Genetic variants near MLST8 and DHX57 affect the epigenetic age of the cerebellum

Nat Commun. 2016 Feb 2;7:10561. doi: 10.1038/ncomms10561.

Abstract

DNA methylation (DNAm) levels lend themselves for defining an epigenetic biomarker of aging known as the 'epigenetic clock'. Our genome-wide association study (GWAS) of cerebellar epigenetic age acceleration identifies five significant (P<5.0 × 10(-8)) SNPs in two loci: 2p22.1 (inside gene DHX57) and 16p13.3 near gene MLST8 (a subunit of mTOR complex 1 and 2). We find that the SNP in 16p13.3 has a cis-acting effect on the expression levels of MLST8 (P=6.9 × 10(-18)) in most brain regions. In cerebellar samples, the SNP in 2p22.1 has a cis-effect on DHX57 (P=4.4 × 10(-5)). Gene sets found by our GWAS analysis of cerebellar age acceleration exhibit significant overlap with those of Alzheimer's disease (P=4.4 × 10(-15)), age-related macular degeneration (P=6.4 × 10(-6)), and Parkinson's disease (P=2.6 × 10(-4)). Overall, our results demonstrate the utility of a new paradigm for understanding aging and age-related diseases: it will be fruitful to use epigenetic tissue age as endophenotype in GWAS.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Aging
  • Cell Line
  • Cerebellum / physiology*
  • Epigenesis, Genetic / physiology*
  • Gene Expression Regulation / physiology*
  • Genetic Variation
  • Genome-Wide Association Study
  • Humans
  • Linkage Disequilibrium
  • mTOR Associated Protein, LST8 Homolog

Substances

  • Adaptor Proteins, Signal Transducing
  • MLST8 protein, human
  • mTOR Associated Protein, LST8 Homolog