Abstract
Alzheimer's disease (AD), Parkinson's disease (PD) and sporadic frontotemporal dementia (FTD) represent a spectrum of clinical syndromes characterized by variable regional specific neurodegeneration. Nevertheless, although some clinical, pathological and genetic evidence suggests overlapping pathobiology between the three neurodegenerative diseases, such relationships are yet not well understood. Using summary statistics (odds ratios and p-values) from large genome-wide association studies (total n > 75,000 cases and controls), we investigated pleiotropy between these three disorders. We found > 120-fold enrichment of FTD SNPs for different levels of association with AD and PD at a false discovery rate of < 0.05. Particularly, SNPs within the HLA, MAPT and APOE regions were shared between FTD and either AD or PD. By conditioning on polymorphisms associated with PD and AD, we found 11 loci associated with increased risk for FTD particularly indicating a genome-wide signal within the APOE region (rs6857, chromosome 19, 3’-UTR = PVRL2, meta-analysis p = 2.21 x 10-12), and a suggestive signal for rs1358071 within the MAPT region (chromosome 17, intronic = CRHR1, meta-analysis p = 9.89 x 10-7) with the effect allele tagging the H1 haplotype. Our findings demonstrate genetic pleiotropy in three common neurodegenerative diseases and indicate a polygenic component where multiple pleiotropic loci with small effects contribute to increased disease risk.
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