Genetic Mutation Analysis of Parkinson’s Disease Patients Using Multigene Next-Generation Sequencing Panels (original) (raw)
Related papers
2017
Parkinson's disease (PD) can be caused by genetic changes in a lot of genes. The effect of these changes is determined by the nature of the mutation and ranges from weak associations to pathogenic mutation which leads to loss of protein function. Our study is based on epidemiological data which show significantly increased prevalence of PD (2.9 %) in an isolated population of South-Eastern Moravia in the Czech Republic. We compared two different Next Generation Sequencing (NGS) data analysis approaches in DNA from 28 PD patients in the genes responsible for Parkinsonism (ADH1C, ATP13A2, EIF4G1, FBXO7, GBA + GBAP1, GIGYF2, HTRA2, LRRK2, MAPT, PARK2, PARK7, PINK1, PLA2G6, SNCA, UCHL1 and VPS35) using: 1) already described missense rare variants or pathogenic mutations 2) twelve control DNA samples from the same isolated population. Ion Torrent NGS data processing and trimming from Fastaq through “bam” to “vcf” files was done parallely by Torrent Suite/Ion Reporter and NextGENe sof...
Frontiers in aging neuroscience, 2018
Background: Parkinson's disease (PD) is a complex disease with its monogenic forms accounting for less than 10% of all cases. Whole-exome sequencing (WES) technology has been used successfully to find mutations in large families. However, because of the late onset of the disease, only small families and unrelated patients are usually available. WES conducted in such cases yields in a large number of candidate variants. There are currently a number of imperfect software tools that allow the pathogenicity of variants to be evaluated. Objectives: We analyzed 48 unrelated patients with an alleged autosomal dominant familial form of PD using WES and developed a strategy for selecting potential pathogenetically significant variants using almost all available bioinformatics resources for the analysis of exonic areas. Methods: DNA sequencing of 48 patients with excluded frequent mutations was performed using an Illumina HiSeq 2500 platform. The possible pathogenetic significance of identified variants and their involvement in the pathogenesis of PD was assessed using SNP and Variation Suite (SVS), Combined Annotation Dependent Depletion (CADD) and Rare Exome Variant Ensemble Learner (REVEL) software. Functional evaluation was performed using the Pathway Studio database. Results: A significant reduction in the search range from 7082 to 25 variants in 23 genes associated with PD or neuronal function was achieved. Eight (FXN, MFN2, MYOC, NPC1, PSEN1, RET, SCN3A and SPG7) were the most significant. Conclusions: The multistep approach developed made it possible to conduct an effective search for potential pathogenetically significant variants, presumably involved in the pathogenesis of PD. The data obtained need to be further verified experimentally.
Genome‐Wide Analysis of Structural Variants in Parkinson Disease
Annals of Neurology
ObjectiveIdentification of genetic risk factors for Parkinson disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large‐scale characterization of SVs in PD.MethodsWe leveraged a recently developed computational pipeline to detect and genotype SVs from 7,772 Illumina short‐read whole genome sequencing samples. Using this set of SV variants, we performed a genome‐wide association study using 2,585 cases and 2,779 controls and identified SVs associated with PD risk. Furthermore, to validate the presence of these variants, we generated a subset of matched whole‐genome long‐read sequencing data.ResultsWe genotyped an...
Hunting for Familial Parkinson’s Disease Mutations in the Post Genome Era
Genes, 2021
Parkinson’s disease (PD) is typically sporadic; however, multi-incident families provide a powerful platform to discover novel genetic forms of disease. Their identification supports deciphering molecular processes leading to disease and may inform of new therapeutic targets. The LRRK2 p.G2019S mutation causes PD in 42.5–68% of carriers by the age of 80 years. We hypothesise similarly intermediately penetrant mutations may present in multi-incident families with a generally strong family history of disease. We have analysed six multiplex families for missense variants using whole exome sequencing to find 32 rare heterozygous mutations shared amongst affected members. Included in these mutations was the KCNJ15 p.R28C variant, identified in five affected members of the same family, two elderly unaffected members of the same family, and two unrelated PD cases. Additionally, the SIPA1L1 p.R236Q variant was identified in three related affected members and an unrelated familial case. Whil...
