Replogle Joseph M, Chan Gail, White Charles C, Raj Towfique, Winn Phoebe A, Evans Denis A, Sperling Reisa A, Chibnik Lori B, Bradshaw Elizabeth M, Schneider Julie A, Bennett David A, De Jager Philip L
Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, MA; Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA; Harvard Medical School, Boston, MA.
Ann Neurol. 2015 Mar;77(3):469-77. doi: 10.1002/ana.24337.
Genome-wide association studies have linked variants in TREM2 (triggering receptor expressed on myeloid cells 2) and TREML2 with Alzheimer disease (AD) and AD endophenotypes. Here, we pursue a targeted analysis of the TREM locus in relation to cognitive decline and pathological features of AD.
Clinical, cognitive, and neuropathological phenotypes were collected in 3 prospective cohorts on aging (n = 3,421 subjects). Our primary analysis was an association with neuritic plaque pathology. To functionally characterize the associated variants, we used flow cytometry to measure TREM1 expression on monocytes.
We provide evidence that an intronic variant, rs6910730(G) , in TREM1, is associated with an increased burden of neuritic plaques (p = 3.7 × 10(-4) ), diffuse plaques (p = 4.1 × 10(-3) ), and Aβ density (p = 2.6 × 10(-3) ) as well as an increased rate of cognitive decline (p = 5.3 × 10(-3) ). A variant upstream of TREM2, rs7759295(C) , is independently associated with an increased tau tangle density (p = 4.9 × 10(-4) ), an increased burden of neurofibrillary tangles (p = 9.1 × 10(-3) ), and an increased rate of cognitive decline (p = 2.3 × 10(-3) ). Finally, a cytometric analysis shows that the TREM1 rs6910730(G) allele is associated with decreased TREM1 expression on the surface of myeloid cells (p = 1.7 × 10(-3) ).
We provide evidence that 2 common variants within the TREM locus are associated with pathological features of AD and aging-related cognitive decline. Our evidence suggests that these variants are likely to be independent of known AD variants and that they may work through an alteration of myeloid cell function.
全基因组关联研究已将髓系细胞触发受体2（TREM2）和髓系细胞触发受体样分子2（TREML2）中的变异与阿尔茨海默病（AD）及AD内表型联系起来。在此，我们针对TREM基因座与AD的认知衰退及病理特征进行靶向分析。
在3个关于衰老的前瞻性队列（n = 3421名受试者）中收集临床、认知和神经病理表型。我们的主要分析是与神经炎性斑块病理的关联。为从功能上表征相关变异，我们使用流式细胞术测量单核细胞上的TREM1表达。
我们提供证据表明，TREM1中的一个内含子变异rs6910730(G)与神经炎性斑块负担增加（p = 3.7×10⁻⁴）、弥漫性斑块（p = 4.1×10⁻³）和Aβ密度增加（p = 2.6×10⁻³）以及认知衰退率增加（p = 5.3×10⁻³）相关。TREM2上游的一个变异rs7759295(C)独立地与tau缠结密度增加（p = 4.9×10⁻⁴）、神经原纤维缠结负担增加（p = 9.1×10⁻³）和认知衰退率增加（p = 2.3×10⁻³）相关。最后，细胞分析表明TREM1 rs6910730(G)等位基因与髓系细胞表面TREM1表达降低相关（p = 1.7×10⁻³）。
我们提供证据表明，TREM基因座内的2个常见变异与AD的病理特征及衰老相关的认知衰退有关。我们的证据表明这些变异可能独立于已知的AD变异，并且它们可能通过髓系细胞功能的改变起作用。
