Parkinson's Disease Genes Research Articles

A co-expression network based molecular characterization of genes responsive for Braak stages in Parkinson's disease.

The progression of Parkinson's disease (PD) is defined by six Braak stages. We used transcriptome data from PD patients with Braak stage information to understand underlying molecular mechanisms for the progress of the disease. We created networks of genes with continuously decreased/increased co-expression from control group to Braak 5-6 stages. These networks are significantly associated with PD-related mechanisms such as mitochondrial dysfunction and synaptic signalling among others. Applying weighted gene co-expression network analysis (WGCNA) algorithm to the co-expression networks led to more specific modules enriched with neurodegeneration-related disease pathways, seizure, abnormality of coordination, and hypotonia. Furthermore, we showed that one of the co-expression networks is clustered into three major communities with dedicated molecular functions: (i) tubulin folding pathway, gap junction-related mechanisms, neuronal system; (ii) synaptic vesicle, intracellular vesicle, proteasome complex, PD genes; (iii) energy metabolism, mitochondrial mechanisms, oxidative phosphorylation, TCA cycle, PD genes. The co-expression relations we identified in this study as crucial players in the disease progression cover several known PD-associated genes and genes whose products are known to physically interact with alpha-synuclein protein.

2021 Workshop: Neurodegenerative Diseases in the Gut-Brain Axis—Parkinson's Disease

2021 Workshop: Neurodegenerative Diseases in the Gut-Brain Axis—Parkinson's Disease

Multiple Criteria Optimization (MCO): A gene selection deterministic tool in RStudio.

Identifying genes with the largest expression changes (gene selection) to characterize a given condition is a popular first step to drive exploration into molecular mechanisms and is, therefore, paramount for therapeutic development. Reproducibility in the sciences makes it necessary to emphasize objectivity and systematic repeatability in biological and informatics analyses, including gene selection. With these two characteristics in mind, in previous works our research team has proposed using multiple criteria optimization (MCO) in gene selection to analyze microarray datasets. The result of this effort is the MCO algorithm, which selects genes with the largest expression changes without user manipulation of neither informatics nor statistical parameters. Furthermore, the user is not required to choose either a preference structure among multiple measures or a predetermined quantity of genes to be deemed significant a priori. This implies that using the same datasets and performance measures (PMs), the method will converge to the same set of selected differentially expressed genes (repeatability) despite who carries out the analysis (objectivity). The present work describes the development of an open-source tool in RStudio to enable both: (1) individual analysis of single datasets with two or three PMs and (2) meta-analysis with up to five microarray datasets, using one PM from each dataset. The capabilities afforded by the code include license-free portability and the possibility to carry out analyses via modest computer hardware, such as personal laptops. The code provides affordable, repeatable, and objective detection of differentially expressed genes from microarrays. It can be used to analyze other experiments with similar experimental comparative layouts, such as microRNA arrays and protein arrays, among others. As a demonstration of the capabilities of the code, the analysis of four publicly-available microarray datasets related to Parkinson´s Disease (PD) is presented here, treating each dataset individually or as a four-way meta-analysis. These MCO-supported analyses made it possible to identify MMP9 and TUBB2A as potential PD genetic biomarkers based on their persistent appearance across each of the case studies. A literature search confirmed the importance of these genes in PD and indeed as PD biomarkers, which evidences the code´s potential.

Narcolepsy in Parkinson's disease with insulin resistance.

Background: Parkinson's disease (PD) is characterized by its progression of motor-related symptoms such as tremors, rigidity, slowness of movement, and difficulty with walking and balance. Comorbid conditions in PD individuals include insulin resistance (IR) and narcolepsy-like sleep patterns. The intersecting sleep symptoms of both conditions include excessive daytime sleepiness, hallucinations, insomnia, and falling into REM sleep more quickly than an average person. Understanding of the biological basis and relationship of these comorbid disorders with PD may help with early detection and intervention strategies to improve quality of life. Methods: In this study, an integrative genomics and systems biology approach was used to analyze gene expression patterns associated with PD, IR, and narcolepsy in order to identify genes and pathways that may shed light on how these disorders are interrelated. A correlation analysis with known genes associated with these disorders (LRRK2, HLA-DQB1, and HCRT) was used to query microarray data corresponding to brain regions known to be involved in PD and narcolepsy. This includes the hypothalamus, dorsal thalamus, pons, and subcoeruleus nucleus. Risk factor genes for PD, IR, and narcolepsy were also incorporated into the analysis. Results: The PD and narcolepsy signaling networks are connected through insulin and immune system pathways. Important genes and pathways that link PD, narcolepsy, and IR are CACNA1C, CAMK1D, BHLHE41, HMGB1, and AGE-RAGE. Conclusions:We have identified the genetic signatures that link PD with its comorbid disorders, narcolepsy and insulin resistance, from the convergence and intersection of dopaminergic, insulin, and immune system related signaling pathways. These findings may aid in the design of early intervention strategies and treatment regimes for non-motor symptoms in PD patients as well as individuals with diabetes and narcolepsy.

