%0 Journal Article %J Nature Communications %D 2017 %T Genetic architecture of epigenetic and neuronal ageing rates in human brain regions %A Lu, Ake T %A Hannon, Eilis %A Morgan E. Levine %A Eileen M. Crimmins %A Lunnon, Katie %A Mill, Jonathan %A Daniel H. Geschwind %A Horvath, Steve %K Genetics %X Identifying genes regulating the pace of epigenetic ageing represents a new frontier in genome-wide association studies (GWASs). Here using 1,796 brain samples from 1,163 individuals, we carry out a GWAS of two DNA methylation-based biomarkers of brain age: the epigenetic ageing rate and estimated proportion of neurons. Locus 17q11.2 is significantly associated (P=4.5 × 10 -9 ) with the ageing rate across five brain regions and harbours a cis-expression quantitative trait locus for EFCAB5 (P=3.4 × 10-20 ). Locus 1p36.12 is significantly associated (P=2.2 × 10-8 ) with epigenetic ageing of the prefrontal cortex, independent of the proportion of neurons. Our GWAS of the proportion of neurons identified two genome-wide significant loci (10q26 and 12p13.31) and resulted in a gene set that overlaps significantly with sets found by GWAS of age-related macular degeneration (P=1.4 × 10 -12 ), ulcerative colitis (P<1.0 × 10-20 ), type 2 diabetes (P=2.8 × 10-13 ), hip/waist circumference in men (P=1.1 × 10-9 ), schizophrenia (P=1.6 × 10-9 ), cognitive decline (P=5.3 × 10-4 ) and Parkinson's disease (P=8.6 × 10-3 ). %B Nature Communications %V 8 %8 Jun-05-2018 %G eng %U http://www.nature.com/doifinder/10.1038/ncomms15353http://www.nature.com/doifinder/10.1038/ncomms15353 %! Nat Comms %R 10.1038/ncomms15353 %0 Journal Article %J Nat Commun %D 2016 %T Genetic variants near MLST8 and DHX57 affect the epigenetic age of the cerebellum. %A Lu, Ake T %A Hannon, Eilis %A Morgan E. Levine %A Hao, Ke %A Eileen M. Crimmins %A Lunnon, Katie %A Kozlenkov, Alexey %A Mill, Jonathan %A Dracheva, Stella %A Horvath, Steve %K Adaptor Proteins, Signal Transducing %K Aging %K Cell Line %K Cerebellum %K Epigenesis, Genetic %K Gene Expression Regulation %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K mTOR Associated Protein, LST8 Homolog %X

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.

%B Nat Commun %V 7 %P 10561 %8 2016 Feb 02 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/26830004?dopt=Abstract %R 10.1038/ncomms10561