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
JournalNature Communications
Date Published2016
ISSN Number2041-1723
KeywordsAging, Genetics, Older Adults

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.

Alternate JournalNat Commun
Citation Key8653
PubMed ID26830004
PubMed Central IDPMC4740877
Grant List5R01AG042511-02 / AG / NIA NIH HHS / United States
I01 BX001829 / BX / BLRD VA / United States
T32 NS048004 / NS / NINDS NIH HHS / United States