Coding variants in TREM2 increase risk for Alzheimer's disease
Coding variants in TREM2 increase risk for Alzheimer's disease
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DOI：
10.1093/hmg/ddu277
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发表时间：
2014-11-01
影响因子：
3.5
通讯作者：
Cruchaga, Carlos
中科院分区：
文献类型：
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作者：
Jin, Sheng Chih;Benitez, Bruno A.;Cruchaga, Carlos
髓样细胞2上表达的触发受体（TREM2）是一种在脑小胶质细胞上表达的免疫吞噬受体，已知可触发吞噬并调节炎症反应。TREM2的纯合突变导致Nasu-Hakola病，这是一种罕见的隐性痴呆。一种杂合的TREM2变体p.R47H最近被证明会增加阿尔茨海默病（AD）的风险。我们假设，如果TREM2确实是一个AD风险基因，那么TREM2中会有其他罕见的变异，这些变异会显著影响AD风险。为了验证这一假设，我们对2082例AD患者和1648例认知正常的欧美裔老年对照进行了TREM2编码区合并测序。我们发现了16个非同义变体，其中6个在以前的AD研究中没有发现。在单变异分析中，P . r47h [P = 9.17 × 10(-4)，比值比(OR) = 2.63(1.44-4.81)]和P . r62h [P = 2.36 × 10(-4), OR = 2.36(1.47-3.80)]与疾病风险显著相关。基于基因的测试表明，TREM2的变异与AD在全基因组范围内显著相关[PSKAT-O = 5.37 x 10(-7)]；Or = 2.55(1.80-3.67)]。排除p.R47H后，TREM2变异与AD的关联仍然非常显著[PSKAT-O = 7.72 × 10(-5)；OR = 2.47(1.62-3.87)]，表明额外的TREM2变异会影响AD风险。先证家族成员的基因分型结果显示，与对照组相比，P . r47h （P = 4.65 x 10(-2)）和P . r62h （P = 6.87 x 10(-3)）在AD病例中更为常见。凝胶电泳分析证实，至少有三个TREM2转录本在人脑中表达，其中一个编码TREM2的可溶性形式。
The triggering receptor expressed on myeloid 2 (TREM2) is an immune phagocytic receptor expressed on brain microglia known to trigger phagocytosis and regulate the inflammatory response. Homozygous mutations in TREM2 cause Nasu-Hakola disease, a rare recessive form of dementia. A heterozygous TREM2 variant, p.R47H, was recently shown to increase Alzheimer''s disease (AD) risk. We hypothesized that if TREM2 is truly an AD risk gene, there would be additional rare variants in TREM2 that substantially affect AD risk. To test this hypothesis, we performed pooled sequencing of TREM2 coding regions in 2082 AD cases and 1648 cognitively normal elderly controls of European American descent. We identified 16 non-synonymous variants, six of which were not identified in previous AD studies. Two variants, p.R47H [P = 9.17 x 10(-4), odds ratio (OR) = 2.63 (1.44-4.81)] and p.R62H [P = 2.36 x 10(-4), OR = 2.36 (1.47-3.80)] were significantly associated with disease risk in single-variant analyses. Gene-based tests demonstrate variants in TREM2 are genome-wide significantly associated with AD [PSKAT-O = 5.37 x 10(-7); OR = 2.55 (1.80-3.67)]. The association of TREM2 variants with AD is still highly significant after excluding p.R47H [PSKAT-O = 7.72 x 10(-5); OR = 2.47 (1.62-3.87)], indicating that additional TREM2 variants affect AD risk. Genotyping in available family members of probands suggested that p.R47H (P = 4.65 x 10(-2)) and p.R62H (P = 6.87 x 10(-3)) were more frequently seen in AD cases versus controls within these families. Gel electrophoresis analysis confirms that at least three TREM2 transcripts are expressed in human brains, including one encoding a soluble form of TREM2.