Benitez Bruno A, Jin Sheng Chih, Guerreiro Rita, Graham Rob, Lord Jenny, Harold Denise, Sims Rebecca, Lambert Jean-Charles, Gibbs J Raphael, Bras Jose, Sassi Celeste, Harari Oscar, Bertelsen Sarah, Lupton Michelle K, Powell John, Bellenguez Celine, Brown Kristelle, Medway Christopher, Haddick Patrick C G, van der Brug Marcel P, Bhangale Tushar, Ortmann Ward, Behrens Tim, Mayeux Richard, Pericak-Vance Margaret A, Farrer Lindsay A, Schellenberg Gerard D, Haines Jonathan L, Turton Jim, Braae Anne, Barber Imelda, Fagan Anne M, Holtzman David M, Morris John C, Williams Julie, Kauwe John S K, Amouyel Philippe, Morgan Kevin, Singleton Andy, Hardy John, Goate Alison M, Cruchaga Carlos
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Neurobiol Aging. 2014 Jun;35(6):1510.e19-26. doi: 10.1016/j.neurobiolaging.2013.12.010. Epub 2013 Dec 21.
TREM and TREM-like receptors are a structurally similar protein family encoded by genes clustered on chromosome 6p21.11. Recent studies have identified a rare coding variant (p.R47H) in TREM2 that confers a high risk for Alzheimer's disease (AD). In addition, common single nucleotide polymorphisms in this genomic region are associated with cerebrospinal fluid biomarkers for AD and a common intergenic variant found near the TREML2 gene has been identified to be protective for AD. However, little is known about the functional variant underlying the latter association or its relationship with the p.R47H. Here, we report comprehensive analyses using whole-exome sequencing data, cerebrospinal fluid biomarker analyses, meta-analyses (16,254 cases and 20,052 controls) and cell-based functional studies to support the role of the TREML2 coding missense variant p.S144G (rs3747742) as a potential driver of the meta-analysis AD-associated genome-wide association studies signal. Additionally, we demonstrate that the protective role of TREML2 in AD is independent of the role of TREM2 gene as a risk factor for AD.
触发受体表达上调分子（TREM）和类TREM受体是一个结构相似的蛋白质家族，由位于6号染色体p21.11上的成簇基因编码。最近的研究在触发受体表达上调分子2（TREM2）中发现了一种罕见的编码变体（p.R47H），它会增加患阿尔茨海默病（AD）的风险。此外，该基因组区域的常见单核苷酸多态性与AD的脑脊液生物标志物相关，并且已确定在触发受体表达上调分子样蛋白2（TREML2）基因附近发现的一个常见基因间变体对AD具有保护作用。然而，对于后一种关联背后的功能变体及其与p.R47H的关系知之甚少。在这里，我们报告了使用全外显子组测序数据、脑脊液生物标志物分析、荟萃分析（16254例病例和20052例对照）以及基于细胞的功能研究进行的综合分析，以支持TREML2编码错义变体p.S144G（rs3747742）作为荟萃分析AD相关全基因组关联研究信号的潜在驱动因素的作用。此外，我们证明TREML2在AD中的保护作用独立于TREM2基因作为AD风险因素的作用。
