人类大脑区域中表观遗传和神经元衰老速度的遗传结构。
Genetic architecture of epigenetic and neuronal ageing rates in human brain regions.
机构信息
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, RILD Building, Barrack Road, Exeter EX2 5DW, UK.
出版信息
Nat Commun. 2017 May 18;8:15353. doi: 10.1038/ncomms15353.
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) with the ageing rate across five brain regions and harbours a cis-expression quantitative trait locus for EFCAB5 (P=3.4 × 10). Locus 1p36.12 is significantly associated (P=2.2 × 10) 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), ulcerative colitis (P<1.0 × 10), type 2 diabetes (P=2.8 × 10), hip/waist circumference in men (P=1.1 × 10), schizophrenia (P=1.6 × 10), cognitive decline (P=5.3 × 10) and Parkinson's disease (P=8.6 × 10).
鉴定调控表观遗传衰老速度的基因是全基因组关联研究（GWASs）的一个新领域。在这里，我们使用来自 1163 个人的 1796 个大脑样本，对两种基于 DNA 甲基化的大脑年龄生物标志物进行了 GWAS：表观遗传衰老率和估计的神经元比例。17q11.2 基因座与五个大脑区域的衰老率显著相关（P=4.5×10），并且包含 EFCAB5 的顺式表达数量性状基因座（P=3.4×10）。1p36.12 基因座与前额叶皮层的表观遗传衰老显著相关（P=2.2×10），与神经元比例无关。我们对神经元比例的 GWAS 确定了两个全基因组显著的基因座（10q26 和 12p13.31），并导致一个与年龄相关性黄斑变性的 GWAS 显著重叠的基因集（P=1.4×10），溃疡性结肠炎（P<1.0×10），2 型糖尿病（P=2.8×10），男性臀围/腰围（P=1.1×10），精神分裂症（P=1.6×10），认知能力下降（P=5.3×10）和帕金森病（P=8.6×10）。
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