Lu Ake T, Hannon Eilis, Levine Morgan E, Hao Ke, Crimmins Eileen M, Lunnon Katie, Kozlenkov Alexey, Mill Jonathan, Dracheva Stella, Horvath Steve
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK.
Nat Commun. 2016 Feb 2;7:10561. doi: 10.1038/ncomms10561.
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.
DNA甲基化（DNAm）水平有助于定义一种被称为“表观遗传时钟”的衰老表观遗传生物标志物。我们对小脑表观遗传年龄加速的全基因组关联研究（GWAS）在两个基因座中鉴定出五个显著（P<5.0×10^(-8)）的单核苷酸多态性（SNP）：2p22.1（基因DHX57内部）和16p13.3（靠近基因MLST8，mTOR复合物1和2的一个亚基）。我们发现，16p13.3中的SNP对大多数脑区中MLST8的表达水平具有顺式作用（P=6.9×10^(-18)）。在小脑样本中，2p22.1中的SNP对DHX57具有顺式效应（P=4.4×10^(-5)）。我们对小脑年龄加速的GWAS分析发现基因集与阿尔茨海默病（P=4.4×10^(-15)）、年龄相关性黄斑变性（P=6.4×10^(-6)）和帕金森病（P=2.6×10^(-4)）的基因集有显著重叠。总体而言，我们的结果证明了一种理解衰老和与年龄相关疾病的新范式的实用性：在GWAS中使用表观遗传组织年龄作为内表型将富有成效。
