Allele-Skewed DNA Modification in the Brain: Relevance to a Schizophrenia GWAS

Am J Hum Genet. 2016 May 5;98(5):956-962. doi: 10.1016/j.ajhg.2016.03.006. Epub 2016 Apr 14.

Abstract

Numerous recent studies have suggested that phenotypic effects of DNA sequence variants can be mediated or modulated by their epigenetic marks, such as allele-skewed DNA modification (ASM). Using Affymetrix SNP microarrays, we performed a comprehensive search of ASM effects in human post-mortem brain and sperm samples (total n = 256) from individuals with major psychosis and control individuals. Depending on the phenotypic category of the brain samples, 1.4%-7.5% of interrogated SNPs exhibited ASM effects. Next, we investigated ASM in the context of genetic studies of schizophrenia and detected that brain ASM SNPs were significantly overrepresented among sub-threshold SNPs from a schizophrenia genome-wide association study (GWAS). Brain ASM SNPs showed a much stronger enrichment in a schizophrenia GWAS than in 17 large GWASs of non-psychiatric diseases and traits, arguing that ASM effects are at least partially tissue specific. Studies of germline and control brain ASM SNPs supported a causal association between ASM and schizophrenia. Finally, significantly higher proportions of ASM SNPs than of non-ASM SNPs were detected at loci exhibiting epigenetic signatures of enhancers and promoters, and they were overrepresented within transcription factor binding regions and DNase I hypersensitive sites. All of these findings collectively indicate that ASM SNPs should be prioritized in follow-up GWASs.

Publication types

  • Comparative Study

MeSH terms

  • Alleles
  • Brain / metabolism*
  • Case-Control Studies
  • DNA Methylation*
  • Epigenomics*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study / methods*
  • Humans
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics*
  • Promoter Regions, Genetic / genetics
  • Regulatory Sequences, Nucleic Acid / genetics*
  • Schizophrenia / genetics*