Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease.
Parkinson's disease is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study of 2,000 individuals with Parkinson's disease (cases) and 1,986 unaffected controls from the NeuroGenetics Research Consortium (NGRC). We confirmed associations with SNCA and MAPT, replicated an association with GAK (using data from the NGRC and a previous study, P = 3.2 x 10(-9)) and detected a new association with the HLA region (using data from the NGRC only, P = 2.9 x 10(-8)), which replicated in two datasets (meta-analysis P = 1.9 x 10(-10)). The HLA association was uniform across all genetic and environmental risk strata and was strong in sporadic (P = 5.5 x 10(-10)) and late-onset (P = 2.4 x 10(-8)) disease. The association peak we found was at rs3129882, a noncoding variant in HLA-DRA. Two studies have previously suggested that rs3129882 influences expression of HLA-DR and HLA-DQ. The brains of individuals with Parkinson's disease show upregulation of DR antigens and the presence of DR-positive reactive microglia, and nonsteroidal anti-inflammatory drugs reduce Parkinson's disease risk. The genetic association with HLA supports the involvement of the immune system in Parkinson's disease and offers new targets for drug development.
Hamza
Taye H
TH
New York State Department of Health Wadsworth Center, Albany, New York, USA.
Zabetian
Cyrus P
CP
Tenesa
Albert
A
Laederach
Alain
A
Montimurro
Jennifer
J
Yearout
Dora
D
Kay
Denise M
DM
Doheny
Kimberly F
KF
Paschall
Justin
J
Pugh
Elizabeth
E
Kusel
Victoria I
VI
Collura
Randall
R
Roberts
John
J
Griffith
Alida
A
Samii
Ali
A
Scott
William K
WK
Nutt
John
J
Factor
Stewart A
SA
Payami
Haydeh
H
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000502:physiology; D055106:Genome-Wide Association Study; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D016017:Odds Ratio; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics*; D055815:Young Adult
D006680:HLA Antigens