Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci

Nat Neurosci. 2016 Jan;19(1):48-54. doi: 10.1038/nn.4182. Epub 2015 Nov 30.


We characterized DNA methylation quantitative trait loci (mQTLs) in a large collection (n = 166) of human fetal brain samples spanning 56-166 d post-conception, identifying >16,000 fetal brain mQTLs. Fetal brain mQTLs were primarily cis-acting, enriched in regulatory chromatin domains and transcription factor binding sites, and showed substantial overlap with genetic variants that were also associated with gene expression in the brain. Using tissue from three distinct regions of the adult brain (prefrontal cortex, striatum and cerebellum), we found that most fetal brain mQTLs were developmentally stable, although a subset was characterized by fetal-specific effects. Fetal brain mQTLs were enriched amongst risk loci identified in a recent large-scale genome-wide association study (GWAS) of schizophrenia, a severe psychiatric disorder with a hypothesized neurodevelopmental component. Finally, we found that mQTLs can be used to refine GWAS loci through the identification of discrete sites of variable fetal brain methylation associated with schizophrenia risk variants.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Brain / embryology*
  • Brain / metabolism*
  • Cerebellum / embryology
  • Cerebellum / metabolism
  • DNA Methylation / genetics*
  • Epigenesis, Genetic / genetics*
  • Female
  • Fetus
  • Gene Expression / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation / genetics*
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Genotyping Techniques
  • Humans
  • Male
  • Neostriatum / embryology
  • Neostriatum / metabolism
  • Polymorphism, Single Nucleotide
  • Prefrontal Cortex / embryology
  • Prefrontal Cortex / metabolism
  • Quantitative Trait Loci / genetics*
  • Risk
  • Schizophrenia / genetics*
  • Tissue Banks*