Placental Methylome Reveals a 22q13.33 Brain Regulatory Gene Locus Associated with Autism

Details

• Personal Author:
  Bakulski KM ; Benke KS ; Daniels J ; Dennis MY ; Dou J ; Fallin MD ; Feinberg JI ; Gomez JA ; Grosvenor LP ; Gutierrez Fugón OJ ; Hertz-Picciotto I ; Jianu JM ; LaSalle JM ; Laufer BI ; Marathe R ; Mordaunt CE ; Mouat JS ; Ozonoff S ; Schmidt RJ ; Soto DC ; Volk HE ; Walker CK ; Williams LA ; Yasui DH ; Zhu Y
• Description:
  Background: Autism spectrum disorder (ASD) involves complex genetics interacting with the perinatal environment, complicating the discovery of common genetic risk. The epigenetic layer of DNA methylation shows dynamic developmental changes and molecular memory of in utero experiences, particularly in placenta, a fetal tissue discarded at birth. However, current array-based methods to identify novel ASD risk genes lack coverage of the most structurally and epigenetically variable regions of the human genome. Results: We use whole genome bisulfite sequencing in placenta samples from prospective ASD studies to discover a previously uncharacterized ASD risk gene, LOC105373085, renamed NHIP. Out of 134 differentially methylated regions associated with ASD in placental samples, a cluster at 22q13.33 corresponds to a 118-kb hypomethylated block that replicates in two additional cohorts. Within this locus, NHIP is functionally characterized as a nuclear peptide-encoding transcript with high expression in brain, and increased expression following neuronal differentiation or hypoxia, but decreased expression in ASD placenta and brain. NHIP overexpression increases cellular proliferation and alters expression of genes regulating synapses and neurogenesis, overlapping significantly with known ASD risk genes and NHIP-associated genes in ASD brain. A common structural variant disrupting the proximity of NHIP to a fetal brain enhancer is associated with NHIP expression and methylation levels and ASD risk, demonstrating a common genetic influence. Conclusions: Together, these results identify and initially characterize a novel environmentally responsive ASD risk gene relevant to brain development in a hitherto under-characterized region of the human genome. [Description provided by NIOSH]
• Subjects:
  Epidemiology Genetics Lung Lung Diseases Occupational Health Respiratory System Respiratory Tract Diseases Safety
• Keywords:
  ASDs Author Keywords: Autism Spectrum Disorder Autism Spectrum Disorders DNA Damage DNA Methylation Epigenomics Gene Expression Genomics Human Genetics Hypoxia Neurodevelopment Placenta Postmortem Brain Prospective Study Structural Variants

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• ISSN:
  1474-760X
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  California ; Maryland ; Michigan ; OSHA Region 3 ; OSHA Region 5 ; OSHA Region 9
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  46
• Volume:
  23
• NIOSHTIC Number:
  nn:20070623
• Citation:
  Genome Biol 2022 Feb; 23:46
• Contact Point Address:
  Janine M. LaSalle, Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA
• Email:
  jmlasalle@ucdavis.edu
• Federal Fiscal Year:
  2022
• Performing Organization:
  University of Michigan, Ann Arbor
• Peer Reviewed:
  True
• Start Date:
  20050701
• Source Full Name:
  Genome Biology
• End Date:
  20280630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:33bd1a7bef0a838a60320e49daef356c515a15b0261e484b32cc4dbc98889a7c5bbfcd916e9b3fd9f5c752a56e0c66253a5eb437e230111f98be95ad8453fb9a
• Download URL:
  https://stacks.cdc.gov/view/cdc/208802/cdc_208802_DS1.pdf
• File Type:
  [PDF - 2.44 MB ]