Genome-wide analysis of Structural Variants in Parkinson’s Disease using Short-Read Sequencing data
Parkinson’s disease is a complex neurodegenerative disorder, affecting approximately one million individuals in the USA alone. A significant proportion of risk for Parkinson’s disease is driven by genetics. Despite this, the majority of the common genetic variation that contributes to disease risk is unknown, in-part because previous genetic studies have focussed solely on the contribution of single nucleotide variants. Structural variants represent a significant source of genetic variation in the human genome. However, because assay of this variability is challenging, structural variants have not been cataloged on a genome-wide scale, and their contribution to the risk of Parkinson’s disease remains unknown. In this study, we 1) leveraged the GATK-SV pipeline to detect and genotype structural variants in 7,772 short-read sequencing data and 2) generated a subset of matched whole-genome Oxford Nanopore Technologies long-read sequencing data from the PPMI cohort to allow for comprehe...
PLoS Genetics, 2012
More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson's disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of ,27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Metaanalyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P,5610 28 ) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P = 1.3610 28 ). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies.
Complete Genomic Screen in Parkinson Disease
JAMA, 2001
Context The relative contribution of genes vs environment in idiopathic Parkinson disease (PD) is controversial. Although genetic studies have identified 2 genes in which mutations cause rare single-gene variants of PD and observational studies have suggested a genetic component, twin studies have suggested that little genetic contribution exists in the common forms of PD. Objective To identify genetic risk factors for idiopathic PD. Design, Setting, and Participants Genetic linkage study conducted 1995-2000 in which a complete genomic screen (n=344 markers) was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. A total of 870 family members were studied: 378 diagnosed as having PD, 379 unaffected by PD, and 113 with unclear status. Main Outcome Measures Logarithm of odds (lod) scores generated from parametric and nonparametric genetic linkage analysis. Results Two-point parametric maximum parametric lod score (MLOD) and multipoint nonparametric lod score (LOD) linkage analysis detected significant evidence for linkage to 5 distinct chromosomal regions: chromosome 6 in the parkin gene (MLOD=5.07; LOD=5.47) in families with at least 1 individual with PD onset at younger than 40 years, chromosomes 17q (MLOD = 2.28; LOD = 2.62), 8p (MLOD = 2.01; LOD = 2.22), and 5q (MLOD = 2.39; LOD = 1.50) overall and in families with lateonset PD, and chromosome 9q (MLOD = 1.52; LOD = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients. Conclusions Our data suggest that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic late-onset PD.
Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort
Movement Disorders
BackgroundAs gene‐targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial‐ready cohorts is limited.ObjectiveThe objectives are to (1) establish an international cohort of affected and unaffected individuals with PD‐linked variants; (2) provide harmonized and quality‐controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD.MethodsWe conducted a worldwide, systematic online survey to collect individual‐level data on individuals with PD‐linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ‐1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical,...
Genome-Wide Polygenic Risk Score Identifies Individuals at Elevated Parkinson’s Disease Risk
2020
SUMMARYParkinson’s Disease (PD) is the second most common and fastest-growing neurological disorder. Polygenic Risk Scores (PRS) using hundreds to thousands of PD-associated variants support polygenic heritability. Here, for the first time, we apply a genome-wide polygenic risk score approach using 6.2 million variants to compute a PD genome-wide polygenic risk score (PD-GPRS) via the LDPred algorithm. PD-GPRS validation and testing used Accelerating Medicines Partnership – Parkinson’s Disease (AMP-PD) and FinnGen Consortia genomic data from 1,654 PD Cases and 79,123 Controls. PD odds for the top 8%, 2.5%, and 1% of PD-GPRS were three-, four-, and seven times greater compared with lower percentiles, respectively (p<1e-10). PD age of onset and MDS-UPDRS motor scores also differed by PD-GPRS decile. Enrichment for phagosome related, dopamine signaling, immune related, and neuronal signaling pathways was found for genes nearest high PD-GPRS variants identified by MAF analysis. PD-GP...