Brain Transcriptional and Epigenetic Associations with Autism
Open accessAbstract
BACKGROUND: Autism is a common neurodevelopmental syndrome. Numerous rare genetic etiologies are reported; most cases are idiopathic. METHODOLOGY/PRINCIPAL FINDINGS: To uncover important gene dysregulation in autism we analyzed carefully selected idiopathic autistic and control cerebellar and BA19 (occipital) brain tissues using high resolution whole genome gene expression and whole genome DNA methylation microarrays. No changes in DNA methylation were identified in autistic brain but gene expression abnormalities in two areas of metabolism were apparent: down-regulation of genes of mitochondrial oxidative phosphorylation and of protein translation. We also found associations between specific behavioral domains of autism and specific brain gene expression modules related to myelin/myelination, inflammation/immune response and purinergic signaling. CONCLUSIONS/SIGNIFICANCE: This work highlights two largely unrecognized molecular pathophysiological themes in autism and suggests differing molecular bases for autism behavioral endophenotypes.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Transcriptional studies of ASD post-mortem brains have been limited by paucity of available tissue, making them underpowered to identify reproducible pathways with statistical rigour.
“More transcriptional studies of ASD post-mortem brains have been limited by the paucity of available tissue, which has made them underpowered to identify reproducible pathways with statistical rigour92–95.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [94]
Themes across ASD post-mortem studies include increased expression of immune-microglial genes and decreased expression of synaptic genes in cerebral cortex.
“Nevertheless, some themes have emerged across studies, including the increased expression of immune-microglial genes and the decreased expression of synaptic genes in the cerebral cortex.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [94]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
WGCNA: an R package for weighted correlation network analysis
Langfelder, P., & Horvath, S. (2008) · BMC Bioinformatics · doi:10.1186/1471-2105-9-559 · Cited by 27,252 · see citing works
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations
O’Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., Levy, R., Ko, A., Lee, C., Smith, J. D., et al. (2012) · Nature · doi:10.1038/nature10989 · Cited by 2,165 · cited 3× · see citing works
“Recent whole-exome sequencing studies have had limited success in identifying strong effect mutations in many persons with autism [5–9].”
BackgroundResultDe novo mutations revealed by whole-exome sequencing are strongly associated with autism
Sanders, S. J., Murtha, M. T., Gupta, A. R., Murdoch, J. D., Raubeson, M. J., Willsey, A. J., Ercan-Sencicek, A. G., DiLullo, N. M., Parikshak, N. N., Stein, J. L., et al. (2012) · Nature · doi:10.1038/nature10945 · Cited by 2,084 · see citing works
Functional impact of global rare copy number variation in autism spectrum disorders
Pinto, D., Pagnamenta, A. T., Klei, L., Anney, R., Merico, D., Regan, R., Conroy, J., Magalhaes, T. R., Correia, C., Abrahams, B. S., et al. (2010) · Nature · doi:10.1038/nature09146 · Cited by 2,013 · see citing works
Transcriptomic Analysis of Autistic Brain Reveals Convergent Molecular Pathology
Voineagu, I., Wang, X., Johnston, P., Lowe, J. K., Tian, Y., Horvath, S., Mill, J., Cantor, R. M., Blencowe, B. J., & Geschwind, D. H. (2011) · Nature · doi:10.1038/nature10110 · Cited by 1,874 · cited 4× · see citing works
“The top 300 differentially expressed probes were used to generate a non-redundant gene list and compared with two published differentially expressed autism gene lists in brain [13,28] (Table S6).”
