Ancestry-specific peripheral immune gene-expression mediates the risk of neurodegenerative disease

Aims It is hypothesised that peripheral immune states responding to regional environmental triggers contribute to central neurodegeneration. Region-specific genetic selection pressures require this hypothesis to be assessed in an ancestry specific manner. Here we explore a) whether genes causally linked to Alzheimer’s disease (AD), Parkinson’s disease (PD) and Frontotemporal dementia, are themselves active in the peripheral immune response, and b) whether this peripheral immune activity contributes to the risk of neurodegenerative diseases in African, East Asian and European populations. Methods We systematically explore the expression of 39 genes causally implicated in neurodegenerative diseases (NDDs) in expression quantitative trait studies (eQTL) of peripheral immune cell types from diverse ancestries. Bayesian colocalisation analyses between ancestry-specific eQTLs and genome wide association studies identify whether the expression of NDD-genes in peripheral immune cells is associated with the risk of AD and PD. Results 82% of NDD-genes are expressed in peripheral immune cells, with key genes including APOE, PSEN1, PSEN2, APP, TREM2, LRRK2 and C9orf72 showing expression specific to myeloid cell lines. Using genetic colocalisation, we show that the expression of multiple NDD-genes mediate the risk of NDDs in peripheral monocytes in an ancestry-specific manner. Increased expression of LRRK2 is causally associated with the risk of Parkinson’s disease in European populations only, while in East Asian populations this risk is associated with decreased expression of SNCA. Conclusions Genes causally implicated in NDDs mediate the risk of disease partially through effects in the peripheral immune system, in a manner specific to ancestry. This suggests that across different ancestries regional selection pressures may have differentially modulated disease mechanisms. It also identifies innate immune cells, especially monocytes, as potential therapeutic targets in NDDs.