scholarly journals An Increased Burden of Highly Active Retrotransposition Competent L1s Is Associated with Parkinson’s Disease Risk and Progression in the PPMI Cohort

2020 ◽  
Vol 21 (18) ◽  
pp. 6562 ◽  
Author(s):  
Abigail L. Pfaff ◽  
Vivien J. Bubb ◽  
John P. Quinn ◽  
Sulev Koks
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Risk ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Highly Active ◽  
Germline Variation ◽  
Progression Markers ◽  
Long Interspersed Element

Long interspersed element-1 (LINE-1/L1s) contributes 17% of the human genome with more than 1 million elements present; however, fewer than 100 of these have evidence for being retrotransposition competent (RC). In addition to those RC-L1s present in the reference genome, there are a small number of known non-reference L1 insertions that are also retrotransposition competent. L1 activity, whether through the potentially detrimental effects of their mRNA or protein expression or somatic retrotransposition events, has been linked to several neurological conditions. The polymorphic nature of both reference and non-reference RC-L1s in terms of their presence or absence will result in individuals harboring a different combination of these elements and it is currently unknown if this type of germline variation contributes to the risk of neurological disease. Here, we utilized whole-genome sequencing data from 178 healthy controls and 372 Parkinson’s disease (PD) subjects from the Parkinson’s Progression Markers Initiative (PPMI) to investigate the role of RC-L1s in PD. In the PPMI cohort, we identified 22 reference and 50 non-reference polymorphic RC-L1 loci. Focusing on 16 highly active RC-L1 loci, an increased burden of these elements (≥9) was associated with PD (OR 1.25, 95% CI 1.03–1.51, p = 0.02). In addition, we identified significant associations of progression markers of PD and the burden of highly active RC-L1s. This study has identified a novel type of genetic element associated with PD risk and disease progression.

scholarly journals TOMM40 ‘523’ poly-T repeat length is a determinant of longitudinal cognitive decline in Parkinson’s disease

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Megan C. Bakeberg ◽  
Anastazja M. Gorecki ◽  
Abigail L. Pfaff ◽  
Madison E. Hoes ◽  
Sulev Kõks ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Decline ◽  
Cognitive Performance ◽  
Disease Onset ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Progression Markers ◽  
The Relationship

AbstractThe translocase of outer mitochondrial membrane 40 (TOMM40) ‘523’ polymorphism has previously been associated with age of Alzheimer’s disease onset and cognitive functioning in non-pathological ageing, but has not been explored as a candidate risk marker for cognitive decline in Parkinson’s disease (PD). Therefore, this longitudinal study investigated the role of the ‘523’ variant in cognitive decline in a patient cohort from the Parkinson’s Progression Markers Initiative. As such, a group of 368 people with PD were assessed annually for cognitive performance using multiple neuropsychological protocols, and were genotyped for the TOMM40 ‘523’ variant using whole-genome sequencing data. Covariate-adjusted generalised linear mixed models were utilised to examine the relationship between TOMM40 ‘523’ allele lengths and cognitive scores, while taking into account the APOE ε genotype. Cognitive scores declined over the 5-year study period and were lower in males than in females. When accounting for APOE ε4, the TOMM40 ‘523’ variant was not robustly associated with overall cognitive performance. However, in APOE ε3/ε3 carriers, who accounted for ~60% of the whole cohort, carriage of shorter ‘523’ alleles was associated with more severe cognitive decline in both sexes, while carriage of the longer alleles in females were associated with better preservation of global cognition and a number of cognitive sub-domains, and with a delay in progression to dementia. The findings indicate that when taken in conjunction with the APOE genotype, TOMM40 ‘523’ allele length is a significant independent determinant and marker for the trajectory of cognitive decline and risk of dementia in PD.

scholarly journals Assessment of LIN28A variants in Parkinson’s disease

2020 ◽  
Author(s):  
Monica Diez-Fairen ◽  
Mary B. Makarious ◽  
Sara Bandres-Ciga ◽  
Cornelis Blauwendraat
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Large Scale ◽  
Disease Risk ◽  
Age At Onset ◽  
European Ancestry ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Common Genetic Variants

AbstractParkinson’s disease (PD) is a complex neurodegenerative disease with a strong genetic component in which both rare and common genetic variants contribute to disease risk, onset and progression. Despite that several genes have been associated with familial forms of disease, validation of novel genes associated with PD remains extremely challenging. Recently, a heterozygous loss-of-function variant in LIN28A was associated with PD pathogenesis in the Asian population. Here, we comprehensively assess the role of LIN28A variants in PD susceptibility using individual-level genotyping data from 14,671 PD cases and 17,667 controls, as well as whole-genome sequencing data from 1,647 PD patients and 1,050 controls. Additionally, we further assessed the summary statistics from the most recent GWAS meta-analyses to date for PD risk and age at onset. After evaluating these data, we did not find evidence to support a role for LIN28A as a major causal gene for PD. However, additional large-scale familial and case-control studies in non-European ancestry populations are necessary to further evaluate the role of LIN28A in PD etiology.

scholarly journals A genetic and transcriptomic assessment of the KTN1 gene in Parkinson’s disease risk

