scholarly journals Genome-wide association study of Parkinson’s disease progression biomarkers in 12 longitudinal patients’ cohorts

2019 ◽  
Author(s):  
Hirotaka Iwaki ◽  
Cornelis Blauwendraat ◽  
Hampton L. Leonard ◽  
Jonggeol J. Kim ◽  
Ganqiang Liu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Progression ◽  
Genetic Factors ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
P Value ◽  
Risk Variants ◽  
Genome Wide ◽  
A Genome

AbstractBackgroundSeveral reports have identified different patterns of Parkinson’s disease progression in individuals carrying missense variants in theGBAorLRRK2genes. The overall contribution of genetic factors to the severity and progression of Parkinson’s disease, however, has not been well studied.ObjectivesTo test the association between genetic variants and the clinical features and progression of Parkinson’s disease on a genome-wide scale.MethodsWe accumulated individual data from 12 longitudinal cohorts in a total of 4,093 patients with 25,254 observations over a median of 3.81 years. Genome-wide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently-identified disease risk variants, were also investigated for the associations with these phenotypes.ResultsTwo variants were genome-wide significant. Rs382940(T>A), within the intron ofSLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (HR 2.04 [1.58, 2.62], P-value = 3.46E-8). Rs61863020(G>A), an intergenic variant and eQTL forADRA2A, was associated with a lower prevalence of insomnia at baseline (OR 0.63 [0,52, 0.75], P-value = 4.74E-8). In the targeted analysis, we found nine associations between known Parkinson’s risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports ofGBAcoding variants (rs2230288: p.E365K, rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, andAPOEE4 tagging variant (rs429358) being associated with greater cognitive deficits in patients.ConclusionsWe identified novel genetic factors associated with heterogeneity of progression in Parkinson’s disease. The results provide new insights into the pathogenesis of Parkinson’s disease as well as patient stratification for clinical trials.

scholarly journals α-Synuclein BAC transgenic mice exhibit RBD-like behaviour and hyposmia: a prodromal Parkinson’s disease model

Brain ◽  
2019 ◽  
Vol 143 (1) ◽  
pp. 249-265 ◽  
Author(s):  
Tomoyuki Taguchi ◽  
Masashi Ikuno ◽  
Mari Hondo ◽  
Laxmi Kumar Parajuli ◽  
Katsutoshi Taguchi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transgenic Mice ◽  
Rem Sleep ◽  
Genome Wide Association Study ◽  
Artificial Chromosome ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome ◽  
Familial Parkinson’S Disease

Abstract Parkinson’s disease is one of the most common movement disorders and is characterized by dopaminergic cell loss and the accumulation of pathological α-synuclein, but its precise pathogenetic mechanisms remain elusive. To develop disease-modifying therapies for Parkinson’s disease, an animal model that recapitulates the pathology and symptoms of the disease, especially in the prodromal stage, is indispensable. As subjects with α-synuclein gene (SNCA) multiplication as well as point mutations develop familial Parkinson’s disease and a genome-wide association study in Parkinson’s disease has identified SNCA as a risk gene for Parkinson’s disease, the increased expression of α-synuclein is closely associated with the aetiology of Parkinson’s disease. In this study we generated bacterial artificial chromosome transgenic mice harbouring SNCA and its gene expression regulatory regions in order to maintain the native expression pattern of α-synuclein. Furthermore, to enhance the pathological properties of α-synuclein, we inserted into SNCA an A53T mutation, two single-nucleotide polymorphisms identified in a genome-wide association study in Parkinson’s disease and a Rep1 polymorphism, all of which are causal of familial Parkinson’s disease or increase the risk of sporadic Parkinson’s disease. These A53T SNCA bacterial artificial chromosome transgenic mice showed an expression pattern of human α-synuclein very similar to that of endogenous mouse α-synuclein. They expressed truncated, oligomeric and proteinase K-resistant phosphorylated forms of α-synuclein in the regions that are specifically affected in Parkinson’s disease and/or dementia with Lewy bodies, including the olfactory bulb, cerebral cortex, striatum and substantia nigra. Surprisingly, these mice exhibited rapid eye movement (REM) sleep without atonia, which is a key feature of REM sleep behaviour disorder, at as early as 5 months of age. Consistent with this observation, the REM sleep-regulating neuronal populations in the lower brainstem, including the sublaterodorsal tegmental nucleus, nuclei in the ventromedial medullary reticular formation and the pedunculopontine nuclei, expressed phosphorylated α-synuclein. In addition, they also showed hyposmia at 9 months of age, which is consistent with the significant accumulation of phosphorylated α-synuclein in the olfactory bulb. The dopaminergic neurons in the substantia nigra pars compacta degenerated, and their number was decreased in an age-dependent manner by up to 17.1% at 18 months of age compared to wild-type, although the mice did not show any related locomotor dysfunction. In conclusion, we created a novel mouse model of prodromal Parkinson’s disease that showed RBD-like behaviour and hyposmia without motor symptoms.

