Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS ...data to identify novel risk loci and gain further insight into the causes of Parkinson's disease.
We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation.
Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7).
These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data.
The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources).
Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals ...from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.
To determine the relationship between intraoperative flash visual evoked potential (FVEP) monitoring and visual function.
Intraoperative FVEPs were recorded from electrodes placed in the scalp ...overlying the visual cortex (Oz) after flashing red light stimulation delivered by Cadwell LED stimulating goggles in 89 patients. Restrictive filtering (typically 10-100 Hz), optimal reject window settings, mastoid reference site, total intravenous anesthetic (TIVA), and stable retinal stimulation (ensured by concomitant electroretinogram ERG recording) were used to enhance FVEP reproducibility.
The relationship between FVEP amplitude change and visual outcome was determined from 179 eyes. One eye had a permanent intraoperative FVEP loss despite stable ERG, and this eye had new, severe postoperative visual dysfunction. Seven eyes had transient significant FVEP change (>50% amplitude decrease that recovered by the end of surgery), but only one of those had a decrease in postoperative visual acuity. FVEP changes in all eight eyes (one permanent FVEP loss plus seven transient FVEP changes) were related to surgical manipulation. In each case the surgeon was promptly informed of the FVEP deterioration and took remedial action. The other eyes did not have FVEP changes, and none of those eyes had new postoperative visual deficits.
Our FVEP findings relate to visual outcome with a sensitivity and specificity of 1.0. New methods for rapidly acquiring reproducible FVEP waveforms allowed for timely reporting of significant FVEP change resulting in prompt surgical action. This may have accounted for the low postoperative visual deficit rate (1%) in this series.
The microtubule-associated protein tau (encoded by MAPT) and several tau kinases have been implicated in neurodegeneration, but only MAPT has a proven role in disease. We identified mutations in the ...gene encoding tau tubulin kinase 2 (TTBK2) as the cause of spinocerebellar ataxia type 11. Affected brain tissue showed substantial cerebellar degeneration and tau deposition. These data suggest that TTBK2 is important in the tau cascade and in spinocerebellar degeneration.
The emergence of high-throughput DNA sequencing methods provides unprecedented opportunities to further unravel bacterial biodiversity and its worldwide role from human health to ecosystem ...functioning. However, despite the abundance of sequencing studies, combining data from multiple individual studies to address macroecological questions of bacterial diversity remains methodically challenging and plagued with biases. Here, using a machine-learning approach that accounts for differences among studies and complex interactions among taxa, we merge 30 independent bacterial data sets comprising 1,998 soil samples from 21 countries. Whereas previous meta-analysis efforts have focused on bacterial diversity measures or abundances of major taxa, we show that disparate amplicon sequence data can be combined at the taxonomy-based level to assess bacterial community structure. We find that rarer taxa are more important for structuring soil communities than abundant taxa, and that these rarer taxa are better predictors of community structure than environmental factors, which are often confounded across studies. We conclude that combining data from independent studies can be used to explore bacterial community dynamics, identify potential 'indicator' taxa with an important role in structuring communities, and propose hypotheses on the factors that shape bacterial biogeography that have been overlooked in the past.
To relate early somatosensory evoked potential grades from comatose traumatic brain injury patients to neuropsychological and functional outcome 1 yr later; to determine the day (within the first ...week after traumatic brain injury) that somatosensory evoked potential grade best correlates with outcome; to determine whether somatosensory evoked potential grade improvement in the first week after traumatic brain injury is associated with improved outcome.
Prospective cohort study.
Critical care unit at a university hospital.
Median nerve somatosensory evoked potentials were obtained from 81 comatose patients with traumatic brain injury. Somatosensory evoked potential grades were calculated from results obtained on days 1, 3, and 7 after traumatic brain injury. Glasgow Outcome Scale, Barthel Index, Rivermead Head Injury Follow-up Questionnaire, General Health Questionnaire, Stroop Color-Word Test, Paced Auditory Serial Addition Task, and Symbol-Digit Modalities Test scores were obtained 1 yr after injury.
None.
Somatosensory evoked potential grade on days 1, 3, and 7 related significantly with Glasgow Outcome Scale and Barthel scores (day 3 better than day 1) but did not relate with Rivermead Head Injury Follow-up Questionnaire or General Health Questionnaire scores. Day 3 and day 7 somatosensory evoked potential grades related significantly with Stroop scores. Day 3 somatosensory evoked potential grades related significantly with Symbol-Digit Modalities Test scores. Patients with bilaterally present but abnormal somatosensory evoked potentials, whose somatosensory evoked potential grade improved between days 1 and 3, had marginally better functional outcome than those without somatosensory evoked potential grade improvement.
