Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.
Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.
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DOI：
10.1371/journal.pgen.1004606
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发表时间：
2014-09
期刊：
影响因子：
4.5
通讯作者：
Montine TJ
中科院分区：
文献类型：
--
作者：
Beecham GW;Hamilton K;Naj AC;Martin ER;Huentelman M;Myers AJ;Corneveaux JJ;Hardy J;Vonsattel JP;Younkin SG;Bennett DA;De Jager PL;Larson EB;Crane PK;Kamboh MI;Kofler JK;Mash DC;Duque L;Gilbert JR;Gwirtsman H;Buxbaum JD;Kramer P;Dickson DW;Farrer LA;Frosch MP;Ghetti B;Haines JL;Hyman BT;Kukull WA;Mayeux RP;Pericak-Vance MA;Schneider JA;Trojanowski JQ;Reiman EM;Alzheimer's Disease Genetics Consortium (ADGC);Schellenberg GD;Montine TJ
阿尔茨海默病（AD）和相关痴呆是一个重大的公共卫生挑战，提出了治疗的必要性，我们需要进一步了解分子发病机制。我们利用4914例脑尸检的神经病理学数据进行了一项全基因组关联研究，并分析了AD痴呆的已知遗传风险位点。神经病理学数据用于定义临床病理AD痴呆或对照，评估AD的核心神经病理学特征（神经性斑块，NPs；神经原纤维缠结，nft），并评估常见的共病神经病理学改变：脑淀粉样血管病（CAA）、路易体病（LBD）、老年海马硬化（HS）和血管性脑损伤（VBI）。临床病理性阿尔茨海默病、NPs、nft、CAA和LBD在载脂蛋白E基因（APOE）内及其周围存在大量变异，在全基因组范围内具有显著意义。GalNAc转移酶7 （GALNT7）、atp结合盒、G亚家族（WHITE）、成员1 （ABCG1）和9号染色体上的基因间区与NP评分相关；钾大电导钙活化通道M亚家族β成员2 （KCNMB2）与HS密切相关。我们的临床病理样本中证实了21个临床定义的AD痴呆非apoe遗传风险位点中的12个：CR1、BIN1、CLU、MS4A6A、PICALM、ABCA7、CD33、PTK2B、SORL1、MEF2C、ZCWPW1和CASS4，其中9个位点在临床病理样本中显示出较大的优势比。AD痴呆风险的效应量与nft或NPs的效应量呈正相关，而VBI风险的效应量呈中度负相关。其他共病的神经病理特征显示仅与已知的AD位点有名义上的联系。我们的研究结果发现了与特定神经病理特征的新的遗传关联，并在最大规模的阿尔茨海默病和相关痴呆症的脑尸检研究中，将阿尔茨海默病痴呆的已知遗传风险与特定神经病理变化相一致。阿尔茨海默病（AD）和相关痴呆是一个重大的公共卫生挑战，提出了治疗的必要性，我们需要进一步了解分子发病机制。我们进行了一项全基因组关联研究（GWAS），并分析了已知的AD痴呆遗传风险位点，使用了4,914例脑尸检的数据。观察了7个基因与AD及相关疾病的病理特征的全基因组意义。在我们的病理样本中，临床定义的阿尔茨海默病的22个遗传风险位点中有12个被证实。阿尔茨海默病痴呆风险的效应量与阿尔茨海默病标志性病理特征的效应量呈强烈的正相关和线性关系。我们的研究发现了与特定病理特征的新的遗传关联，并通过对阿尔茨海默病和相关痴呆症的大型脑尸检研究，将阿尔茨海默病痴呆的已知遗传风险与特定病理变化相一致。
Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias. Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study (GWAS), as well as an analysis of known genetic risk loci for AD dementia, using data from 4,914 brain autopsies. Genome-wide significance was observed for 7 genes and pathologic features of AD and related diseases. Twelve of the 22 genetic risk loci for clinically-defined AD dementia were confirmed in our pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for hallmark pathologic features of AD were strongly positive and linear. Our study discovered new genetic associations with specific pathologic features and aligned known genetic risk for AD dementia with specific pathologic changes in a large brain autopsy study of AD and related dementias.