Linking a genome-wide association study signal to aLRRK2coding variant in Parkinson's disease

2015 ◽  
Vol 31 (4) ◽  
pp. 484-487 ◽  
Author(s):  
Jia Nee Foo ◽  
Sun Ju Chung ◽  
Louis C. Tan ◽  
Herty Liany ◽  
Ho-Sung Ryu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

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

Brain ◽  
2019 ◽  
Vol 143 (1) ◽  
pp. 234-248 ◽  
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.

scholarly journals Japan COVID-19 Task Force: a nation-wide consortium to elucidate host genetics of COVID-19 pandemic in Japan

2021 ◽  
Author(s):  
Ho Namkoong ◽  
Ryuya Edahiro ◽  
Koichi Fukunaga ◽  
Yuya Shirai ◽  
Kyuto Sonehara ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Risk Allele ◽  
Task Force ◽  
European Population ◽  
P Value ◽  
Host Genetics ◽  
Risk Variants ◽  
Genome Wide ◽  
A Genome ◽  
The Face

To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5p35 (rs60200309-A at DOCK2) that was significantly associated with severe COVID-19 in younger (<65 years of age) patients with a genome-wide significant p-value of 1.2 × 10-8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.

297 Genetic associations of ICD in parkinson’s disease

2018 ◽  
Vol 89 (10) ◽  
pp. A47.2-A47
Author(s):  
Rees Richard ◽  
Hubbard Leon ◽  
Ben-Shlomo Yoav ◽  
Grosset Donald ◽  
Williams Nigel ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genome Wide Association Study ◽  
Early Stage ◽  
Age At Onset ◽  
Genetic Associations ◽  
Longitudinal Assessment ◽  
Genetic Determinants ◽  
Genome Wide ◽  
A Genome

IntroductionImpuse Control Disorders (ICD) are a potentially devastating side-effect of dopaminergic therapy in Parkinson’s disease (PD). We explore the genetic factors associated with ICD in Tracking Parkinson’s/PRoBaND – a UK-wide cohort of early-stage PD.MethodsParticipants were diagnosed with PD within 3 years and had longitudinal assessment including the Questionnaire for ICD in Parkinson’s (QUIP) for up to 5 years. We defined cases as having any positive response to the QUIP (lax criteria) or 2 positive responses in any domain (strict criteria). We performed a candidate-gene analysis based on systematic review, followed by a genome-wide association study. We used age at onset, gender, and three significant principle components as covariates.ResultsAfter clinical and genetic quality control steps, we analysed 1602 participants. Prevalence was significantly affected by classification criteria (strict/lax): ICD – 26.8%/11.1%, IRB 29.3%/27.2%, any 31.7%/41.9%. Six SNPs in dopamine, glutamate and adreno- receptor genes achieved nominal significance (p<0.05) in the candidate study. We have identified several SNPs in the GWAS that approach genome wide significance (p<5 × 10–7).ConclusionsThis work is the first genome-wide study of genetic determinants of ICD. Our findings support the hypothesis of genetic determinants of ICD in Parkinson’s and further work will allow understanding of the biology of ICD.

