, missense mutations, copy number variation, histone-modifying enzymes
- MeSH terms
- Amino Acid Sequence, Child Development Disorders, Pervasive, Chromatin, Female, Humans, Male, Molecular Sequence Data, Mutation, Nerve Net, Synapses, Transcription, Genetic, Odds Ratio, Germ-Line Mutation, Genetic Predisposition to Disease, Mutation, Missense, Chromatin Assembly and Disassembly, Exome
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