Evidence for More than One Parkinson's Disease-Associated Variant within the HLA Region

Parkinson's disease (PD) was recently found to be associated with HLA in a genome-wide association study (GWAS). Follow-up GWAS's replicated the PD-HLA association but their top hits differ. Do the different hits tag the same locus or is there more than one PD-associated variant within HLA? We show that the top GWAS hits are not correlated with each other (0.00≤r(2)≤0.15). Using our GWAS (2000 cases, 1986 controls) we conducted step-wise conditional analysis on 107 SNPs with P<10(-3) for PD-association; 103 dropped-out, four remained significant. Each SNP, when conditioned on the other three, yielded P(SNP1) = 5×10(-4), P(SNP2) = 5×10(-4), P(SNP3) = 4×10(-3) and P(SNP4) = 0.025. The four SNPs were not correlated (0.01≤r(2)≤0.20). Haplotype analysis (excluding rare SNP2) revealed increasing PD risk with increasing risk alleles from OR = 1.27, P = 5×10(-3) for one risk allele to OR = 1.65, P = 4×10(-8) for three. Using additional 843 cases and 856 controls we replicated the independent effects of SNP1 (P(conditioned-on-SNP4) = 0.04) and SNP4 (P(conditioned-on-SNP1) = 0.04); SNP2 and SNP3 could not be replicated. In pooled GWAS and replication, SNP1 had OR(conditioned-on-SNP4) = 1.23, P(conditioned-on-SNP4) = 6×10(-7); SNP4 had OR(conditioned-on-SNP1) = 1.18, P(conditioned-on-SNP1) = 3×10(-3); and the haplotype with both risk alleles had OR = 1.48, P = 2×10(-12). Genotypic OR increased with the number of risk alleles an individual possessed up to OR = 1.94, P = 2×10(-11) for individuals who were homozygous for the risk allele at both SNP1 and SNP4. SNP1 is a variant in HLA-DRA and is associated with HLA-DRA, DRB5 and DQA2 gene expression. SNP4 is correlated (r(2) = 0.95) with variants that are associated with HLA-DQA2 expression, and with the top HLA SNP from the IPDGC GWAS (r(2) = 0.60). Our findings suggest more than one PD-HLA association; either different alleles of the same gene, or separate loci.