Abstract
Using genome-wide association data, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s (PD) or Alzheimer’s (AD) disease versus controls across ancestry groups. A shared genetic association was observed across diseases at rs601945 (PD: odds ratio (OR)=0.84; 95% confidence interval, [0.80; 0.88]; p=2.2×10−13; AD: OR=0.91[0.89; 0.93]; p=1.8×10−22), and with a protective HLA association recently reported in amyotrophic lateral sclerosis (ALS). Hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03, and absent for HLA-DRB1*04:05. The same signal was associated with decreased neurofibrillary tangles (but not neuritic plaque density) in postmortem brains and was more strongly associated with Tau levels than Aβ42 levels in the cerebrospinal fluid. Finally, protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone Tau PHF6 sequence, but only when acetylated at K311, a modification central to aggregation. An HLA-DRB1*04-mediated adaptive immune response, potentially against Tau, decreases PD, AD and ALS risk, offering the possibility of new therapeutic avenues.
Guen, Yann Le