title: Genetic variants near MLST8 and DHX57 affect the epigenetic age of the cerebellum.
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.
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Ake T
authors.initials: AT
authors.lastname: Lu
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK.
authors.forename: Eilis
authors.initials: E
authors.lastname: Hannon
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Morgan E
authors.initials: ME
authors.lastname: Levine
authors.affiliation: Department of Genetics and Genomic Sciences, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029-6574, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Hao
authors.affiliation: Davis School of Gerontology, University of Southern California, Ethel Percy Andrus Gerontology Center, 3715 McClintock Avenue, Los Angeles, California 90089-0191, USA.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Crimmins
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK.
authors.forename: Katie
authors.initials: K
authors.lastname: Lunnon
authors.affiliation: Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029-6574, USA.|James J. Peters VA Medical Center, Bronx, New York 10468, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Kozlenkov
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK.|Institute of Psychiatry, King's College London, London SE5 8AF, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
authors.affiliation: Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029-6574, USA.|James J. Peters VA Medical Center, Bronx, New York 10468, USA.
authors.forename: Stella
authors.initials: S
authors.lastname: Dracheva
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.|Biostatistics, School of Public Health, University of California Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Horvath
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000375:Aging; D002460:Cell Line; D002531:Cerebellum / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D000076242:mTOR Associated Protein, LST8 Homolog
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C555285:MLST8 protein, human; D000076242:mTOR Associated Protein, LST8 Homolog
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