Genetic factors, environmental factors, and gene-environment interactions have been found to modify PD risk, age at onset (AAO), and disease progression. The objective of this study was to explore ...the association of coffee drinking, aspirin intake, and smoking, with motor and non-motor symptoms in a cohort of 35,959 American patients with PD from the Fox Insight Study using generalized linear models. Coffee drinkers had fewer problems swallowing but dosage and duration of coffee intake were not associated with motor or non-motor symptoms. Aspirin intake correlated with more tremor (p = 0.0026), problems getting up (p = 0.0185), light-headedness (p = 0.0043), and problems remembering (p = 1 × 10
). Smoking was directly associated with symptoms: smokers had more problems with drooling (p = 0.0106), swallowing (p = 0.0002), and freezing (p < 1 × 10
). Additionally, smokers had more possibly mood-related symptoms: unexplained pains (p < 1 × 10
), problems remembering (p = 0.0001), and feeling sad (p < 1 × 10
). Confirmatory and longitudinal studies are warranted to investigate the clinical correlation over time.
Parkinson disease (PD) is a multifactorial neurodegenerative disease that was long considered the result of environmental factors. In the past 15 years, however, a genetic aetiology for PD has begun ...to emerge. Here, we review results from linkage and next-generation sequencing studies of familial parkinsonism, as well as candidate gene and genome-wide association findings in sporadic PD. In these studies, many of the genetic findings overlap, despite different designs and study populations, highlighting novel therapeutic targets. The molecular results delineate a sequence of pathological events whereby deficits in synaptic exocytosis and endocytosis, endosomal trafficking, lysosome-mediated autophagy and mitochondrial maintenance increase susceptibility to PD. These discoveries provide the rationale, molecular insight and research tools to develop neuroprotective and disease-modifying therapies.
In recent years, the molecular etiology of parkinsonism has yielded to genetic analysis.(1) Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have the highest genotypic and population ...attributable risk. Disparate penetrance estimates have been reported using a variety of statistical analyses, ethnic populations, and sample sizes.(2) We compared the age-associated cumulative incidence (penetrance) of LRRK2 p.G2019S patients from Tunisia and Norway.
Abstract The objective of this study was to investigate the association between a Parkinson’s disease (PD)-specific polygenic score (PGS) and protective lifestyle factors on age at onset (AAO) in PD. ...We included data from 4367 patients with idiopathic PD, 159 patients with GBA1 -PD, and 3090 healthy controls of European ancestry from AMP-PD, PPMI, and Fox Insight cohorts. The association between PGS and lifestyle factors on AAO was assessed with linear and Cox proportional hazards models. The PGS showed a negative association with AAO ( β = − 1.07, p = 6 × 10 –7 ) in patients with idiopathic PD. The use of one, two, or three of the protective lifestyle factors showed a reduction in the hazard ratio by 21% ( p = 0.0001), 44% ( p < 2 × 10 –16 ), and 55% ( p < 2 × 10 –16 ), compared to no use. An additive effect of aspirin ( β = 7.62, p = 9 × 10 –7 ) and PGS ( β = − 1.58, p = 0.0149) was found for AAO without an interaction ( p = 0.9993) in the linear regressions, and similar effects were seen for tobacco. In contrast, no association between aspirin intake and AAO was found in GBA1 -PD ( p > 0.05). In our cohort, coffee, tobacco, aspirin, and PGS are independent predictors of PD AAO. Additionally, lifestyle factors seem to have a greater influence on AAO than common genetic risk variants with aspirin presenting the largest effect.
Sequencing quality has improved over the last decade for long-reads, allowing for more accurate detection of somatic low-frequency variants. In this study, we used mixtures of mitochondrial samples ...with different haplogroups (i.e., a specific set of mitochondrial variants) to investigate the applicability of nanopore sequencing for low-frequency single nucleotide variant detection.
We investigated the impact of base-calling, alignment/mapping, quality control steps, and variant calling by comparing the results to a previously derived short-read gold standard generated on the Illumina NextSeq. For nanopore sequencing, six mixtures of four different haplotypes were prepared, allowing us to reliably check for expected variants at the predefined 5%, 2%, and 1% mixture levels. We used two different versions of Guppy for base-calling, two aligners (i.e., Minimap2 and Ngmlr), and three variant callers (i.e., Mutserve2, Freebayes, and Nanopanel2) to compare low-frequency variants. We used F
score measurements to assess the performance of variant calling.
We observed a mean read length of 11 kb and a mean overall read quality of 15. Ngmlr showed not only higher F
scores but also higher allele frequencies (AF) of false-positive calls across the mixtures (mean F
score = 0.83; false-positive allele frequencies < 0.17) compared to Minimap2 (mean F
score = 0.82; false-positive AF < 0.06). Mutserve2 had the highest F
scores (5% level: F
score >0.99, 2% level: F
score >0.54, and 1% level: F
score >0.70) across all callers and mixture levels.
We here present the benchmarking for low-frequency variant calling with nanopore sequencing by identifying current limitations.
GBA1 variants are the strongest genetic risk factor for Parkinson's disease (PD). However, the pathogenicity of GBA1 variants concerning PD is still not fully understood. Additionally, the frequency ...of GBA1 variants varies widely across populations.
To evaluate Oxford Nanopore sequencing as a strategy, to determine the frequency of GBA1 variants in Norwegian PD patients and controls, and to review the current literature on newly identified variants that add to pathogenicity determination.
We included 462 Norwegian PD patients and 367 healthy controls. We sequenced the full-length GBA1 gene on the Oxford Nanopore GridION as an 8.9 kb amplicon. Six analysis pipelines were compared using two aligners (NGMLR, Minimap2) and three variant callers (BCFtools, Clair3, Pepper-Margin-Deepvariant). Confirmation of GBA1 variants was performed by Sanger sequencing and the pathogenicity of variants was evaluated.
We found 95.8% (115/120) true-positive GBA1 variant calls, while 4.2% (5/120) variant calls were false-positive, with the NGMLR/Minimap2-BCFtools pipeline performing best. In total, 13 rare GBA1 variants were detected: two were predicted to be (likely) pathogenic and eleven were of uncertain significance. The odds of carrying one of the two common GBA1 variants, p.L483P or p.N409S, in PD patients were estimated to be 4.11 times the odds of carrying one of these variants in controls (OR = 4.11 1.39, 12.12).
In conclusion, we have demonstrated that Oxford long-read Nanopore sequencing, along with the NGMLR/Minimap2-BCFtools pipeline is an effective tool to investigate GBA1 variants. Further studies on the pathogenicity of GBA1 variants are needed to assess their effect on PD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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