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

Ake T Lu,Stella Dracheva,Steve Horvath,Ke Hao,Katie Lunnon,Morgan E Levine,Eileen M Crimmins,Eilis Hannon,Alexey Kozlenkov,Jonathan Mill

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.

Highlights

DNA methylation (DNAm) levels lend themselves for defining an epigenetic biomarker of aging known as the ‘epigenetic clock’
We focus on the cerebellum for two reasons: (a) we are interested in studying aging effects in a relatively homogeneous nervous tissue, and (b) epigenetic age acceleration is highly heritable in this brain region as described below
While our primary genome-wide association study (GWAS) aimed to identify single-nucleotide polymorphisms (SNPs) that are associated with the epigenetic age of the cerebellum, we related the resulting SNPs to epigenetic age acceleration in other brain regions and to transcriptional data, as described below

Summary

Introduction

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 (Po5.0 Â 10 À 8) SNPs in two loci: 2p22.1 (inside gene DHX57) and 16p13.3 near gene MLST8 (a subunit of mTOR complex 1 and 2). The weighted average of these 353 epigenetic markers gives rise to an estimate of tissue age (in units of years), which is referred to as ‘DNA methylation age’ or as ‘epigenetic age’ This epigenetic clock method for estimating age seems to apply to any tissue or cell type that contains DNA (with the exception of sperm) including sorted cell types (helper T cells, neurons and glial cells), complex tissues, and organs (blood, brain, bone, breast, kidney, liver and lung15–17) and even prenatal brain samples[18]. Our results show that genetic studies of epigenetic age acceleration may illuminate the mechanism underlying the epigenetic clock and identify genes that relate to various age-related diseases

Methods

Results

Conclusion