Proteo‐genomics of soluble TREM2 in cerebrospinal fluid provides novel insights for TREM2 biology and identifies novel modulators for Alzheimer’s disease

Abstract

Background: 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). Here, we pursued the largest CSF study to identify additional novel genetic modifiers of sTREM2. Method: We performed the genome‐wide association study (GWAS) of CSF sTREM2 in 3350 individuals of European ancestry from eight cohorts. To identify functional genes, we performed multi‐ethnic fine mapping with 250 non‐European individuals. Functional validation using peripheral blood mononuclear cell‐derived macrophages was performed. Colocalization and Mendelian randomization (MR) was performed for the causality of sTREM2 in AD. Result: The known MS4A locus and three novel loci were identified at genome‐wide significance. In the MS4A locus, we identified two independent missense variants (p.M178V in MS4A4A and p.A112T in MS4A6A) that drove the association through multi‐ethnic fine mapping. They showed an epistatic effect for sTREM2 and AD risk. The novel TREM2 locus on chromosome 6 contained two rare missense variants (rs142232675 p.D87N, P = 2.71×10‐10; rs75932628 p.R47H, P = 7.16×10‐19) associated with sTREM2 and AD risk. Another novel locus in the intergenic region between TGFBR2 and RBMS3 (rs73823326, P = 3.86×10‐9) included a regulatory variant with a microglia‐specific chromatin loop for promoters of TGFBR2. Using cell‐ based assays we demonstrate that TGFBR2, but not RBMS3, modify sTREM2 levels. The last novel locus NECTIN2 on chromosome 19 (rs11666329, P = 2.52×10‐8) was independent of APOE genotype and colocalized with cis‐eQTL of NECTIN2 in the brain cortex and cis‐pQTL of NECTIN2 in CSF (PP.H4 = 0.83). This variant was also associated with AD risk (P = 1.52×10‐66) and age at onset (P = 3.26×10‐5). Our MR results confirmed the significant protective effect of sTREM2 on reducing AD risk. Conclusion: To our knowledge, this is the largest study to date aiming at identifying genetic modifiers of CSF sTREM2. We provided novel insights for MS4A and TREM2, the two well‐ known gens for AD risk. We also identified TGFBR2 and NECTIN2 as additional modulators involved in TREM2 biology. Our findings provide new insight to unravel sTREM2 modulators and their role in AD.