Cruchaga lab paired genomics and proteomics to research factors involved in TREM2 signaling and shedding. By compiling CSF samples from more than 3000 participants, they measured sTREM2 and ran a GWAS to find variants associated with protein levels.
1) Carriers of the p.R47H AD risk variant tended to have less sTREM2 in their CSF than non-carriers.
2) Two variants within this multigene locus (MS4a4a and MS4a6a) are both associated with higher sTREM2 levels.
3) A GWAS signal popped up in the ApoE locus, which has been associated with high mRNA expression of the Nectin-2 gene and its encoded protein PVRL2, hinting that PVRL2 might play a role in AD risk by influencing TREM2 homeostasis.
4) A hit came in from a locus containing RBMS3 and TGFBR2, further experiments suggesting that TGFBR2 is the one influencing the CSF sTREM2.
5)Among participants, higher CSF sTREM2 correlated with a reduced risk of AD.
To read the full article, please go to https://www.alzforum.org/news/conference-coverage/all-roads-lead-trem2-gearing-target-receptor