Day 3 somatosensory evoked potential grade related to information-processing speed, working memory, and the ability to attend to tasks 1 yr after traumatic brain injury. Day 3 somatosensory evoked potential grade had the strongest relationship with functional outcome. Somatosensory evoked potential grades were not related to emotional well-being.
The aim of this study was to evaluate the association between common exonic variants in the leucine-rich repeat kinase 2 (LRRK2) gene and risk of multiple system atrophy (MSA).
One series from the ...United States (92 patients with pathologically confirmed MSA, 416 controls) and a second series from the United Kingdom (85 patients with pathologically confirmed MSA, 352 controls) were included in this case-control study. We supplemented these data with those of 53 patients from the United States with clinically probable or possible MSA. Seventeen common LRRK2 exonic variants were genotyped and assessed for association with MSA.
In the combined series of 177 patients with pathologically confirmed MSA and 768 controls, there was a significant association between LRRK2 p.M2397T and MSA (odds ratio OR = 0.60, p = 0.002). This protective effect was observed more strongly in the US series (OR = 0.46, p = 0.0008) than the UK series (OR = 0.82, p = 0.41). We observed other noteworthy associations with MSA for p.G1624G (OR = 0.63, p = 0.006) and p.N2081D (OR = 0.15, p = 0.010). The p.G1624G-M2397T haplotype was significantly associated with MSA in the US series (p < 0.0001) and combined series (p = 0.003) but not the UK series (p = 0.67). Results were consistent when additionally including the US patients with clinical MSA, where the strongest single-variant association was again observed for p.M2397T (OR = 0.59, p = 0.0005).
These findings provide evidence that LRRK2 exonic variants may contribute to susceptibility to MSA. Validation in other series and meta-analytic studies will be important.
The amplitude of the cortically generated somatosensory evoked potential (SSEP) is used to predict outcome in comatose patients. The relationship between epileptiform discharges and SSEP amplitude ...has not been elucidated in those patients.
Bilateral median nerve SSEP and electroencephalograph (EEG) studies were performed in a comatose patient (patient 1) 1 day after cardiac surgery and repeated 4 days later. He had tranexamic acid administered before and during surgery. Another comatose patient (patient 2) had the same studies performed 1 day after sustaining 10 minutes of pulseless electrical cardiac activity.
Both comatose patients had epileptiform discharges (on EEG) that were coincident with giant cortically generated SSEPs. In patient 1, the EEG and SSEP studies repeated 5 days postoperatively showed no epileptiform discharges, and the cortically generated SSEP amplitude was decreased (normalized) compared with that obtained one day postoperatively. He emerged from coma and had a good recovery. Patient 2 died shortly after EEG and SSEP testing.
Epileptiform discharges were associated with giant cortically generated median nerve SSEP amplitude (tranexamic acid was implicated in patient 1 and anoxic brain injury in patient 2). Accordingly, those who use the amplitude of cortically generated SSEPs for predicting outcome in comatose patients should consider the presence of epileptiform discharges (detected by EEG) as a potential confounding factor.
Flash visual evoked potentials (FVEPs) are often irreproducible during surgery. We assessed the relationship between intraoperative FVEP reproducibility and EEG amplitude. Left then right eyes were ...stimulated by goggle light emitting diodes, and FVEPs were recorded from Oz–Fz′ (International 10-20 system) in 12 patients. Low cut filters were ≤5 Hz in all patients; two patients also had recordings using 10 and 30 Hz. The reproducibility of FVEP and the amplitude of the concomitant EEG from C4′–Fz were measured. Nine patients had low amplitude EEG (<30 μV); reproducible FVEPs were obtained from all eyes with normal pre-operative vision. The other three patients had high amplitude EEG (>50 μV); FVEPs were absent from three of four eyes with normal pre-operative vision (the other normal eye had a present but irreproducible FVEP). Raising the low cut filter to 10 and 30 Hz (in two patients) progressively reduced EEG and FVEP amplitude, reduced amplifier blocking time and improved FVEP reproducibility. FVEPs were more reproducible in the presence of low amplitude EEG than high amplitude EEG. This is the first report describing the effect of EEG amplitude on FVEP reproducibility during surgery.
The four LEP collaborations, ALEPH, DELPHI, L3 and OPAL, have searched for pair-produced charged Higgs bosons in the framework of Two Higgs Doublet Models (2HDMs). The data of the four experiments ...have been statistically combined. The results are interpreted within the 2HDM for Type I and Type II benchmark scenarios. No statistically significant excess has been observed when compared to the Standard Model background prediction, and the combined LEP data exclude large regions of the model parameter space. Charged Higgs bosons with mass below 80
(Type II scenario) or 72.5
(Type I scenario, for pseudo-scalar masses above 12
) are excluded at the 95 % confidence level.
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