Dataset Information

Evidence for more than one Parkinson's disease-associated variant within the HLA region.

ABSTRACT: 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.

SUBMITTER: Hill-Burns EM

PROVIDER: S-EPMC3212531 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Evidence for more than one Parkinson's disease-associated variant within the HLA region.

Hill-Burns Erin M EM Factor Stewart A SA Zabetian Cyrus P CP Thomson Glenys G Payami Haydeh H

PloS one 20111109 11

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-asso ...[more]

PMID: 22096524

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Project description:Background: Cognitive deficits are prominent non-motor symptoms in Parkinson's disease (PD) and have been shown to involve the neurovascular unit (NVU). However, there is a lack of sufficient neuroimaging research on the associated modulating mechanisms. The objective of this study was to identify the contribution of neurovascular decoupling to the pathogenesis of cognitive decline in PD. Methods: Regional homogeneity (ReHo), a measure of neuronal activity, and cerebral blood flow (CBF), a measure of vascular responses, were obtained from patients with PD with mild cognitive impairment (MCI) and normal cognition (NC) as well as matched healthy controls (HCs). Imaging metrics of neurovascular coupling (global and regional CBF-ReHo correlation coefficients and CBF-ReHo ratios) were compared among the groups. Results: Neurovascular coupling was impaired in patients with PD-MCI with a decreased global CBF-ReHo correlation coefficient relative to HC subjects (P < 0.05). Regional dysregulation was specific to the PD-MCI group and localized to the right middle frontal gyrus, right middle cingulate cortex, right middle occipital gyrus, right inferior parietal gyrus, right supramarginal gyrus, and right angular gyrus (P < 0.05). Compared with HC subjects, patients with PD-MCI showed higher CBF-ReHo ratios in the bilateral lingual gyri (LG), bilateral putamen, and left postcentral gyrus and lower CBF-ReHo ratios in the right superior temporal gyrus, bilateral middle temporal gyri, bilateral parahippocampal gyri, and right inferior frontal gyrus. Relative to the HC and PD-NC groups, the PD-MCI group showed an increased CBF-ReHo ratio in the left LG, which was correlated with poor visual-spatial performance (r = -0.36 and P = 0.014). Conclusion: The involvement of neurovascular decoupling in cognitive impairment in PD is regionally specific and most prominent in the visual-spatial cortices, which could potentially provide a complementary understanding of the pathophysiological mechanisms underlying cognitive deficits in PD.

Project description:Cord blood transplantation (CBT) provides a treatment scheme for hematologic diseases and leukemia in both children and adults. However, adverse reactions and transplantation-related death may still occur in patients receiving CBT even when donor and recipient have fully matched HLA in high-resolution HLA typing analysis. Single nucleotide polymorphisms (SNPs) of HLA-related and unrelated genes are known to associate with disease status of patients with unrelated stem cell transplantation. In this study, the genomic regions ranging from 500 base pairs upstream to 500 base pairs downstream of the eight SNPs that were reported as transplantation determinants by Petersdorf et al. were analyzed to evaluate whether genetic variants were associated with the survival status of patients, and the risk for severe (grades 3–4) graft-versus-host disease (GVHD) or cytomegalovirus (CMV) infection/reactivation. The analyses were performed in the mode of recipient genotype, donor genotype, and recipient-donor mismatching, respectively. By analysis of sixty-five patients and their HLA-matched unrelated donors, we found that five SNPs were associated with patient survival which included the recipient genotype with SNPs of rs107822 in the RING1 gene, and rs2070120, rs17220087 and rs17213693 in the HLA-DOB gene; and the recipient-donor mismatching with SNPs of rs9282369 in HLA-DOA gene, and rs2070120, rs17220087 and rs17213693 in the HLA-DOB gene. Five SNPs were associated with the risk for severe GVHD which included the donor genotype with SNPs of rs213210 and rs2523675; the recipient genotype with SNPs of rs9281491 in the HCP5 gene; and the recipient-donor mismatching with SNPs of rs209130 in the TRIM27 gene, and rs986522 in the COL11A2 gene. Six SNPs were related to the risk for CMV infection/reactivation which included the donor genotype with SNPs of rs435766, rs380924, and rs2523957; and the recipient-donor mismatching with SNPs of rs2070120, rs17220087, and rs17213693 in the HLA-DOB gene; and rs435766 and rs380924 in the MICD gene. This study provides the basis for larger analyses and if the results are confirmed, a way of selecting better unrelated CBT candidate donors.

Dataset Information

Evidence for more than one Parkinson's disease-associated variant within the HLA region.

Publications

Evidence for more than one Parkinson's disease-associated variant within the HLA region.

Similar Datasets

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