Coding variation in GBA explains the majority of the SYT11-GBA Parkinson's disease GWAS locus.
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ABSTRACT:
SUBMITTER: Blauwendraat C
PROVIDER: S-EPMC6379910 | biostudies-literature | 2018 Nov
REPOSITORIES: biostudies-literature
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Coding variation in GBA explains the majority of the SYT11-GBA Parkinson's disease GWAS locus.
Blauwendraat Cornelis C Bras Jose M JM Nalls Mike A MA Lewis Patrick A PA Hernandez Dena G DG Singleton Andrew B AB
Movement disorders : official journal of the Movement Disorder Society 20181009 11
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Project description:Parkinson's disease (PD) is a multifactorial movement disorder characterized by progressive neurodegeneration. Genome-wide association studies (GWAS) have nominated over fifteen distinct loci associated with risk of PD, however the biological mechanisms by which these loci influence disease risk are mostly unknown. GWAS are only the first step in the identification of disease genes: the specific causal variants responsible for the risk within the associated loci and the interactions between them must be identified to fully comprehend their impact on the development of PD. In the present study, we first attempted to replicate the association signals of 17 PD GWAS loci in our series of 1381 patients with PD and 1328 controls. BST1, SNCA, HLA-DRA, CCDC62/HIP1R and MAPT all showed a significant association with PD under different models of inheritance and LRRK2 showed a suggestive association. We then examined the role of coding LRRK2 variants in the GWAS association signal for that gene. The previously identified LRRK2 risk mutant p.M1646T and protective haplotype p.N551K-R1398H-K1423K did not explain the association signal of LRRK2 in our series. Finally, we investigated the gene-gene interaction between PARK16 and LRRK2 that has previously been proposed. We observed no interaction between PARK16 and LRRK2 GWAS variants, but did observe a non-significant trend toward interaction between PARK16 and LRRK2 variants within the protective haplotype. Identification of causal variants and the interactions between them is the crucial next step in making biological sense of the massive amount of data generated by GWAS studies. Future studies combining larger sample sizes will undoubtedly shed light on the complex molecular interplay leading to the development of PD.
| S-EPMC3852568 | biostudies-literature
Project description:IntroductionGenome-wide association studies (GWAS) have confirmed the leucine-rich repeat kinase 2 (LRRK2) gene as a susceptibility locus for idiopathic Parkinson's disease (PD) in Caucasians. Though the rs1491942 and rs76904798 variants have shown the strongest associations, the causal variant(s) remains unresolved. Therefore, the aim of this study was to identify variants that may be driving the LRRK2 GWAS signal by sequencing the entire LRRK2 gene in Caucasian PD patients and controls.MethodsA discovery series (287 PD patients, 294 controls) and replication series (362 PD patients, 168 controls) were included. The entire LRRK2 gene as well as 10 Kb upstream/downstream was sequenced. Candidate potential causal variants were considered to be those that (a) were in at least weak linkage disequilibrium with the two GWAS-nominated variants (rs1491942 and rs76904798), and (b) displayed an association odds ratio (OR) that is stronger than the two GWAS variants.ResultsThirty-four candidate variants (all intronic/intergenic) that may drive the LRRK2 PD GWAS signal were identified in the discovery series. However, examination of the replication series for these variants did not reveal any with a consistently stronger OR than both PD GWAS variants. Evaluation of public databases to determine which candidate variants are most likely to have a direct functional effect on LRRK2 expression was inconclusive.ConclusionThough our findings provide novel insights into the LRRK2 GWAS association, a clear causal variant was not identified. The identified candidate variants can form the basis for future experiments and functional studies that can more definitively assess causal LRRK2 variants.
