TREM2 variants in Alzheimer's disease.
TREM2 variants in Alzheimer's disease.
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DOI：
10.1056/nejmoa1211851
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发表时间：
2013-01-10
期刊：
影响因子：
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通讯作者：
Alzheimer Genetic Analysis Group
中科院分区：
文献类型：
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作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
TREM2的纯合子功能丧失突变，编码髓细胞2蛋白上表达的触发受体，以前与常染色体隐性形式的早发性痴呆有关。我们使用基因组、外显子组和Sanger测序分析了1092名阿尔茨海默病患者和1107名对照组（发现组）TREM2的遗传变异性。然后，我们对来自三个阿尔茨海默病全基因组关联研究的TREM2变体rs75932628（预计会导致R47H替代）的输入数据进行了荟萃分析，并测试了该变体与疾病的关联。我们在另外的1887例病例和4061例对照中对R47H变异进行了基因分型。然后，我们分析了TREM2在人脑不同区域的表达，并确定了在阿尔茨海默病小鼠模型和对照小鼠中差异表达的基因。在发现集中，我们发现阿尔茨海默病患者的TREM2外显子2变异明显多于对照组（P = 0.02）。1092例阿尔茨海默病患者中有22个变异等位基因，1107例对照组中有5个变异等位基因（P<0.001）。最常见的相关变异rs75932628（编码R47H）与阿尔茨海默病高度显著相关（P<0.001）。来自全基因组关联研究的rs75932628基因型的荟萃分析证实了这种关联（P = 0.002），另外一系列1887例阿尔茨海默病患者和4061例对照组的直接基因分型也证实了这种关联（P<0.001）。Trem2的表达在对照小鼠和阿尔茨海默病小鼠模型之间存在差异。TREM2中的杂合罕见变异与阿尔茨海默病风险的显着增加相关。（由英国阿尔茨海默氏症研究中心和其他机构资助。）
Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P = 0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P = 0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.)