Histone Acetylome-wide Association Study of Autism Spectrum Disorder

Wenjie Sun, Jeremie Poschmann, Ricardo Cruz-Herrera del Rosario, Neelroop N. Parikshak, Hajira Shreen Hajan, Vibhor Kumar, Ramalakshmi Ramasamy, T. Grant Belgard, Bavani Elanggovan, Chloe Chung Yi Wong, Jonathan Mill, Daniel H. Geschwind*, Shyam Prabhakar

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

187 Citations (Scopus)
265 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)1385-1397.e11
Number of pages1
JournalCell
Volume167
Issue number5
Early online date17 Nov 2016
DOIs
Publication statusPublished - 17 Nov 2016

Keywords

  • autism spectrum disorder
  • disease-epigenetic alterations
  • epigenetics
  • histone acetylation
  • histone acetylation quantitative trait loci
  • regulome profiling

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