Logue Mark W, Schu Matthew, Vardarajan Badri N, Farrell John, Lunetta Kathryn L, Jun Gyungah, Baldwin Clinton T, Deangelis Margaret M, Farrer Lindsay A
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
Neurobiol Aging. 2014 Jun;35(6):1510.e7-18. doi: 10.1016/j.neurobiolaging.2013.12.007. Epub 2013 Dec 19.
Several lines of inquiry point to overlapping molecular mechanisms between late-onset Alzheimer disease (AD) and age-related macular degeneration (AMD). We evaluated summarized results from large genome-wide association studies for AD and AMD to test the hypothesis that AD susceptibility loci are also associated with AMD. We observed association of both disorders with genes in a region of chromosome 7, including PILRA and ZCWPW1 (peak AMD SNP rs7792525, minor allele frequency [MAF] = 19%, odds ratio [OR] = 1.14, p = 2.34 × 10(-6)), and with ABCA7 (peak AMD SNP rs3752228, MAF = 0.054, OR = 1.22, p = 0.00012). Next, we evaluated association of AMD with genes in AD-related pathways identified by canonical pathway analysis of AD-associated genes. Significant associations were observed with multiple previously identified AMD risk loci and 2 novel genes: HGS (peak SNP rs8070488, MAF = 0.23, OR = 0.91, p = 7.52 × 10(-5)), which plays a role in the clathrin-mediated endocytosis signaling pathway, and TNF (peak SNP rs2071590, MAF = 0.34, OR = 0.89, p = 1.17 × 10(-5)), which is a member of the atherosclerosis signaling and the LXR/RXR activation pathways. Our results suggest that AMD and AD share genetic mechanisms.
多条研究线索表明，晚发型阿尔茨海默病（AD）和年龄相关性黄斑变性（AMD）之间存在重叠的分子机制。我们评估了AD和AMD大型全基因组关联研究的汇总结果，以检验AD易感基因座也与AMD相关的假设。我们观察到这两种疾病都与7号染色体上一个区域的基因有关联，包括PILRA和ZCWPW1（AMD峰值单核苷酸多态性rs7792525，次要等位基因频率[MAF]=19%，优势比[OR]=1.14，p=2.34×10⁻⁶），以及与ABCA7（AMD峰值单核苷酸多态性rs3752228，MAF=0.054，OR=1.22，p=0.00012）有关联。接下来，我们评估了AMD与通过对AD相关基因进行典型通路分析确定的AD相关通路中的基因之间的关联。观察到与多个先前确定的AMD风险基因座和2个新基因存在显著关联：HGS（峰值单核苷酸多态性rs8070488，MAF=0.23，OR=0.91，p=7.52×10⁻⁵），其在网格蛋白介导的内吞信号通路中起作用；以及TNF（峰值单核苷酸多态性rs2071590，MAF=0.34，OR=0.89，p=1.17×10⁻⁵），它是动脉粥样硬化信号通路和LXR/RXR激活通路的成员。我们的结果表明，AMD和AD共享遗传机制。
