HLA-DR region GWAS signal

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Taye Hamza (Wadsworth Center, New York State Department of Health), Cyrus Zabetian, Haydeh Payami (last author) and the NeuroGenetics Research Consortium, Nature Genetics 2010. Europe PMC lists NIH (intramural and extramural) support; the full funder list was not read.

What happened

The team ran a genome-wide association study (testing hundreds of thousands of DNA markers in cases and controls). They confirmed SNCA and MAPT, replicated GAK (P = 3.2 x 10^-9) and found a new signal in the HLA region (P = 2.9 x 10^-8; meta-analysis with two replication sets, P = 1.9 x 10^-10). The peak was rs3129882, a non-coding variant in HLA-DRA. It was strong in sporadic (P = 5.5 x 10^-10) and late-onset (P = 2.4 x 10^-8) disease. The authors noted that this variant affects HLA-DR and HLA-DQ expression, that Parkinson's brains show DR-positive microglia, and that anti-inflammatory painkillers (NSAIDs) lower Parkinson's risk.

Why it moved us toward a cure

It gave genome-wide evidence that immune genes influence Parkinson's (the authors said it supports involvement of the immune system), adding to older autopsy evidence of activated microglia (landmark 52). It is the genetic backdrop for the later finding that T cells react to synuclein fragments tied to HLA variants (landmark 38 should list this as a parent). Later GWAS meta-analyses (landmark 19) were not checked for the HLA locus here.

Outcome

Open. The finding replicated within the paper, and the larger 2014 meta-analysis again found the HLA region, with a second independent variant (landmark 237). Europe PMC lists no correction or retraction. The biology (how an HLA change alters risk) is still being worked out, and no drug has been derived from it.

Sources

• Hamza et al., Nat Genet 2010;42:781–785, DOI 10.1038/ng.642
• Not yet verified: the 2019 meta-analysis HLA result (a search did not retrieve it); the effect size (odds ratio) per allele; the mechanism.