Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer's disease (AD). However, mLOY estimation from genotype microarray data ...only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (
= 4.22 × 10
) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23,
= 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.
•We studied five polymorphisms previously associated to PD, in PD-patients and healthy controls.•Only two loci (ACMSD/TMEM163 and MAPT) were related with the susceptibility to PD in our population.•A ...suggestive association between ACMSD/TMEM163 and an increased risk of PD was found.•A suggestive association between MAPT and a decreased risk of PD was found.
Recently, 5 previously Parkinson’s disease (PD)-related loci: ACMSD/TMEM163, STK39, MIR4697, SREBF1/RAI1PD and MAPT, have been associated to PD in a Southern Spanish population. However, due to the small sample size of the cohort, this association did not reach genome wide significance. Our aim was to investigate the robustness of this association in a larger and independent cohort from the South of Spain. Variants were genotyped employing TaqMan SNP Genotyping Assay and high resolution melting analysis in 738 PD patients and 1138 healthy controls. Furthermore, a meta-analysis study was carried out with both cohorts. In the replication analysis, only two loci (ACMSD/TMEM163 and MAPT) were replicated with a Bonferroni significance level. In the meta-analysis study no loci reached a genome-wide significance level (P<5xE-8), but a suggestive association (P-value = 1.04E-6) between rs6430538 (ACMSD/TMEM163) and an increased risk of PD was found. In addition, rs9468 (MAPT) was associated with a decreased risk of PD (P-value = 5.70E-7). Our results add further support for the genetic involvement of these two loci in the susceptibility to PD in population from the South of Spain. We believe that our findings will be very useful for future genetic studies on PD.
Recruitment is a major rate-limiting factor in Parkinson's disease (PD) research. AccessPD is a unique platform that aims to create a registry of more than 2000 PD patients and a rich database of ...PD-relevant information. Potential participants are identified using electronic health records (EHRs) in primary care. They are contacted via text message with an individualized link to the study portal. Electronic patient-reported outcomes (ePRO) are collected via online questionnaires and integrated with existing EHR. 200 participants were recruited within the first 6 months, of which 191 answered the follow-up questionnaire. Here, to showcase the potential of AccessPD, we described the most common diagnoses before and after PD diagnosis, the most commonly prescribed drugs, and identified participants who could benefit from device-aided therapies using consensus criteria. AccessPD shows its unique ability to link different data sources for patient stratification in longitudinal studies and recruitment into clinical trials.
Lipoprotein receptor-related protein 10 (LRP10) has been proposed as a novel causative gene for autosomal dominant Parkinson’s disease (PD), and the c.919T>A (p.Tyr307Asn) variant has been identified ...as possibly involved in the development of familial PD and PD with dementia. We screened for the p.Tyr307Asn variant in a southern Spain population of 679 PD patients, of who 129 were familial cases, and 1217 unrelated healthy controls. A total of 3 carriers of the LRP10 p.Tyr307Asn variant were identified: 1 PD patient and 2 healthy controls. Together with the absence of a family history of PD, this finding might suggest a low penetrance variant as well as a limited role for p.Tyr307Asn in PD in our cohort. Nevertheless, a family history of Alzheimer’s disease in the LRP10 p.Tyr307Asn carriers provides evidence for a possible association with dementia.
•LRP10 gene has been recently associated with PD, PDD and DLB.•One PD patient and two healthy controls carried the previously reported LRP10 p.Tyr307Asn variant.•There was no family history of PD among the LRP10 p.Tyr307Asn carriers.•These findings suggest a limited role of LRP10 p.Tyr307Asn in PD.•A family history of AD in LRP10 p.Tyr307Asn carriers provides evidence for a possible association with dementia.
Peripheral inflammatory immune responses are thought to play a major role in the pathogenesis of Parkinson's disease (PD). The neutrophil-to-lymphocyte ratio (NLR), a biomarker of systemic ...inflammation, has been reported to be higher in patients with PD than in healthy controls (HCs). The present study was aimed at determining if the peripheral inflammatory immune response could be influenced by the genetic background of patients with PD. We included a discovery cohort with 222 patients with PD (132 sporadic PD, 44 LRRK2-associated PD (with p.G2019S and p.R1441G variants), and 46 GBA-associated PD), as well as 299 HCs. Demographic and clinical data were recorded. Leukocytes and their subpopulations, and the NLR were measured in peripheral blood. Multivariate lineal regression and post-hoc tests were applied to determine the differences among the groups. Subsequently, a replication study using the Parkinson's Progression Markers Initiative cohort was performed which included 401 patients with PD (281 sPD patients, 66 LRRK2-PD patients, 54 GBA-PD patients) and a group of 174 HCs. Patients with sporadic PD and GBA-associated PD showed a significantly lower lymphocyte count, a non-significantly higher neutrophil count and a significantly higher NLR than HCs. The peripheral inflammatory immune response of patients with LRRK2-associated PD did not differ from HCs. Our study supports the involvement of a peripheral inflammatory immune response in the pathophysiology of sPD and GBA-associated PD. However, this inflammatory response was not found in LRRK2-associated PD, probably reflecting different pathogenic inflammatory mechanisms.
