Ziv Gan-Or, Canada
McGill Montreal Neurological InstituteAuthor Of 3 Presentations
FINE MAPPING OF THE HLA LOCUS IN PARKINSON’S DISEASE IN EUROPEANS
Abstract
Aims
Previous studies suggested a role for the immune system in Parkinson’s disease (PD), and one of the hits in recent genome-wide association studies (GWASs) of PD is within the human leukocyte antigen (HLA) locus. Several associations of different HLA genes have been suggested, yet it is not clear which associations are relevant for PD.
Methods
We performed a thorough analysis of the HLA locus for 13,770 PD patients, 20,214 proxy-cases and 490,861 controls of European origin. We used GWAS data to impute HLA types and performed multiple regression models to examine the association of specific HLA types, different haplotypes and specific amino acid changes. We further performed conditional analyses to identify specific alleles or genetic variants that drive the association with PD.
Results
Four HLA types were associated with PD after correction for multiple comparisons, HLA-DQA1*03:01, HLA-DQB1*03:02, HLA-DRB1*04:01 and HLA-DRB1*04:04. Haplotype analyses followed by amino-acid analysis and conditional analyses suggested that the association is protective and primarily driven by three specific amino acid polymorphisms present in most HLA-DRB1*04 subtypes - 11V, 13H and 33H (OR=0.87 95%CI=0.83-0.90, p<8.23x10-9 for all three variants). No other effects were present after adjustment for these amino acids.
Conclusions
Our results suggest that specific variants in the HLA-DRB1 gene are associated with reduced risk of PD, providing additional evidence for the role of the immune system in PD. Although effect size is small and has no diagnostic significance, understanding the mechanism underlying this association may lead to identification of new targets for therapeutics development.
GENETIC CORRELATION AND CAUSALITY OF CANCERS AND PARKINSON’S DISEASE
Abstract
Aims
To examine whether certain types of cancers have causal relationships and shared genetic architecture with Parkinson's disease.
Methods
Mendelian randomization (MR) uses common single nucleotide polymorphisms (SNPs) as instrumental variables (IVs), as a tool to randomize subjects to different groups. In two-sample MR, SNPs identified through genome-wide association studies (GWAS) in one sample, are used as IVs for causality in a second GWAS sample. We applied a two-sample MR to study the causal relationship between 16 different types of cancers (exposures) and PD (outcome). As an outcome, we used data from the most recent PD GWAS. Linkage disequilibrium score regression(LDSC) was applied for four cancer studies with available full summary statistics to examine genetic correlations with PD.
Results
Overall, 16 cancer studies were selected for analysis. All selected IVs had high F-statistics(>10), supporting the strength of these chosen instruments. We did not reveal causal association between the tested cancers and PD. LDSC analysis revealed nominal genetic correlations with PD for prostate cancer (p=0.05), breast cancer (p=0.03) and melanoma (p=0.049). Only the genetic correlation between melanoma and PD was reproduced in both analyses excluding and including the UKBB cohort (p=0.035) in the PD summary statistics.
Conclusions
Our results do not support a causal relationship between the tested cancers and PD. Thus, it is possible that the low prevalence of most cancers observed in PD is due to survival biases. The genetic correlation between PD and melanoma may explain the increased frequency of melanoma in PD patients and the increased frequency of PD in melanoma patients.
LRRK2 P.M1646T IS ASSOCIATED WITH GLUCOCEREBROSIDASE ACTIVITY AND WITH PARKINSON’S DISEASE
Abstract
Aims
The LRRK2 p.G2019S Parkinson’s disease (PD)-associated variant is associated with glucocerebrosidase (GCase) activity in peripheral blood. We aimed to evaluate the effects of other LRRK2 variants on GCase activity in peripheral blood and estimate their association with PD.
Methods
LRRK2 and GBA were fully sequenced in 1,123 PD patients and 576 controls from two cohorts. GCase activity was measured in dried blood spots by liquid chromatography-tandem mass spectrometry in the Columbia University cohort from New York and in the Parkinson’s Progression Markers Initiative (PPMI) cohort. To test the association between LRRK2 variants and GCase activity, linear regression adjusted for age, sex, PD status and GBA status was performed.
Results
LRRK2 p.M1646T was associated with increased GCase activity in the Columbia University cohort (β=1.58, p=0.0003), and increased but not significantly in the PPMI cohort (β=0.29, p=0.58). p.M1646T was associated with PD in 37,688 PD patients, 18,618 UK Biobank proxy-cases and 1.4 million controls from the International Parkinson’s Disease Genomic Consortium (IPDGC) (OR=1.18, 95% CI=1.09-1.28, p=7.33E-05).
Conclusions
Our results suggest that the p.M1646T variant is associated with risk of PD with a small effect and with increased GCase activity in peripheral blood.