title: Histone Acetylome-wide Association Study of Autism Spectrum Disorder.
abstract: The association of histone modification changes with autism spectrum disorder (ASD) has not been systematically examined. We conducted a histone acetylome-wide association study (HAWAS) by performing H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) on 257 postmortem samples from ASD and matched control brains. Despite etiological heterogeneity, ≥68% of syndromic and idiopathic ASD cases shared a common acetylome signature at >5,000 cis-regulatory elements in prefrontal and temporal cortex. Similarly, multiple genes associated with rare genetic mutations in ASD showed common "epimutations." Acetylome aberrations in ASD were not attributable to genetic differentiation at cis-SNPs and highlighted genes involved in synaptic transmission, ion transport, epilepsy, behavioral abnormality, chemokinesis, histone deacetylation, and immunity. By correlating histone acetylation with genotype, we discovered >2,000 histone acetylation quantitative trait loci (haQTLs) in human brain regions, including four candidate causal variants for psychiatric diseases. Due to the relative stability of histone modifications postmortem, we anticipate that the HAWAS approach will be applicable to multiple diseases.
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Sun
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Jeremie
authors.initials: J
authors.lastname: Poschmann
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Cruz-Herrera Del Rosario
authors.affiliation: Program in Neurogenetics, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Neelroop N
authors.initials: NN
authors.lastname: Parikshak
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Hajira Shreen
authors.initials: HS
authors.lastname: Hajan
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Vibhor
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Ramalakshmi
authors.initials: R
authors.lastname: Ramasamy
authors.affiliation: Program in Neurogenetics, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: T Grant
authors.initials: TG
authors.lastname: Belgard
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Bavani
authors.initials: B
authors.lastname: Elanggovan
authors.affiliation: Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, UK.
authors.forename: Chloe Chung Yi
authors.initials: CCY
authors.lastname: Wong
authors.affiliation: Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, UK; University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
authors.affiliation: Program in Neurogenetics, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: dhg@mednet.ucla.edu.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore. Electronic address: prabhakars@gis.a-star.edu.sg.
authors.forename: Shyam
authors.initials: S
authors.lastname: Prabhakar
mesh_terms: D000107:Acetylation; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000378:metabolism; D001344:Autopsy; D002531:Cerebellum / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D004742:Enhancer Elements, Genetic; D042421:Histone Code; D006801:Humans; D017397:Prefrontal Cortex / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci; D013702:Temporal Lobe / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014157:Transcription Factors
keywords: autism spectrum disorder; disease-epigenetic alterations; epigenetics; histone acetylation; histone acetylation quantitative trait loci; regulome profiling