BackgroundMethodResultInfluentialPatterns and rates of exonic de novo mutations in autism spectrum disorders
Neale, B. M., Kou, Y., Liu, L., Ma’ayan, A., Samocha, K. E., Sabo, A., Lin, C.-F., Stevens, C., Wang, L.-S., Makarov, V., et al. (2012) · Nature · doi:10.1038/nature11011 · Cited by 1,734 · see citing works
De Novo Gene Disruptions in Children on the Autistic Spectrum
Iossifov, I., Ronemus, M., Levy, D., Wang, Z., Hakker, I., Rosenbaum, J., Yamrom, B., Lee, Y.-H., Narzisi, G., Leotta, A., et al. (2012) · Neuron · doi:10.1016/j.neuron.2012.04.009 · Cited by 1,446 · see citing works
Autism genome-wide copy number variation reveals ubiquitin and neuronal genes
Glessner, J. T., Wang, K., Cai, G., Korvatska, O., Kim, C. E., Wood, S., Zhang, H., Estes, A., Brune, C. W., Bradfield, J. P., et al. (2009) · Nature · doi:10.1038/nature07953 · Cited by 1,421 · see citing works
Betancur, C. (2011) · Brain Research · doi:10.1016/j.brainres.2010.11.078 · Cited by 954 · see citing works
Consensus Paper: Pathological Role of the Cerebellum in Autism
Fatemi, S. H., Aldinger, K. A., Ashwood, P., Bauman, M. L., Blaha, C. D., Blatt, G. J., Chauhan, A., Chauhan, V., Dager, S. R., Dickson, P. E., et al. (2012) · The Cerebellum · doi:10.1007/s12311-012-0355-9 · Cited by 723 · see citing works
Rare de novo and transmitted copy-number variation in autistic spectrum disorders
Levy, D., Ronemus, M., Yamrom, B., Lee, Y.-H., Leotta, A., Kendall, J., Marks, S., Lakshmi, B., Pai, D., Ye, K., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.05.015 · Cited by 712 · see citing works
Gilman, S. R., Iossifov, I., Levy, D., Ronemus, M., Wigler, M., & Vitkup, D. (2011) · Neuron · doi:10.1016/j.neuron.2011.05.021 · Cited by 701 · see citing works
Genetics of autism spectrum disorders
Geschwind, D. H. (2011) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2011.07.003 · Cited by 696 · see citing works
Levy, S. E., Mandell, D. S., & Schultz, R. T. (2009) · The Lancet · doi:10.1016/s0140-6736(09)61376-3 · Cited by 651 · see citing works
The role of immune dysfunction in the pathophysiology of autism
Onore, C., Careaga, M., & Ashwood, P. (2012) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2011.08.007 · Cited by 635 · see citing works
Mutations causing syndromic autism define an axis of synaptic pathophysiology
Auerbach, B. D., Osterweil, E. K., & Bear, M. F. (2011) · Nature · doi:10.1038/nature10658 · Cited by 592 · see citing works
Genomic and epigenetic evidence for oxytocin receptor deficiency in autism
Gregory, S. G., Connelly, J. J., Towers, A. J., Johnson, J., Biscocho, D., Markunas, C. A., Lintas, C., Abramson, R. K., Wright, H. H., Ellis, P., et al. (2009) · BMC Medicine · doi:10.1186/1741-7015-7-62 · Cited by 576 · see citing works
Genetic architecture in autism spectrum disorder
Devlin, B., & Scherer, S. W. (2012) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2012.03.002 · Cited by 545 · see citing works
Mitochondrial dysfunction in autism
Giulivi, C., Zhang, Y.-F., Omanska-Klusek, A., Ross-Inta, C., Wong, S., Hertz-Picciotto, I., Tassone, F., & Pessah, I. N. (2010) · JAMA · doi:10.1001/jama.2010.1706 · Cited by 466 · see citing works
Immune transcriptome alterations in the temporal cortex of subjects with autism
Garbett, K., Ebert, P. J., Mitchell, A., Lintas, C., Manzi, B., Mirnics, K., & Persico, A. M. (2008) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.01.012 · Cited by 375 · cited 3× · see citing works
“The top 300 differentially expressed probes were used to generate a non-redundant gene list and compared with two published differentially expressed autism gene lists in brain [13,28] (Table S6).”
MethodResultNguyen, A., Rauch, T. A., Pfeifer, G. P., & Hu, V. W. (2010) · The FASEB Journal · doi:10.1096/fj.10-154484 · Cited by 350 · see citing works
Review of neuroimaging in autism spectrum disorders: what have we learned and where we go from here
Anagnostou, E., & Taylor, M. J. (2011) · Molecular Autism · doi:10.1186/2040-2392-2-4 · Cited by 321 · see citing works
Cerebral correlates of preserved cognitive skills in autism
RING, H. A., Baron‐Cohen, S., Wheelwright, S. J., Williams, S., Brammer, M. J., Andrew, C., & Bullmore, E. T. (1999) · Brain · doi:10.1093/brain/122.7.1305 · Cited by 306 · see citing works
Filipovic-Sadic, S., Sah, S., Chen, L., Krosting, J., Sekinger, E. A., Zhang, W., Hagerman, P. J., Stenzel, T. T., Hadd, A. G., Latham, G. J., et al. (2010) · Clinical Chemistry · doi:10.1373/clinchem.2009.136101 · Cited by 280 · see citing works
