Common X-chromosome variants are associated with Parkinson’s disease risk

AbstractObjectiveIdentify genetic variants on the X-chromosome associated with Parkinson’s disease (PD) risk.MethodsWe performed an X-chromosome-wide association study (XWAS) of PD risk by meta-analyzing results from sex-stratified analyses. To avoid spurious associations, we designed a specific harmonization pipeline for the X-chromosome and focused on a European ancestry sample. We included 11,324 cases, 280,060 controls, and 5,379 proxy cases, based on parental history of PD. Additionally, we tested the association of significant variants with: (i) PD risk in an independent replication with 1,564 cases and 2,467 controls, and (ii) putamen volume in 33,360 individuals from the UK Biobank.ResultsIn the discovery meta-analysis, we identified: rs7066890 (OR=1.10 [1.06-1.14]; P=2.2×10−9) intron of GPM6B, and rs28602900 (OR=1.10 [1.07-1.14]; P=1.6×10−8) in a high gene density region including RPL10, ATP6A1, FAM50A, PLXNA3. The rs28602900 association with PD was replicated (OR=1.16 [1.03-1.30]; P=0.016) and shown to colocalize with a significant expression quantitative locus (eQTL) regulating RPL10 expression in the putamen and other brain tissues in GTEx. Additionally, the rs28602900 locus was found to be associated with reduced brain putamen volume. No results reached genome-wide significance in the sex-stratified analyses.InterpretationWe report the first XWAS of PD and identify two genome-wide significant loci. The rs28602900 association replicated in an independent PD dataset and showed concordant effects in its association with putamen volume. Critically, rs26802900 is a significant eQTL of RPL10.These results support a role for ribosomal proteins in PD pathogenesis and show that the X-chromosome contributes to PD genetic risk.

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LRRK2 coding variants and the risk of Parkinson’s disease

10.1101/2021.04.22.21255928 ◽

2021 ◽

Author(s):

Julie Lake ◽

Xylena Reed ◽

Rebekah G. Langston ◽

Mike A. Nalls ◽

Ziv Gan-Or ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Risk ◽

Meta Analysis ◽

European Ancestry ◽

Allele Distribution ◽

Gwas Signal ◽

Lower Effect ◽

Independent Association ◽

Coding Variants

AbstractBackgroundThe leucine-rich repeat kinase 2 (LRRK2) gene harbors both rare highly damaging missense variants (e.g. p.G2019S) and common non-coding variants (e.g. rs76904798) with lower effect sizes that are associated with Parkinson’s disease risk.ObjectivesThis study aimed to investigate in a large meta-analysis whether the LRRK2 GWAS signal represented by rs76904798 is independently associated with Parkinson’s disease risk from LRRK2 coding variation, and whether complex linkage disequilibrium structures with p.G2019S and the 5’ non-coding haplotype account for the association of LRRK2 coding variants.MethodsWe performed a meta-analysis using imputed genotypes from 17,838 cases, 13,404 proxy-cases and 173,639 healthy controls of European ancestry. We excluded carriers of p.G2019S and/or rs76904798 to clarify the role of LRRK2 coding variation in mediating disease risk, and excluded carriers of relatively rare LRRK2 coding variants to assess the independence of rs76904798. We also investigated the co-inheritance of LRRK2 coding variants with p.G2019S, rs76904798 and p.N2081D.ResultsLRRK2 rs76904798 remained significantly associated with Parkinson’s disease after excluding carriers of relatively rare LRRK2 coding variants. LRRK2 p.R1514Q and p.N2081D were frequently co-inherited with rs76904798 and the allele distribution of p.S1647T significantly changed among cases after removing rs76904798 carriers.ConclusionsThese data suggest that the LRRK2 coding variants previously linked to Parkinson’s disease (p.N551K, p.R1398H, p.M1646T and p.N2081D) do not drive the 5’ non-coding GWAS signal. These data, however, do not preclude the independent association of the haplotype p.N551K-p.R1398H and p.M1646T with altered disease risk.

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A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci

Nature Genetics ◽

10.1038/ng.3955 ◽

2017 ◽

Vol 49 (10) ◽

pp. 1511-1516 ◽

Cited By ~ 461

Author(s):

Diana Chang ◽

◽

Mike A Nalls ◽

Ingileif B Hallgrímsdóttir ◽

Julie Hunkapiller ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Risk ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide

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Novel Parkinson's disease risk loci identified through a meta-analysis of genome-wide association studies

Movement Disorders ◽

10.1002/mds.27276 ◽

2017 ◽

Vol 33 (1) ◽

pp. 74-74

Author(s):

Zhenhua Liu ◽

Beisha Tang

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Risk ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide

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Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

Brain ◽

10.1093/brain/awz350 ◽

2019 ◽

Vol 143 (1) ◽

pp. 234-248 ◽

Cited By ~ 22

Author(s):

Cornelis Blauwendraat ◽

Xylena Reed ◽

Lynne Krohn ◽

Karl Heilbron ◽

Sara Bandres-Ciga ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Genetic Risk ◽

Lewy Body ◽

Disease Risk ◽

Genetic Risk Score ◽

Age At Onset ◽

Lewy Body Dementia ◽

Risk Variants ◽

Genome Wide

Abstract Parkinson’s disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson’s disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson’s disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson’s disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson’s disease cases, 13 431 Parkinson’s disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson’s disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson’s disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson’s disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson’s disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions.

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The Effect of Caffeine on the Risk and Progression of Parkinson’s Disease: A Meta-Analysis

Nutrients ◽

10.3390/nu12061860 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1860 ◽

Cited By ~ 5

Author(s):

Chien Tai Hong ◽

Lung Chan ◽

Chyi-Huey Bai

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Risk ◽

Meta Analysis ◽

Motor Fluctuation ◽

New Drugs ◽

Caffeine Consumption ◽

Healthy Cohort ◽

Adenosine 2A Receptor

Coffee and caffeine are speculated to be associated with the reduced risk of Parkinson’s disease (PD). The present study aimed to investigate the disease-modifying potential of caffeine on PD, either for healthy people or patients, through a meta-analysis. The electronic databases were searched using terms related to PD and coffee and caffeinated food products. Articles were included only upon fulfillment of clear diagnostic criteria for PD and details regarding their caffeine content. Reference lists of relevant articles were reviewed to identify eligible studies not shortlisted using these terms. In total, the present study enrolled 13 studies, nine were categorized into a healthy cohort and the rest into a PD cohort. The individuals in the healthy cohort with regular caffeine consumption had a significantly lower risk of PD during follow-up evaluation (hazard ratio (HR) = 0.797, 95% CI = 0.748–0.849, p < 0.001). The outcomes of disease progression in PD cohorts included dyskinesia, motor fluctuation, symptom onset, and levodopa initiation. Individuals consuming caffeine presented a significantly lower rate of PD progression (HR = 0.834, 95% CI = 0.707–0.984, p = 0.03). In conclusion, caffeine modified disease risk and progression in PD, among both healthy individuals or those with PD. Potential biological benefits, such as those obtained from adenosine 2A receptor antagonism, may require further investigation for designing new drugs.

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