| S-EPMC9310432 | biostudies-literature
Project description:Introduction: Genome-wide association studies (GWAS) have identified multiple loci associated with Parkinson's disease (PD) risk. The presence of rare variants within these loci that may account for the increased susceptibility requires further investigation. Methods: Using exome sequencing, we performed a comprehensive rare variant screen of genes located within 56 novel PD loci. We first analyzed exomes from 109 subjects in the discovery cohort (85 diagnosed with PD and 24 healthy controls) and filtered for rare coding variants with minor allele frequency <0.01 and combined annotation-dependent depletion > 15. Further investigation of exome data from a replication cohort of 2,859 European patients with PD (International Parkinson's Disease Genomics Consortium) and 24,146 non-Finnish European controls from gnomAD were used for association testing of specific rare variants found in the discovery cohort. Results: Our genetic screening identified 54 potential disease-relevant variants in 71 genes in 109 subjects. Six out of 54 variants were found in two or more patients and were not observed in healthy controls: DNAH1 p.A3639T, STAB1 p.S1089G, ANK2 p.V3634D, ANK2 p.R3906W, SH3GL2 p.G276V, and NOD2 p.G908R. Replication in the International Parkinson's Disease Genomics Consortium (IPDGC) confirmed the association with PD risk for three out of the six identified variants (STAB1 p.S1089G, SH3GL2 p.G276V, and NOD2 p.G908R) (p < 10-3). Conclusion: Our study suggests that some of the associations identified in PD risk loci can be ascribed to rare variants with likely functional effects that modify PD risk.
| S-EPMC6923768 | biostudies-literature
Project description: Not available
| S-EPMC8673698 | biostudies-literature
Project description:IntroductionParkinson's disease patients carrying a heterozygous mutation in the gene glucocerebrosidase (GBA-PD) show faster motor and cognitive decline than idiopathic Parkinson's disease (iPD) patients, but the mechanisms behind this observation are not well understood. Successful dual tasking (DT) requires a smooth integration of motor and nonmotor operations. This study compared the DT performances between GBA-PD and iPD patients.MethodsEleven GBA-PD patients (p.N370S, p.L444P) and eleven matched iPD patients were included. Clinical characterization included a motor score (Unified PD Rating Scale-III, UPDRS-III) and nonmotor scores (Montreal Cognitive Assessment, MoCA, and Beck's Depression Inventory). Quantitative gait analysis during the single-task (ST) and DT assessments was performed using a wearable sensor unit. These parameters corrected for UPDRS and MoCA were then compared between the groups.ResultsUnder the DT condition "walking while checking boxes," GBA-PD patients showed slower gait and box-checking speeds than iPD patients. GBA-PD and iPD patients did not show significant differences regarding dual-task costs.ConclusionThis pilot study suggests that DT performance with a secondary motor task is worse in GBA-PD than in iPD patients. This finding may be associated with the known enhanced motor and cognitive deficits in GBA-PD compared to iPD and should motivate further studies.
| S-EPMC5551514 | biostudies-literature
Project description:Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson's disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson's disease in 2657 patients and 3647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency < 0.01) using optimized sequence Kernel association tests. The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants in SYT11, FGF20 and GCH1 associated with Parkinson's disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that the SYT11 GWAS association is driven by variants in the nearby GBA gene. However, the association of SYT11 was mainly driven by a rare 3' UTR variant (rs945006601) and was independent of GBA variants (P = 5.23 × 10-5 after exclusion of all GBA variant carriers). The association of FGF20 was driven by a rare 5' UTR variant (rs1034608171) located in the promoter region. The previously reported association of GCH1 with Parkinson's disease is driven by rare non-synonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified two LRRK2 variants, p.Arg793Met and p.Gln1353Lys, in 10 and eight controls, respectively, but not in patients. We identified common variants associated with Parkinson's disease in MAPT, TMEM175, BST1, SNCA and GPNMB, which are all in strong linkage disequilibrium with known GWAS hits in their respective loci. A common coding PM20D1 variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson's disease (odds ratio 0.73, 95% confidence interval 0.60-0.89, P = 1.161 × 10-3). This variant is not in linkage disequilibrium with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest that SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB should be considered for future studies as possible Parkinson's disease-related genes.