Chauhan, A., Gu, F., Essa, M. M., Wegiel, J., Kaur, K., Brown, W. T., & Chauhan, V. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07189.x · Cited by 243 · see citing works
Levitt, P., & Campbell, D. B. (2009) · Journal of Clinical Investigation · doi:10.1172/jci37934 · Cited by 234 · see citing works
Protein interactome reveals converging molecular pathways among autism disorders
Sakai, Y., Shaw, C. A., Dawson, B. C., Dugas, D. V., Al-Mohtaseb, Z., Hill, D. E., & Zoghbi, H. Y. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002166 · Cited by 226 · see citing works
Adenosine and ATP Receptors in the Brain
Burnstock, G., Fredholm, B. B., & Verkhratsky, A. (2011) · Current Topics in Medicinal Chemistry · doi:10.2174/156802611795347627 · Cited by 188 · see citing works
Gene expression changes in children with autism
Gregg, J. P., Lit, L., Baron, C. A., Hertz-Picciotto, I., Walker, W., Davis, R. A., Croen, L. A., Ozonoff, S., Hansen, R., Pessah, I. N., et al. (2008) · Genomics · doi:10.1016/j.ygeno.2007.09.003 · Cited by 181 · see citing works
AutismKB: an evidence-based knowledgebase of autism genetics
Xu, L.-M., Li, J.-R., Huang, Y., Zhao, M., Tang, X., & Wei, L. (2012) · Nucleic Acids Research · doi:10.1093/nar/gkr1145 · Cited by 179 · see citing works
Yu, T. W., Lim, E. T., Stevens, C. R., Gabriel, S., Chahrour, M. H., Ataman, B., Coulter, M. E., Hill, R. S., Schubert, C. R., Greenberg, M. E., et al. (2012) · Digital Access to Scholarship at Harvard (DASH) (Harvard University) · Cited by 179 · see citing works
White matter fractional anisotrophy differences and correlates of diagnostic symptoms in autism
Cheung, C., Chua, S. E., Cheung, V., Khong, P. L., Tai, K. S., Wong, T. K. W., Ho, T. P., & McAlonan, G. M. (2009) · Journal of Child Psychology and Psychiatry · doi:10.1111/j.1469-7610.2009.02086.x · Cited by 178 · see citing works
Jiang, Y., Sahoo, T., Michaelis, R. C., Bercovich, D., Bressler, J., Kashork, C. D., Liu, Q., Shaffer, L. G., Schroer, R. J., Stockton, D. W., et al. (2004) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.30297 · Cited by 159 · see citing works
Chahrour, M. H., Yu, T. W., Lim, E. T., Ataman, B., Coulter, M. E., Hill, R. S., Stevens, C. R., Schubert, C. R., ARRA Autism Sequencing Collaboration, Greenberg, M. E., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002635 · Cited by 125 · see citing works
Autism and mitochondrial disease
Haas, R. (2010) · Developmental Disabilities Research Reviews · doi:10.1002/ddrr.112 · Cited by 113 · see citing works
MECP2 promoter methylation and X chromosome inactivation in autism
Nagarajan, R. P., Patzel, K. A., Martin, M. R., Yasui, D. H., Swanberg, S. E., Hertz‐Picciotto, I., Hansen, R. L., de Water, J. V., Pessah, I. N., Jiang, R., et al. (2008) · Autism Research · doi:10.1002/aur.24 · Cited by 110 · see citing works
Gene expression studies in autism: Moving from the genome to the transcriptome and beyond
Voineagu, I. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.07.017 · Cited by 72 · see citing works
Hazlett, E. A., Buchsbaum, M. S., Hsieh, P., Haznedar, M. M., Platholi, J., LiCalzi, E. M., Cartwright, C., & Hollander, E. (2004) · Neuropsychobiology · doi:10.1159/000076719 · Cited by 57 · see citing works
Defects in translational regulation contributing to human cognitive and behavioral disease
Darnell, J. (2011) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2011.05.002 · Cited by 43 · see citing works
Genome-Wide Divergence of DNA Methylation Marks in Cerebral and Cerebellar Cortices
Xin, Y., Chanrion, B., Liu, M.-M., Galfalvy, H., Costa, R., Ilievski, B., Rosoklija, G. B., Arango, V., Dwork, A. J., Mann, J. J., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011357 · Cited by 39 · see citing works
Sbacchi, S., Acquadro, F., Calo, I., Calı̀, F., & Romano, V. (2010) · Current Genomics · doi:10.2174/138920210790886880 · Cited by 33 · see citing works
Regional genome transcriptional response of adult mouse brain to hypoxia
Xu, H., Lu, A., & Sharp, F. R. (2011) · BMC Genomics · doi:10.1186/1471-2164-12-499 · Cited by 31 · see citing works
Beyond cancer genomics: after the end of the beginning
Venkitaraman, A. R. (2012) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2012.02.010 · Cited by 25 · see citing works
A genotype resource for postmortem brain samples from the Autism Tissue Program
