Placental methylome reveals a 22q13.33 brain regulatory gene locus associated with autism

Yihui Zhu, J. Antonio Gomez, Benjamin I. Laufer, Charles E. Mordaunt, Julia S. Mouat, Daniela C. Soto, Megan Y. Dennis, Kelly S. Benke, Kelly M. Bakulski, John Dou, Ria Marathe, Julia M. Jianu, Logan A. Williams, Orangel J. Gutierrez Fugón, Cheryl K. Walker, Sally Ozonoff, Jason Daniels, Luke P. Grosvenor, Heather E. Volk, Jason I. FeinbergM. Daniele Fallin, Irva Hertz-Picciotto, Rebecca J. Schmidt, Dag H. Yasui, Janine M. LaSalle

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)46
Number of pages1
JournalGenome Biology
Volume23
Issue number1
DOIs
StatePublished - Feb 16 2022

Keywords

  • Autism spectrum disorder
  • DNA methylation
  • Epigenomics
  • Human genetics
  • Hypoxia
  • Neurodevelopment
  • Placenta
  • Postmortem brain
  • Prospective study
  • Structural variants

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

Fingerprint

Dive into the research topics of 'Placental methylome reveals a 22q13.33 brain regulatory gene locus associated with autism'. Together they form a unique fingerprint.

Cite this