| S-EPMC7940168 | biostudies-literature
Project description:BackgroundPatients with Parkinson's disease (PD) and GBA gene mutations (GBA-PD) develop nonmotor complications more frequently than noncarriers. However, an objective characterization of both cardiovascular and sudomotor autonomic dysfunction using extensive clinical and instrumental measures has never been provided so far. Survival is reduced in GBA-PD regardless of age and dementia, suggesting that other hitherto unrecognized factors are involved.ObjectivesTo provide instrumental measures of pattern and severity of autonomic dysfunction in GBA-PD and explore their correlation with other non-motor symptoms and implications for clinical practice.MethodsIn this cross-sectional study, 21 GBA-PD and 24 matched PD noncarriers underwent extensive assessment of motor and non-motor features, including neuropsychological testing. Cardiovascular autonomic function was explored through a comprehensive battery of indexes, including power spectral analysis of the R-R intervals and blood pressure short-term variability during resting state and active maneuvers. Dynamic Sweat Test was used to assess post-ganglionic sudomotor dysfunction.ResultsDespite minimal or absent clinical correlates, cardiovagal and sympathetic indexes, heart rate variability parameters and sudomotor postganglionic function were more severely impaired in GBA-PD than noncarriers (overcoming relatively preserved compensatory peripheral sympathetic function), suggesting more prominent cardiac sympatho-vagal demodulation, efferent baroreflex failure and peripheral sympathetic dysfunction in GBA-PD. Cardiovascular dysautonomia showed marginal correlations with cognitive impairment.ConclusionsCompared to PD noncarriers, GBA-PD display more severe instrumental autonomic abnormalities, which may be underestimated by purely clinical measures, despite their relevance on morbidity and mortality. This supports the necessity of implementing instrumental autonomic assessment in all GBA-PD, regardless of clinically overt symptoms.
| S-EPMC10654845 | biostudies-literature
Project description:BackgroundThe leucine-rich repeat kinase 2 (LRRK2) gene harbors both rare highly damaging missense variants (eg, p.G2019S) and common noncoding variants (eg, rs76904798) with lower effect sizes that are associated with Parkinson's disease (PD) risk.ObjectivesThis study aimed to investigate in a large meta-analysis whether the LRRK2 Genome-Wide Association Study (GWAS) signal represented by rs76904798 is independently associated with PD risk from LRRK2 coding variation and whether complex linkage disequilibrium structures with p.G2019S and the 5' noncoding haplotype account for the association of LRRK2 coding variants.MethodsWe performed a meta-analysis using imputed genotypes from 17,838 patients, 13,404 proxy patients, 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 PD after excluding the 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 patients after removing rs76904798 carriers.ConclusionsThese data suggest that the LRRK2 coding variants previously related to PD (p.N551K, p.R1398H, p.M1646T, and p.N2081D) do not drive the 5' noncoding 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. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
| S-EPMC9292230 | biostudies-literature
Project description:Forms of Parkinson's disease (PD) are associated with lysosomal and autophagic dysfunction. ATP13A2, which is mutated in some types of early-onset Parkinsonism, has been suggested as a regulator of the autophagy-lysosome pathway. However, little is known about the ATP13A2 effectors and how they regulate this pathway. Here we show that ATP13A2 depletion negatively regulates another PD-associated gene (SYT11) at both transcriptional and post-translational levels. Decreased SYT11 transcription is controlled by a mechanism dependent on MYCBP2-induced ubiquitination of TSC2, which leads to mTORC1 activation and decreased TFEB-mediated transcription of SYT11, while increased protein turnover is regulated by SYT11 ubiquitination and degradation. Both mechanisms account for a decrease in the levels of SYT11, which, in turn, induces lysosomal dysfunction and impaired degradation of autophagosomes. Thus, we propose that ATP13A2 and SYT11 form a new functional network in the regulation of the autophagy-lysosome pathway, which is likely to contribute to forms of PD-associated neurodegeneration.
| S-EPMC4906231 | biostudies-literature
Project description:Background:Cognitive and motor decline, along with psychiatric symptoms, have a major impact on independence, nursing home admission, caregiver burden, and mortality in Parkinson's disease (PD). The single most common genetic risk factor for developing PD is a mutation in the glucocerebrosidase (GBA) gene. Methods:This work is a literature review regarding "GBA" and "Parkinson's disease" as conducted by PubMed search. Results:There is a higher prevalence of cognitive decline and more rapid trajectory of disease progression in PD-GBA carriers, compared to noncarriers. PD-GBA carriers also have domain-specific cognitive impairment, particularly in visual memory tasks. PD-GBA carriers may also have a more aggressive motor phenotype than noncarriers. Conclusions:Early identification of PD-GBA carriers may lead to targeted therapies and development of new treatments.
| S-EPMC6178756 | biostudies-other