Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
Transl Psychiatry. 2018 May 18;8(1):99. doi: 10.1038/s41398-018-0150-6.
Alzheimer's disease (AD) is a public health priority for the 21st century. Risk reduction currently revolves around lifestyle changes with much research trying to elucidate the biological underpinnings. We show that self-report of parental history of Alzheimer's dementia for case ascertainment in a genome-wide association study of 314,278 participants from UK Biobank (27,696 maternal cases, 14,338 paternal cases) is a valid proxy for an AD genetic study. After meta-analysing with published consortium data (n = 74,046 with 25,580 cases across the discovery and replication analyses), three new AD-associated loci (P < 5 × 10) are identified. These contain genes relevant for AD and neurodegeneration: ADAM10, BCKDK/KAT8 and ACE. Novel gene-based loci include drug targets such as VKORC1 (warfarin dose). We report evidence that the association of SNPs in the TOMM40 gene with AD is potentially mediated by both gene expression and DNA methylation in the prefrontal cortex. However, it is likely that multiple variants are affecting the trait and gene methylation/expression. Our discovered loci may help to elucidate the biological mechanisms underlying AD and, as they contain genes that are drug targets for other diseases and disorders, warrant further exploration for potential precision medicine applications.
阿尔茨海默病（AD）是 21 世纪的公共卫生重点。目前，风险降低主要围绕生活方式的改变展开，许多研究都试图阐明其生物学基础。我们表明，在英国生物库对 314278 名参与者（27696 名母亲病例，14338 名父亲病例）进行的全基因组关联研究中，通过自我报告父母的阿尔茨海默病痴呆病史来确定病例，这是 AD 遗传研究的有效替代方法。在对已发表的联盟数据（n = 74046 名，发现和复制分析中共有 25580 例病例）进行荟萃分析后，确定了三个新的与 AD 相关的基因座（P < 5×10）。这些基因座包含与 AD 和神经退行性变相关的基因：ADAM10、BCKDHK/KAT8 和 ACE。新的基于基因的基因座包括药物靶点，如 VKORC1（华法林剂量）。我们报告的证据表明，TOMM40 基因中的 SNPs 与 AD 的关联可能是由前额叶皮层中的基因表达和 DNA 甲基化共同介导的。然而，很可能有多种变体影响着这种特征，包括基因甲基化/表达。我们发现的基因座可能有助于阐明 AD 的生物学机制，并且由于它们包含了其他疾病和障碍的药物靶点基因，因此值得进一步探索，以寻找潜在的精准医疗应用。