Wintle, R. F., Lionel, A. C., Hu, P., Ginsberg, S. D., Pinto, D., Thiruvahindrapduram, B., Wei, J., Marshall, C. R., Pickett, J., Cook, E. H., et al. (2011) · Autism Research · doi:10.1002/aur.173 · Cited by 24 · see citing works
The ongoing dissection of the genetic architecture of autistic spectrum disorder
Gillis, R. F., & Rouleau, G. A. (2011) · Molecular Autism · doi:10.1186/2040-2392-2-12 · Cited by 21 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
DNA methylation age of human tissues and cell types
Horvath, S. (2013) · Genome Biology · doi:10.1186/gb-2013-14-10-r115 · Cited by 7,075 · see citing works
Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders
Parikshak, N. N., Gandal, M. J., & Geschwind, D. H. (2015) · Nature Reviews Genetics · doi:10.1038/nrg3934 · Cited by 430 · see citing works
Naviaux, J. C., Wang, L., Li, K., Bright, A., Alaynick, W. A., Williams, K. R., Powell, S. B., & Naviaux, R. K. (2015) · Molecular Autism · doi:10.1186/2040-2392-6-1 · Cited by 285 · see citing works
The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders
Morris, G., & Berk, M. (2015) · BMC Medicine · doi:10.1186/s12916-015-0310-y · Cited by 245 · see citing works
Epigenetics of Autism Spectrum Disorder
Siu, M. T., & Weksberg, R. (2017) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-319-53889-1_4 · Cited by 121 · see citing works
Deficits in bioenergetics and impaired immune response in granulocytes from children with autism
Napoli, E., Wong, S., Hertz-Picciotto, I., & Giulivi, C. (2014) · Pediatrics · doi:10.1542/peds.2013-1545 · Cited by 117 · see citing works
Wong, C. C. Y., Smith, R. G., Hannon, E., Ramaswami, G., Parikshak, N. N., Assary, E., Troakes, C., Poschmann, J., Schalkwyk, L. C., Sun, W., et al. (2019) · Human Molecular Genetics · doi:10.1093/hmg/ddz052 · Cited by 98 · see citing works
AlzBase: An Integrative Database for Gene Dysregulation in Alzheimer’s Disease
Bai, Z., Han, G., Xie, B., Wang, J., Song, F., Peng, X., & Lei, H. (2016) · Molecular Neurobiology · doi:10.1007/s12035-014-9011-3 · Cited by 44 · see citing works
Klocke, C., Sherina, V., Graham, U. M., Gunderson, J., Allen, J. L., Sobolewski, M., Blum, J. L., Zelikoff, J. T., & Cory-Slechta, D. A. (2018) · Inhalation Toxicology · doi:10.1080/08958378.2018.1533053 · Cited by 41 · see citing works
Ji, C., Tang, Y., Zhang, Y., Huang, X., Li, C., Yang, Y., Wu, Q., Xia, X., Cai, Q., Qi, X.-R., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112712 · Cited by 16 · see citing works
Hierarchical cortical transcriptome disorganization in autism
Lombardo, M. V., Courchesne, E., Lewis, N. E., & Pramparo, T. (2016) · doi:10.1101/042937 · Cited by 7 · see citing works
- Authors
- Ginsberg, M. R., Rubin, R. A., Falcone, T., Ting, A. H., & Natowicz, M. R.
- Affiliations
- Cleveland Clinic Lerner College of Medicine (US)
- Whittier College (US)
- Cleveland Clinic (US)
- Corresponding author
- Natowicz, Marvin R.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-09-12
- Volume
- 7
- Issue
- 9
- Pages
- e44736
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3440365
- OpenAlex
- W2077232248
- Cited by
- 164
- References
- 45
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 8 · 2023: 9 · 2022: 14 · 2021: 6 · 2020: 14 · 2019: 16 · 2018: 15 · 2017: 14 · 2016: 11 · 2015: 15 · 2014: 12 · 2013: 9 · 2012: 1
- FWCI
- 6.06
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Cleveland Clinic
- Autism Research Institute
- National Institutes of Health (UL1TR000439)
- National Center for Advancing Translational Sciences
- 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 › Genomic variations and chromosomal abnormalities
- Keywords
- autism spectrum disorder, gene expression, DNA methylation, cerebellum, occipital cortex, mitochondrial oxidative phosphorylation, mRNA translation, myelination, inflammation, immune response, purinergic signaling, idiopathic autism, brain transcriptome
- MeSH terms
- Adolescent, Adult, Autistic Disorder, Brain, Child, Child, Preschool, Fragile X Syndrome, Gene Expression Regulation, Humans, Infant, Inflammation, Male, Middle Aged, Mitochondria, Myelin Sheath, Oxidative Phosphorylation, Phenotype, Transcription, Genetic, Protein Biosynthesis, Models, Statistical, Signal Transduction, Sequence Analysis, DNA, Gene Dosage, DNA Methylation, Oligonucleotide Array Sequence Analysis, Epigenesis, Genetic
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
