Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease.
Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease.
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DOI：
10.1001/jamaneurol.2016.0150
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发表时间：
2016-06-01
期刊：
影响因子：
29
通讯作者：
Alzheimer’s Disease Neuroimaging Initiative
中科院分区：
文献类型：
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作者：
Yokoyama JS;Wang Y;Schork AJ;Thompson WK;Karch CM;Cruchaga C;McEvoy LK;Witoelar A;Chen CH;Holland D;Brewer JB;Franke A;Dillon WP;Wilson DM;Mukherjee P;Hess CP;Miller Z;Bonham LW;Shen J;Rabinovici GD;Rosen HJ;Miller BL;Hyman BT;Schellenberg GD;Karlsen TH;Andreassen OA;Dale AM;Desikan RS;Alzheimer’s Disease Neuroimaging Initiative
迟发性阿尔茨海默病(AD)是痴呆症最常见的形式，给家庭和社会带来了巨大的负担。虽然流行病学和临床证据表明炎症和AD之间存在关系，但它们之间的关系尚未被很好地了解，并可能对治疗和预防策略产生影响。以确定与炎症风险增加相关的基因子集是否也与AD风险增加相关。在2015年7月进行的一项遗传流行病学研究中，我们使用多个学术临床研究中心的全基因组关联研究的摘要数据，系统地调查了AD(国际阿尔茨海默病项目第一阶段)与克罗恩病、溃疡性结肠炎、类风湿性关节炎、1型糖尿病、乳糜泻和牛皮癣之间的基因重叠。对100,000多名个体进行的全基因组关联研究的P值和优势比来自先前患者与各自的对照队列的比较。每种疾病的诊断都是先前使用共识标准为父母研究建立的。主要结果是多效性(联合)假发现率P值。对候选变异的随访包括神经炎斑块和神经纤维缠结病理；纵向阿尔茨海默病评估量表认知子量表评分作为认知功能障碍的衡量标准(阿尔茨海默病神经成像倡议)；以及阿尔茨海默病与对照组大脑中的基因表达(基因表达综合数据)。8个单核苷酸多态(假发现率P<；0.05)与阿尔茨海默病和免疫介导性疾病相关。其中rs2516049(最接近基因HLADRB5，联合假发现率P=0.04，AD为5.37×10−5，银屑病为6.03×10−15)和rs12570088(最接近基因IPMK，联合假发现率为P=0.009，AD为5.73×10−6，克罗恩病为6.57×10−5)显示AD与免疫介导性疾病的等位基因效应方向一致。Rs2516049和rs12570088均与神经纤维缠结病理显著相关(P分别为.01352和.03151)；rs2516049还与阿尔茨海默病评定量表认知子量表的纵向下降相关(β[SE]，0.405[0.190]；P=.03)。在基因表达方面，阿尔茨海默病患者脑内HLADRA和IPMK基因的转录表达与对照组相比有显著差异(β[SE]，0.155[0.024]；P=1.97×10−10；IPMK：β[SE]，−0.096[0.013]；P=7.57×10−13)。我们的发现证明了AD和免疫介导性疾病之间的遗传重叠，并表明免疫系统过程影响AD的发病和进展。
Late-onset Alzheimer disease (AD), the most common form of dementia, places a large burden on families and society. Although epidemiological and clinical evidence suggests a relationship between inflammation and AD, their relationship is not well understood and could have implications for treatment and prevention strategies. To determine whether a subset of genes involved with increased risk of inflammation are also associated with increased risk for AD. In a genetic epidemiology study conducted in July 2015, we systematically investigated genetic overlap between AD (International Genomics of Alzheimer’s Project stage 1) and Crohn disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, and psoriasis using summary data from genome-wide association studies at multiple academic clinical research centers. P values and odds ratios from genome-wide association studies of more than 100 000 individuals were from previous comparisons of patients vs respective control cohorts. Diagnosis for each disorder was previously established for the parent study using consensus criteria. The primary outcome was the pleiotropic (conjunction) false discovery rate P value. Follow-up for candidate variants included neuritic plaque and neurofibrillary tangle pathology; longitudinal Alzheimer’s Disease Assessment Scale cognitive subscale scores as a measure of cognitive dysfunction (Alzheimer’s Disease Neuroimaging Initiative); and gene expression in AD vs control brains (Gene Expression Omnibus data). Eight single-nucleotide polymorphisms (false discovery rate P < .05) were associated with both AD and immune-mediated diseases. Of these, rs2516049 (closest gene HLA-DRB5; conjunction false discovery rate P = .04 for AD and psoriasis, 5.37 × 10−5 for AD, and 6.03 × 10−15 for psoriasis) and rs12570088 (closest gene IPMK; conjunction false discovery rate P = .009 for AD and Crohn disease, P = 5.73 × 10−6 for AD, and 6.57 × 10−5 for Crohn disease) demonstrated the same direction of allelic effect between AD and the immune-mediated diseases. Both rs2516049 and rs12570088 were significantly associated with neurofibrillary tangle pathology (P = .01352 and .03151, respectively); rs2516049 additionally correlated with longitudinal decline on Alzheimer’s Disease Assessment Scale cognitive subscale scores (β [SE], 0.405 [0.190]; P = .03). Regarding gene expression, HLA-DRA and IPMK transcript expression was significantly altered in AD brains compared with control brains (HLA-DRA: β [SE], 0.155 [0.024]; P = 1.97 × 10−10; IPMK: β [SE], −0.096 [0.013]; P = 7.57 × 10−13). Our findings demonstrate genetic overlap between AD and immune-mediated diseases and suggest that immune system processes influence AD pathogenesis and progression.