scholarly journals Tau in the Pathophysiology of Parkinson’s Disease

2021 ◽  
Author(s):  
Lina Pan ◽  
Lanxia Meng ◽  
Mingyang He ◽  
Zhentao Zhang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genome Wide Association Study ◽  
Lewy Bodies ◽  
Current Evidence ◽  
Gene Encoding ◽  
Passive Element ◽  
Genome Wide ◽  
A Genome ◽  
And Function

AbstractThe pathological hallmarks of Parkinson's disease (PD) are the progressive loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies (LBs) in remaining neurons. LBs primarily consist of aggregated α-Synuclein (α-Syn). However, accumulating evidence suggests that Tau, which is associated with tauopathies such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and argyrophilic grain disease, is also involved in the pathophysiology of PD. A genome-wide association study (GWAS) identified MAPT, the gene encoding the Tau protein, as a risk gene for PD. Autopsy of PD patients also revealed the colocalization of Tau and α-Syn in LBs. Experimental evidence has shown that Tau interacts with α-Syn and influences the pathology of α-Syn in PD. In this review, we discuss the structure and function of Tau and provide a summary of the current evidence supporting Tau’s involvement as either an active or passive element in the pathophysiology of PD, which may provide novel targets for the early diagnosis and treatment of PD.

scholarly journals Genome-wide association studies of LRRK2 modifiers of Parkinson's disease

2020 ◽  
Author(s):  
Dongbing Lai ◽  
Babak Alipanahi ◽  
Pierre Fontanillas ◽  
Tae-Hwi Schwantes-An ◽  
Jan Aasly ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Age At Onset ◽  
Genome Wide Association ◽  
P Value ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Genome Wide

Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. Methods: We performed the first genome-wide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genome-wide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; P-value=2.5E-08, beta=1.27, SE=0.23, risk allele: C) met genome-wide significance for the penetrance model. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: P-value=1.1E-07; age-at-onset top variant: P-value=9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations.

scholarly journals Genome-Wide Association Study Meta-Analysis for Parkinson’s Disease Motor Subtypes

2020 ◽  
Author(s):  
Isabel Alfradique-Dunham ◽  
Rami Al-Ouran ◽  
Rainer von Coelln ◽  
Cornelis Blauwendraat ◽  
Emily Hill ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Association Study ◽  
Essential Tremor ◽  
Genetic Risk ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Risk Variants ◽  
Genome Wide

AbstractOBJECTIVETo discover genetic determinants of Parkinson disease (PD) motor subtypes, including Tremor Dominant (TD) and Postural Instability/Gait Difficulty (PIGD) forms.METHODSIn 3,212 PD cases of European ancestry, we performed a genome-wide association study (GWAS) examining two complementary outcome traits derived from the Unified Parkinson’s Disease Rating Scale (UPDRS), including dichotomous motor subtype (TD vs. PIGD) or a continuous tremor / PIGD score ratio. Logistic or linear regression models were adjusted for sex, age of onset, disease duration, and 5 ancestry principal components, followed by meta-analysis.RESULTSAmong 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including GPNMB (rs199347, psubtype = 0.01, pratio = 0.03), SH3GL2 (rs10756907, psubtype = 0.02, pratio = 0.01), HIP1R (rs10847864, psubtype = 0.02), RIT2 (rs12456492, psubtype = 0.02), and FBRSL1 (rs11610045, psubtype = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio (p = 0.026, ß = −0.04, 95% CI = −0.07, 0). Based on top results of our GWAS, we identify a novel suggestive association at the STK32B locus (rs2301857, pratio = 6.6×10−7), which harbors an independent risk allele for essential tremor.CONCLUSIONSMultiple PD risk alleles may also modify clinical manifestations to influence PD motor subtype. The discovery of a novel variant at STK32B suggests a possible overlap between genetic risk for essential tremor and tremor-dominant PD.

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