Brain cholesterol metabolism has been described as altered in Parkinson's disease (PD) patients. Serum lipid levels have been widely studied in PD with controversial results among different ...populations and age groups. The present study is aimed at determining if the serum lipid profile could be influenced by the genetic background of PD patients. We included 403 PD patients (342 sporadic PD patients, 30 GBA-associated PD patients, and 31 LRRK2-associated PD patients) and 654 healthy controls (HCs). Total cholesterol, HDL, LDL, and triglycerides were measured in peripheral blood. Analysis of covariance adjusting for sex and age (ANCOVA) and post hoc tests were applied to determine the differences within lipid profiles among the groups. Multivariate ANCOVA revealed significant differences among the groups within cholesterol and LDL levels. GBA-associated PD patients had significantly lower levels of total cholesterol and LDL compared to LRRK2-associated PD patients and HCs. The different serum cholesterol levels in GBA-associated PD might be related to diverse pathogenic mechanisms. Our results support the hypothesis of lipid metabolism disruption as one of the main PD pathogenic mechanisms in patients with GBA-associated PD. Further studies would be necessary to explore their clinical implications.
Abstract
Transcriptomics in Parkinson’s disease (PD) offers new insights into the molecular mechanism of PD pathogenesis. Several pathways, such as inflammation and protein degradation, have been ...identified by differential gene expression analysis. Our aim was to identify gene expression differences underlying the disease etiology and the discovery of pre-symptomatic risk biomarkers for PD from a multicenter study in the context of the PROPAG-AGEING project. We performed RNA sequencing from 47 patients with de novo PD, 10 centenarians, and 65 healthy controls. Using identified differentially expressed genes, functional annotations were assigned using gene ontology to unveil significant enriched biological processes. The expression of 16 selected genes was validated using OpenArray® assays and samples from independent cohorts of 201 patients with advanced PD, 340 healthy siblings of PD patients, and 177 healthy controls. Differential gene expression analysis identified higher
FCGBP
expression in patients with de novo PD compared with healthy controls and compared with centenarians. Furthermore,
FCGBP
showed no differences in terms of population origin or aging process. The increased
FCGBP
expression was validated in patients with advanced PD and their siblings. Thus, we provided evidence for an upregulation of
FCGBP
mRNA levels not only in patients with PD but also in individuals at putative higher risk of PD, suggesting that it could be important in gut–brain PD interaction, mediating the connection between microbiota and intestinal inflammatory processes, as well as neuroinflammation and neurodegeneration.
Objective
We aimed to investigate the prevalence of TOR1A, GNAL and THAP1 variants as the cause of dystonia in a cohort of Spanish patients with isolated dystonia and in the literature.
Methods
A ...population of 2028 subjects (including 1053 patients with different subtypes of isolated dystonia and 975 healthy controls) from southern and central Spain was included. The genes TOR1A, THAP1 and GNAL were screened using a combination of high‐resolution melting analysis and direct DNA resequencing. In addition, an extensive literature search to identify original articles (published before 10 August 2020) reporting mutations in TOR1A, THAP1 or GNAL associated to dystonia was performed.
Results
Pathogenic or likely pathogenic variants in TOR1A, THAP1 and GNAL were identified in 0.48%, 0.57% and 0.29% of our patients, respectively. Five patients carried the variation p.Glu303del in TOR1A. A very rare variant in GNAL (p.Ser238Asn) was found as a putative risk factor for dystonia.
In the literature, variations in TOR1A, THAP1 and GNAL accounted for about 6%, 1.8% and 1.1% of published dystonia patients, respectively.
Conclusions
There is a different genetic contribution to dystonia of these three genes in our patients (about 1.3% of patients) and in the literature (about 3.6% of patients), probably due the high proportion of adult‐onset cases in our cohort. As regards age at onset, site of dystonia onset, and final distribution, in our population there is a clear differentiation between DYT‐TOR1A and DYT‐GNAL, with DYT‐THAP1 likely to be an intermediate phenotype.
Although the molecular mechanisms underlying isolated dystonia are largely unknown, it is known that its pathogenesis is genetically heterogeneous. Causative mutations in three genes (TOR1A, THAP1, and GNAL) have been identified in patients from different populations. This study is the largest and most complete study of TOR1A, THAP1 and GNAL genes in the Spanish population and a review of the recent genetic findings in these genes. The incidence of pathogenic or likely pathogenic variants in these three genes in our population is low. As regards age at onset, site of dystonia onset, and final distribution, in our population there is a clear differentiation between DYT‐TOR1A and DYT‐GNAL, with DYT‐THAP1 likely to be an intermediate phenotype.
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