@article {9090, title = {Genetic architecture of epigenetic and neuronal ageing rates in human brain regions}, journal = {Nature Communications}, volume = {8}, year = {2017}, month = {Jun-05-2018}, abstract = {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 {\texttimes} 10 -9 ) with the ageing rate across five brain regions and harbours a cis-expression quantitative trait locus for EFCAB5 (P=3.4 {\texttimes} 10-20 ). Locus 1p36.12 is significantly associated (P=2.2 {\texttimes} 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 {\texttimes} 10 -12 ), ulcerative colitis (P<1.0 {\texttimes} 10-20 ), type 2 diabetes (P=2.8 {\texttimes} 10-13 ), hip/waist circumference in men (P=1.1 {\texttimes} 10-9 ), schizophrenia (P=1.6 {\texttimes} 10-9 ), cognitive decline (P=5.3 {\texttimes} 10-4 ) and Parkinson{\textquoteright}s disease (P=8.6 {\texttimes} 10-3 ).}, keywords = {Genetics}, doi = {10.1038/ncomms15353}, url = {http://www.nature.com/doifinder/10.1038/ncomms15353http://www.nature.com/doifinder/10.1038/ncomms15353}, author = {Lu, Ake T and Hannon, Eilis and Morgan E. Levine and Eileen M. Crimmins and Lunnon, Katie and Mill, Jonathan and Daniel H. Geschwind and Horvath, Steve} } @article {8653, title = {Genetic variants near MLST8 and DHX57 affect the epigenetic age of the cerebellum.}, journal = {Nat Commun}, volume = {7}, year = {2016}, month = {2016 Feb 02}, pages = {10561}, abstract = {

DNA methylation (DNAm) levels lend themselves for defining an epigenetic biomarker of aging known as the {\textquoteright}epigenetic clock{\textquoteright}. Our genome-wide association study (GWAS) of cerebellar epigenetic age acceleration identifies five significant (P<5.0 {\texttimes} 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 {\texttimes} 10(-18)) in most brain regions. In cerebellar samples, the SNP in 2p22.1 has a cis-effect on DHX57 (P=4.4 {\texttimes} 10(-5)). Gene sets found by our GWAS analysis of cerebellar age acceleration exhibit significant overlap with those of Alzheimer{\textquoteright}s disease (P=4.4 {\texttimes} 10(-15)), age-related macular degeneration (P=6.4 {\texttimes} 10(-6)), and Parkinson{\textquoteright}s disease (P=2.6 {\texttimes} 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.

}, keywords = {Adaptor Proteins, Signal Transducing, Aging, Cell Line, Cerebellum, Epigenesis, Genetic, Gene Expression Regulation, Genetic Variation, Genome-Wide Association Study, Humans, Linkage Disequilibrium, mTOR Associated Protein, LST8 Homolog}, issn = {2041-1723}, doi = {10.1038/ncomms10561}, author = {Lu, Ake T and Hannon, Eilis and Morgan E. Levine and Hao, Ke and Eileen M. Crimmins and Lunnon, Katie and Kozlenkov, Alexey and Mill, Jonathan and Dracheva, Stella and Horvath, Steve} }