2021 ◽  
Author(s):  
Anni Moore ◽  
Sara Bandres-Ciga ◽  
Cornelis Blauwendraat ◽  
Monica Diez-Fairen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Risk ◽  
Association Studies ◽  
Age At Onset ◽  
Brain Regions ◽  
Whole Genome Sequencing Data ◽  
Genome Wide Association Studies ◽  
Sequencing Data ◽  
Increased Risk

AbstractParkinson’s disease (PD) is a progressive neurological disorder caused by both genetic and environmental factors. A recent finding has suggested an association between KTN1 genetic variants and changes in its expression in the putamen and substantia nigra brain regions and an increased risk for PD. Here, we examine the link between PD susceptibility and KTN1 using individual-level genotyping data and summary statistics from the most recent genome-wide association studies (GWAS) for PD risk and age at onset from the International Parkinson’s Disease Genomics Consortium (IPDGC), as well as whole-genome sequencing data from the Accelerating Medicines Partnership Parkinson’s disease (AMP-PD) initiative. To investigate the potential effect of changes in KTN1 expression on PD compared to healthy individuals, we further assess publicly available expression quantitative trait loci (eQTL) results from GTEx v8 and BRAINEAC and transcriptomics data from AMP-PD. Overall, we found no genetic associations between KTN1 and PD in our cohorts but found potential evidence of differences in mRNA expression, which needs to be further explored.

scholarly journals The TOMM40 ‘523’ polymorphism in disease risk and age of symptom onset in two independent cohorts of Parkinson’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Megan C. Bakeberg ◽  
Madison E. Hoes ◽  
Anastazja M. Gorecki ◽  
Frances Theunissen ◽  
Abigail L. Pfaff ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Symptom Onset ◽  
Disease Risk ◽  
Age Of Onset ◽  
Sequencing Analysis ◽  
Age Related ◽  
Australian Cohort ◽  
Progression Markers ◽  
Age Related Cognitive Decline

AbstractAbnormal mitochondrial function is a key process in the pathogenesis of Parkinson’s disease (PD). The central pore-forming protein TOM40 of the mitochondria is encoded by the translocase of outer mitochondrial membrane 40 homologue gene (TOMM40). The highly variant ‘523’ poly-T repeat is associated with age-related cognitive decline and age of onset in Alzheimer’s disease, but whether it plays a role in modifying the risk or clinical course of PD it yet to be elucidated. The TOMM40 ‘523’ allele length was determined in 634 people with PD and 422 healthy controls from an Australian cohort and the Parkinson’s Progression Markers Initiative (PPMI) cohort, using polymerase chain reaction or whole genome sequencing analysis. Genotype and allele frequencies of TOMM40 ‘523’ and APOE ε did not differ significantly between the cohorts. Analyses revealed TOMM40 ‘523’ allele groups were not associated with disease risk, while considering APOE ε genotype. Regression analyses revealed the TOMM40 S/S genotype was associated with a significantly later age of symptom onset in the PPMI PD cohort, but not after correction for covariates, or in the Australian cohort. Whilst variation in the TOMM40 ‘523’ polymorphism was not associated with PD risk, the possibility that it may be a modifying factor for age of symptom onset warrants further investigation in other PD populations.

Parkinson's Disease Genetics and Pathophysiology

2021 ◽  
Vol 44 (1) ◽  
pp. 87-108
Author(s):  
Gabriel E. Vázquez-Vélez ◽  
Huda Y. Zoghbi
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Variants ◽  
Neurodegenerative Disorder ◽  
Disease Risk ◽  
Lewy Bodies ◽  
Substantia Nigra Pars Compacta ◽  
Disease Modifying ◽  
Common Neurodegenerative Disorder

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by degeneration of the substantia nigra pars compacta and by accumulation of α-synuclein in Lewy bodies. PD is caused by a combination of environmental factors and genetic variants. These variants range from highly penetrant Mendelian alleles to alleles that only modestly increase disease risk. Here, we review what is known about the genetics of PD. We also describe how PD genetics have solidified the role of endosomal, lysosomal, and mitochondrial dysfunction in PD pathophysiology. Finally, we highlight how all three pathways are affected by α-synuclein and how this knowledge may be harnessed for the development of disease-modifying therapeutics.

scholarly journals RIC3 variants are not associated with Parkinson's Disease in large European, Latin American, or East Asian cohorts

2021 ◽  
Author(s):  
Kajsa Brolin ◽  
Sara Bandres Ciga ◽  
Hampton Leonard ◽  
Mary B Makarious ◽  
Cornelis Blauwendraat ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Latin American ◽  
Rare Variants ◽  
Neurodegenerative Disorder ◽  
Disease Risk ◽  
East Asian ◽  
European Ancestry ◽  
Common Genetic Variants

