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

TitleGenetic variants near MLST8 and DHX57 affect the epigenetic age of the cerebellum.
Publication TypeJournal Article
Year of Publication2016
AuthorsLu, AT, Hannon, E, Levine, ME, Hao, K, Crimmins, EM, Lunnon, K, Kozlenkov, A, Mill, J, Dracheva, S, Horvath, S
JournalNat Commun
Date Published2016 Feb 02
ISSN Number2041-1723
KeywordsAdaptor Proteins, Signal Transducing, Aging, Cell Line, Cerebellum, Epigenesis, Genetic, Gene Expression Regulation, Genetic Variation, Genome-Wide Association Study, Humans, Linkage Disequilibrium, mTOR Associated Protein, LST8 Homolog

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.

User Guide Notes

Alternate JournalNat Commun
Citation Key8653
PubMed ID26830004
PubMed Central IDPMC4740877
Grant ListU01 AG009740 / AG / NIA NIH HHS / United States
T32 NS048004 / NS / NINDS NIH HHS / United States
5R01AG042511-02 / AG / NIA NIH HHS / United States
U34 AG051425 / AG / NIA NIH HHS / United States
I01 BX001829 / BX / BLRD VA / United States
R01 AG042511 / AG / NIA NIH HHS / United States