Aging populations worldwide, and particularly developed countries, face an increasing burden of neurodegenerative diseases. Cognitive impairment is the most prominent in Alzheimer’s disease (AD) and in Frontotemporal dementia (FTD), but it is also an important feature of Parkinson’s disease (PD) (dementia is present in 80% of patients in studies of long-term follow up).
Although genome-wide meta-analysis failed to identify variants associated with both PD and AD, studies that tested the association of variants identified in one specific disease in another neurodegenerative disease revealed positive results. For example, ours and other groups have identified that the non-synonymous variant in TREM2 R47H initially associated for developing risk for AD also increases risk of PD and FTD-like syndrome. Similarly, there is increasing evidence that common pathways are involved in pathogenesis of FTD, AD and PD. FTD genome-wide studies identified signals encompassing HLA locus, related to the immune system and RAB38/CTSC genes related protein trafficking to lysosomal-related organelles and activation of serine proteinases in cells involved in immune process. Variants in genes involved in the immune system, including CLU, CR1, ABCA7, CD33, and EPHA1; as well as in genes related to endosome–lysosome pathways (BIN1, PICALM, CD2AP, EPHA1, SORL1, RIN3, MEF2C, and MADD) were identified in GWAS of AD. And genetic factors, such as LRRK2, GBA, SNCA, PARK2, PINK1, PARK7 and SCARB2, are involved in the autophagy-lysosome pathway while LRRK2, PARK7 , GBA, BST1, HLA-DRB5, STK39 genes and loci are associated with immune system in PD.
We hypothesize that genetic variants and pathways are associated with all these neurodegenerative diseases. The goal of this study is to use genome-wide association data, exome chip data and whole genome/exome sequence data from unrelated individuals to identify novel genetic modifiers that accelerate disease or protect against development of AD, PD, FTD and other complex traits.
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