Genome-wide association studies (GWAS) have identified multiple genetic risk signals for Parkinson's disease (PD), however translation into underlying biological mechanisms remains scarce. Genomic ...functional annotations of neurons provide new resources that may be integrated into analyses of GWAS findings. Altered transcription factor binding plays an important role in human diseases. Insight into transcriptional networks involved in PD risk mechanisms may thus improve our understanding of pathogenesis. We analysed overlap between genome-wide association signals in PD and open chromatin in neurons across multiple brain regions, finding a significant enrichment in the superior temporal cortex. The involvement of transcriptional networks was explored in neurons of the superior temporal cortex based on the location of candidate transcription factor motifs identified by two de novo motif discovery methods. Analyses were performed in parallel, both finding that PD risk variants significantly overlap with open chromatin regions harboring motifs of basic Helix-Loop-Helix (bHLH) transcription factors. Our findings show that cortical neurons are likely mediators of genetic risk for PD. The concentration of PD risk variants at sites of open chromatin targeted by members of the bHLH transcription factor family points to an involvement of these transcriptional networks in PD risk mechanisms.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Deep brain stimulation (DBS) implant infection is a feared complication, as it is difficult to manage and leads to increased patient morbidity. We wanted to assess the frequency and possible risk ...factors of DBS related infections at our centre. In the purpose of evaluating treatment options, we also analyzed treatment, and the clinical and microbiological characteristics of the infections.
Electronic medical records of all patients undergoing DBS surgery at our centre, from 2001 through 2010, were retrospectively reviewed.
Of the 588 procedures performed 33 (5.6%) led to an infection. Some patients underwent several procedures, thus 32 out of totally 368 patients (8.7%), and 19 out of 285 patients (6.7%) who received primary lead implantation, developed an infection. Most infections (52%) developed within the first month and 79% within three months. In the majority of the infections (79%) hardware removal was performed. Staphylococcus aureus infections were the most frequent (36%), and more likely to have earlier onset, pus formation, a more aggressive development and lead to hardware removal. No risk factors were identified.
Our results indicate that infections with more severe symptoms and growth of staphylococcus aureus should be treated with local hardware removal and antibiotic therapy. In other infections, an initial trial of antibiotic treatment could be considered. New knowledge about the microbiology of DBS related infections may lead to more effective antimicrobial treatment.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A pivotal advance was the identification of mutations in the SNCA gene, which encodes the α-synuclein protein.1 Parkinson's disease is pathologically characterised by the loss of pigmented ...dopaminergic neurons in the substantia nigra and by the presence of Lewy bodies, of which α-synuclein is a major constituent. Based on this existing biological knowledge, Emil Gustavsson and colleagues did a genetic study, reported in The Lancet Neurology,4 whereby they searched for mutations in RAB GTPases using exome sequencing data from individuals with familial Parkinson's disease. The identification of mutations in RAB32 adds new knowledge and emphasises the role of the endolysosomal pathway in the aetiopathogenesis of Parkinson's disease.9 This pathway is formed by dynamic membrane-bound structures that carry out complex functions such as macromolecule sorting, proteostasis, organelle homeostasis, and membrane organisation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Genome-wide association studies have identified genetic variation in genomic loci associated with susceptibility to Parkinson's disease (PD), the most common neurodegenerative movement disorder ...worldwide. We used allelic expression profiling of genes located within PD-associated loci to identify cis-regulatory variation affecting gene expression. DNA and RNA were extracted from post-mortem superior frontal gyrus tissue and whole blood samples from PD patients and controls. The relative allelic expression of transcribed SNPs in 12 GWAS risk genes was analysed by real-time qPCR. Allele-specific expression was identified for 9 out of 12 genes tested (GBA, TMEM175, RAB7L1, NUCKS1, MCCC1, BCKDK, ZNF646, LZTS3, and WDHD1) in brain tissue samples. Three genes (GPNMB, STK39 and SIPA1L2) did not show significant allele-specific effects. Allele-specific effects were confirmed in whole blood for three genes (BCKDK, LZTS3 and MCCC1), whereas two genes (RAB7L1 and NUCKS1) showed brain-specific allelic expression. Our study supports the hypothesis that changes to the cis-regulation of gene expression is a major mechanism behind a large proportion of genetic associations in PD. Interestingly, allele-specific expression was also observed for coding variants believed to be causal variants (GBA and TMEM175), indicating that splicing and other regulatory mechanisms may be involved in disease development.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Hereditary ataxia and spastic paraplegia are heterogeneous monogenic neurodegenerative disorders. To date, a large number of individuals with such disorders remain undiagnosed. Here, we have assessed ...molecular diagnosis by gene panel sequencing in 105 early and late-onset hereditary ataxia and spastic paraplegia probands, in whom extensive previous investigations had failed to identify the genetic cause of disease. Pathogenic and likely-pathogenic variants were identified in 20 probands (19%) and variants of uncertain significance in ten probands (10%). Together these accounted for 30 probands (29%) and involved 18 different genes. Among several interesting findings, dominantly inherited KIF1A variants, p.(Val8Met) and p.(Ile27Thr) segregated in two independent families, both presenting with a pure spastic paraplegia phenotype. Two homozygous missense variants, p.(Gly4230Ser) and p.(Leu4221Val) were found in SACS in one consanguineous family, presenting with spastic ataxia and isolated cerebellar atrophy. The average disease duration in probands with pathogenic and likely-pathogenic variants was 31 years, ranging from 4 to 51 years. In conclusion, this study confirmed and expanded the clinical phenotypes associated with known disease genes. The results demonstrate that gene panel sequencing and similar sequencing approaches can serve as efficient diagnostic tools for different heterogeneous disorders. Early use of such strategies may help to reduce both costs and time of the diagnostic process.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are closely related progressive disorders with no available disease-modifying therapy, neuropathologically characterized by intraneuronal ...aggregates of misfolded α-synuclein. To explore the role of DNA methylation changes in PD and DLB pathogenesis, we performed an epigenome-wide association study (EWAS) of 322 postmortem frontal cortex samples and replicated results in an independent set of 200 donors. We report novel differentially methylated replicating loci associated with Braak Lewy body stage near TMCC2, SFMBT2, AKAP6 and PHYHIP. Differentially methylated probes were independent of known PD genetic risk alleles. Meta-analysis provided suggestive evidence for a differentially methylated locus within the chromosomal region affected by the PD-associated 22q11.2 deletion. Our findings elucidate novel disease pathways in PD and DLB and generate hypotheses for future molecular studies of Lewy body pathology.
