Background Alzheimer's disease (AD) is characterized by robust microgliosis and phenotypic changes that accompany disease pathogenesis. Indeed, genetic variants in microglial genes are linked to risk for late-onset AD (LOAD). Phospholipase C 𝛾 2 (PLCG2) participates in the transduction of signals emanating from immune cell-surface receptors that regulate the inflammatory response and is selectively expressed by microglia in the brain. A rare variant in PLCG2 (P522R) was previously found to be protective against LOAD. Here, we performed association analysis to identify a new genetic variation in PLCG2 that is associated with elevated risk for LOAD.
Methods Using whole genome sequencing (N=1,894) and RNA-Seq (N=1,077) data from the AMP-AD cohort, we investigated whether a missense variant in PLCG2 (M28L) was associated with risk for LOAD. We have examined the homology model and space-filling model of PLCG2 generated with PyMOL to investigate the protein structure of PLCG2 with substitutions of LOAD risk and protective variants in PLCG2 . Gene expression analysis and expression quantitative trait loci (eQTL) of PLCG2 were conducted. We also evaluated the relationship between PLCG2 expression levels and amyloid plaque density and expression levels of microglia specific markers ( AIF1 and TMEM119 ). Age, sex, and APOE ε4 carrier status were used as covariates. Finally, we investigated the longitudinal changes PLCG2 expression in the 5XFAD mouse model of AD and it relationship to amyloid pathology progression.
Results A rare missense variant in PLCG2 (M28L) confers increased AD risk ( p =0.047; OR=1.164 [95% CI=1.002-1.351]). PLCG2 is highly expressed in the brain and was significantly up-regulated in the parahippocampal gyrus, superior temporal gyrus, and inferior temporal gyrus in LOAD. Higher PLCG2 expression levels were associated with increased brain amyloid deposition. The findings were validated in 5xFAD mice, showing a disease progression-dependent increase in Plcg2 expression with amyloid pathology. Furthermore, eQTL analysis identified several variants as associated with increased PLCG2 expression levels in the brain and other organs.
Conclusions Our results provide further evidence that PLCG2 and the M28L variant confers increase risk for LOAD and may play an important role in AD pathophysiology.