Parkinson's disease (PD) is a complex neurodegenerative disorder in which both rare and common genetic variants contribute to disease risk. Multiple genes have been reported to be linked to monogenic PD, but these only explain a fraction of the observed familial aggregation. Rare variants in RIC3 have been suggested to be associated with PD in the Indian population. However, replication studies yielded inconsistent results. We further investigate the role of RIC3 variants in PD in European cohorts using individual-level genotyping data from 14,671 PD patients and 17,667 controls, as well as whole-genome sequencing data from 1,615 patients and 961 controls. We also investigated RIC3 using summary statistics from a Latin American cohort of 1,481 individuals, and from a cohort of 31,575 individuals of East Asian ancestry. We did not identify any association between RIC3 and PD in any of the cohorts. However, more studies of rare variants in non-European ancestry populations, in particular South Asian populations, are necessary to further evaluate the world-wide role of RIC3 in PD etiology.

scholarly journals Establishing the role of rare coding variants in known Parkinson's disease risk loci

2017 ◽  
Vol 59 ◽  
pp. 220.e11-220.e18 ◽  
Author(s):  
Iris E. Jansen ◽  
J. Raphael Gibbs ◽  
Mike A. Nalls ◽  
T. Ryan Price ◽  
Steven Lubbe ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Risk ◽  
Coding Variants

scholarly journals Differential Analysis of A-to-I mRNA Edited Sites in Parkinson’s Disease

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 14
Author(s):  
Denis V. Pozdyshev ◽  
Anastasia A. Zharikova ◽  
Maria V. Medvedeva ◽  
Vladimir I. Muronetz
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Differential Analysis ◽  
Sequencing Data ◽  
Mrna Editing ◽  
Adenosine Deaminases ◽  
Protein Folding Pathways ◽  
Degenerative Disorder

Parkinson’s disease (PD) is a widespread neuronal degenerative disorder with unexplored etiology. It is associated with various pathological events. In particular, the prefrontal cortex Brodmann area 9 (BA9) region is affected in PD. This frontal lobe brain region plays an important role in cognitive, motor, and memory-related functions. BA9 develops Lewy bodies in PD patients and shows essential changes in transcriptome and proteome, connected with mitochondria related pathways, protein folding pathways, and metallothioneins. Recently, altered adenosine to inosine mRNA editing patterns have been detected in various neurological pathologies. In this article, we present an investigation of differences in A-to-I RNA editing levels and specificity of mRNA editing sites in brain tissues of healthy and PD patients based on RNA sequencing data. Overall, decreased editing levels in the brains of PD patients were observed, potential editing sites with altered editing during PD were identified, and the role of different adenosine deaminases in this process was analyzed.

scholarly journals The TOMM40 ‘523’ polymorphism in disease risk and age of symptom onset in two independent cohorts of Parkinson’s disease.

2020 ◽  
Author(s):  
Megan Bakeberg ◽  
Madison Hoes ◽  
Anastazja Gorecki ◽  
Frances Theunissen ◽  
Abigail Pfaff ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Symptom Onset ◽  
Disease Risk ◽  
Age Of Onset ◽  
Sequencing Analysis ◽  
Age Related ◽  
Australian Cohort ◽  
Progression Markers ◽  
Age Related Cognitive Decline

Abstract Abnormal mitochondrial function is a key process in the pathogenesis of Parkinson’s disease (PD). The central pore-forming protein TOM40 of the mitochondria is encoded by the translocase of outer mitochondrial membrane 40 homologue gene (TOMM40). The highly variant poly-T repeat is associated with age-related cognitive decline and age of onset in Alzheimer’s disease, but whether it plays a role in modifying the risk or clinical course of PD it yet to be elucidated. The TOMM40 allele length was determined in 634 people with PD and 422 healthy controls from an Australian cohort and the Parkinson’s Progression Markers Initiative (PPMI) cohort, using polymerase chain reaction or whole genome sequencing analysis. Genotype and allele frequencies of TOMM40 and APOE ε did not differ significantly between the cohorts. Analyses revealed TOMM40 groups were not associated with disease risk, while considering APOE ε genotype. Regression analyses revealed the TOMM40 S/S genotype was associated with a significantly later age of symptom onset in the PPMI PD cohort, but not in the Australian cohort. Variation in the TOMM40 structural variant was not associated with PD risk, but may be a modifying factor for age of symptom onset in some PD populations, warranting further investigation.

Parkinson’s Disease-Overview

2021 ◽  
Author(s):  
Fariha Khaliq
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Modeling ◽  
Disease Risk ◽  
Lewy Bodies ◽  
In Vivo Studies ◽  
Common Genetic Variants

Parkinson’s disease one of the most complex neurological disorder. The disease risk and progression are due to common genetic variants. Approximately 6.2 million cases are reported each year according to the statistics published in 2015 whereas it is expected that this number will be twice by 2040. There are two types of Parkinson’s disease, familial Parkinson’s disease, and sporadic Parkinson’s disease. The disease is characterized by the presence of Lewy bodies. Adult age increases the risk of Parkinson’s disease. In this review, we provide an overview of the disease pathology of Lewy bodies in the occurrence of Parkinson’s disease, in vitro studies to determine the role of iPSCs in treatment of Parkinson’s disease, in vivo studies to determine the role of animal model in studying disease modeling, and future prospective how single-cell RNA sequencing technology is a major advancement in studying and find the treatment for Parkinson’s disease.

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