Objective
The goal of this study was to refine our understanding of disease risk attributable to common genetic variation in SNCA, a major locus in Parkinson disease, with potential implications for ...clinical trials targeting α‐synuclein. We aimed to dissect the multiple independent association signals, stratify individuals by SNCA‐specific risk profiles, and explore expression quantitative trait loci.
Methods
We analyzed participant‐level data from 12,503 patients and 12,502 controls, optimizing a risk model and assessing SNCA‐specific risk scores and haplotypes as predictors of individual risk. We also explored hypotheses about functional mechanisms and correlated risk variants to gene expression in human brain and protein levels in cerebrospinal fluid.
Results
We report and replicate a novel, third independent association signal at genome‐wide significance level downstream of SNCA (rs2870004, p = 3.0*10−8, odds ratio OR = 0.88, 95% confidence interval CI = 0.84–0.92). SNCA risk score stratification showed a 2‐fold difference in disease susceptibility between top and bottom quintiles (OR = 1.99, 95% CI = 1.78–2.23). Contrary to previous reports, we provide evidence supporting top variant rs356182 as functional in itself and associated with a specific SNCA 5′ untranslated region transcript isoform in frontal cortex.
Interpretation
The SNCA locus harbors a minimum of 3 independent association signals for Parkinson disease. We demonstrate a fine‐grained stratification of α‐synuclein–related genetic burden in individual patients of potential future clinical relevance. Further efforts to pinpoint the functional mechanisms are warranted, including studies of the likely causal top variant rs356182 and its role in regulating levels of specific SNCA mRNA transcript variants. Ann Neurol 2018;83:117–129
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
We fine mapped the leukocyte antigen (
HLA)
region in 13,770 Parkinson’s disease (PD) patients, 20,214 proxy-cases, and 490,861 controls of European origin. Four
HLA
types were associated ...with PD after correction for multiple comparisons,
HLA-DQA1
*03:01,
HLA-DQB1
*03:02,
HLA-DRB1
*04:01, and
HLA-DRB1
*04:04. Haplotype analyses followed by amino acid analysis and conditional analyses suggested that the association is protective and primarily driven by three specific amino acid polymorphisms present in most
HLA-DRB1
*04 subtypes—11V, 13H, and 33H (OR = 0.87, 95% CI: 0.83–0.90,
p
< 8.23 × 10
−9
for all three variants). No other effects were present after adjustment for these amino acids. Our results suggest that specific
HLA-DRB1
variants are associated with reduced risk of PD, providing additional evidence for the role of the immune system in PD. Although effect size is small and has no diagnostic significance, understanding the mechanism underlying this association may lead to the identification of new targets for therapeutics development.
The PARK16 locus, spanning five genes on chromosome 1, was among the first genetic regions to show genome-wide association in Parkinson's disease (PD). Subsequent investigations have found ...variability in PARK16 top-hits and association patterns across populations, and the implicated genes and mechanisms are currently unclear. In the present study, we aimed to explore the contribution of PARK16 variability to PD risk in a Scandinavian population. We genotyped 17 single-nucleotide polymorphisms in a case-control sample set of 2570 individuals from Norway and Sweden to fine map the locus. Targeted resequencing of the full coding regions of SLC45A3, NUCKS1, RAB7L1, SLC41A1 and PM20D1 was performed in DNA pools from a subset of 387 patient samples. We find evidence for an association with PD for rs1775143 as well as a haplotype located around the 5' region of RAB7L1, implicating variants which are not in high linkage disequilibrium with the strongest signal from a recent large meta-analysis in Caucasians. We also provide suggestive support for epistasis between RAB7L1 and LRRK2 as previously hypothesized by others. Comparing our results with previous work, allelic heterogeneity at PARK16 appears likely, and further studies are warranted to disentangle the complex patterns of association and pinpoint the functionally relevant variants.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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