Triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well as in Alzheimer’s disease (AD) pathogenesis. We previously reported the MS4A locus as a key modulator for soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF). To identify additional novel genetic modifiers of sTREM2, we performed the largest genome-wide association study (GWAS) and identified four loci for CSF sTREM2 in 3,350 individuals of European ancestry. Through multi-ethnic fine mapping, we identified two independent missense variants (p.M178V in MS4A4A and p.A112T in MS4A6A) that drive the association in MS4A locus and showed an epistatic effect for sTREM2 levels and AD risk. The novel TREM2 locus on chr 6 contains two rare missense variants (rs75932628 p.R47H, P=7.16×10-19; rs142232675 p.D87N, P=2.71×10-10) associated with sTREM2 and AD risk. The third novel locus in the TGFBR2 and RBMS3 gene region (rs73823326, P=3.86×10-9) included a regulatory variant with a microglia-specific chromatin loop for the promoter of TGFBR2. Using cell-based assays we demonstrate that overexpression and knock-down of TGFBR2, but not RBMS3, leads to significant changes of sTREM2. The last novel locus is located on the APOE region (rs11666329, P=2.52×10-8), but we demonstrated that this signal was independent of APOE genotype. This signal colocalized with cis-eQTL of NECTIN2 in the brain cortex and cis-pQTL of NECTIN2 in CSF. Overexpression of NECTIN2 led to an increase of sTREM2 supporting the genetic findings. To our knowledge, this is the largest study to date aimed at identifying genetic modifiers of CSF sTREM2. This study provided novel insights into the MS4A and TREM2 loci, two well-known AD risk genes, and identified TGFBR2 and NECTIN2 as additional modulators involved in TREM2 biology.

中文翻译：

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脑脊液中可溶性 TREM2 的蛋白质基因组学提供了新的见解并确定了阿尔茨海默病的新调节剂

骨髓细胞 2 (TREM2) 上表达的触发受体在小胶质细胞激活、存活和凋亡以及阿尔茨海默病 (AD) 发病机制中发挥着关键作用。我们之前报道过 MS4A 基因座是脑脊液 (CSF) 中可溶性 TREM2 (sTREM2) 的关键调节剂。为了确定 sTREM2 的其他新型遗传修饰因子，我们进行了最大的全基因组关联研究 (GWAS)，并在 3,350 名欧洲血统个体中确定了 CSF sTREM2 的四个位点。通过多种族精细定位，我们确定了两个独立的错义变异（MS4A4A 中的 p.M178V 和 MS4A6A 中的 p.A112T），它们驱动 MS4A 基因座中的关联，并显示出对 sTREM2 水平和 AD 风险的上位效应。Chr 6 上的新 TREM2 位点包含两个与 sTREM2 和 AD 风险相关的罕见错义变异（rs75932628 p.R47H，P=7.16×10-19；rs142232675 p.D87N，P=2.71×10-10）。TGFBR2和RBMS3基因区域中的第三个新位点（rs73823326，P=3.86×10-9）包括具有TGFBR2启动子的小胶质细胞特异性染色质环的调节变体。使用基于细胞的测定，我们证明 TGFBR2（而非 RBMS3）的过度表达和敲低会导致 sTREM2 的显着变化。最后一个新位点位于APOE区域（rs11666329，P=2.52×10-8），但我们证明该信号与APOE基因型无关。该信号与大脑皮层中 NECTIN2 的 cis-eQTL 和 CSF 中 NECTIN2 的 cis-pQTL 共定位。NECTIN2 的过度表达导致 sTREM2 的增加，支持了遗传发现。据我们所知，这是迄今为止规模最大的旨在识别 CSF sTREM2 基因修饰因子的研究。这项研究为 MS4A 和 TREM2 位点（两个著名的 AD 风险基因）提供了新的见解，并确定 TGFBR2 和 NECTIN2 作为参与 TREM2 生物学的额外调节剂。