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

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

Author information

1
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
2
University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK.
3
Department of Genetics and Genomic Sciences, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029-6574, USA.
4
Davis School of Gerontology, University of Southern California, Ethel Percy Andrus Gerontology Center, 3715 McClintock Avenue, Los Angeles, California 90089-0191, USA.
5
Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029-6574, USA.
6
James J. Peters VA Medical Center, Bronx, New York 10468, USA.
7
Institute of Psychiatry, King's College London, London SE5 8AF, UK.
8
Biostatistics, School of Public Health, University of California Los Angeles, Los Angeles, California 90095, USA.

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.

PMID:
26830004
PMCID:
PMC4740877
DOI:
10.1038/ncomms10561
[Indexed for MEDLINE]
Free PMC Article

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