Atlas of genetic effects in human microglia transcriptome across brain regions, aging and disease pathologies

Microglia are tissue-resident macrophages of the central nervous system that are essential for homeostasis, immune response, neurogenesis, and neuronal plasticity. Genetic studies have strongly implicated microglial dysfunction in multiple neurodegenerative diseases. However, investigating genetically-driven changes in gene expression in microglia has been limited by lack of access to these cells from the number of subjects required to perform well-powered genomic analysis.Here we describe the transcriptome analysis of 255 primary human CD11b+ microglia samples isolated at autopsy from multiple brain regions of 100 human subjects with neurodegenerative and neuropsychiatric disorders. We performed systematic analyses to investigate various aspects of microglial heterogeneities including brain region, age, sex, and disease. By intersecting transcriptomics and genetics, we performed expression and splicing QTL analyses and by combining microglia from four different brain regions using a multivariate meta-analysis method (mashR).We observed widespread transcriptome variation associated with microglia, suggesting that these genes may play important role in diversified responses to pathological stimuli of microglia at different locations. We also observed 1,693 genes (FDR < 0.05) whose expression is associated with age including many genes in Alzheimer's (AD) (MS4A6A, FCER1G, and CR1) or Parkinson's disease (PD) (BST1 and FCGR2A) GWAS loci. We identified 3,611 eQTLs (mashR local false sign rate < 0.05), of which 50% (1,791) show region-specific effects. We identified over 300 eQTLs that colocalize with a known risk locus for a neurodegenerative or neuropsychiatric disease, nearly half of which are not found in prefrontal cortex or in peripheral monocytes. We prioritized 7 and 13 putative causal genes for AD and PD, respectively, many of which are novel genes (ITGAX, USP6NL, TSPOAP1, P2RY12, FCGR2C, and FGF20). Fine-mapping of these colocalized loci with CNS chromatin accessibility (ATAC-seq) and histone modification (H3K27ac) data nominates candidate causal variants that are within microglia-specific enhancers and are likely to modify disease susceptibility by regulating gene expression and/or splicing in microglia.In summary, we have built the most comprehensive catalog to date of genetic effects on the microglia transcriptome and propose molecular mechanisms of action of candidate functional variants in several neurological and neuropsychiatric diseases.

Glucocerebrosidase (GBA) gene variants in a multi-ethnic Asian cohort with Parkinson's disease: mutational spectrum and clinical features.

GBA variants are associated with increased risk and earlier onset of Parkinson's disease (PD), and more rapid disease progression especially with "severe" variants typified by p.L483P. GBA mutation screening studies from South-East Asia, with > 650 million inhabitants of diverse ancestries, are very limited. We investigated the spectrum of GBA variants, and associated clinico-demographic features, in a multi-ethnic PD cohort in Malaysia. Patients (n = 496) were recruited from seven centres, primarily of Chinese (45%), Malay (37%), and Indian (13%) ethnicities. All GBA coding exons were screened using a next-generation sequencing-based PD gene panel and verified with Sanger sequencing. We identified 14 heterozygous GBA alleles consisting of altogether 17 missense variants (8 classified as pathogenic or likely pathogenic for PD) in 25 (5.0%) patients, with a substantially higher yield among early (< 50years) vs. late-onset patients across all three ethnicities (9.1-13.2% vs. 1.0-3.2%). The most common variant was p.L483P (including RecNciI, n = 11, 2.2%), detected in all three ethnicities. Three novel variants/recombinant alleles of uncertain significance were found; p.P71L, p.L411P, and p.L15S(;)S16G(;)I20V. The common European risk variants, p.E365K, p.T408M, and p.N409S, were not detected. A severe disease course was noted in the majority of GBA-variant carriers, across a range of detected variants. We report a potentially novel observation of spine posture abnormalities in GBA-variant carriers. This represents the largest study on GBA variation from South-East Asia, and highlights that these populations, especially those with EOPD, would be relevant for studies including clinical trials targeting GBA pathways.

Disease Duration Influences Gene Expression in Neuromelanin-Positive Cells From Parkinson's Disease Patients.

Analyses of gene expression in cells affected by neurodegenerative disease can provide important insights into disease mechanisms and relevant stress response pathways. Major symptoms in Parkinson’s disease (PD) are caused by the degeneration of midbrain dopamine (mDA) neurons within the substantia nigra. Here we isolated neuromelanin-positive dopamine neurons by laser capture microdissection from post-mortem human substantia nigra samples recovered at both early and advanced stages of PD. Neuromelanin-positive cells were also isolated from individuals with incidental Lewy body disease (ILBD) and from aged-matched controls. Isolated mDA neurons were subjected to genome-wide gene expression analysis by mRNA sequencing. The analysis identified hundreds of dysregulated genes in PD. Results showed that mostly non-overlapping genes were differentially expressed in ILBD, subjects who were early after diagnosis (less than five years) and those autopsied at more advanced stages of disease (over five years since diagnosis). The identity of differentially expressed genes suggested that more resilient, stably surviving DA neurons were enriched in samples from advanced stages of disease, either as a consequence of positive selection of a less vulnerable long-term surviving mDA neuron subtype or due to up-regulation of neuroprotective gene products.

Cancer in Parkinson’s Disease: An Approximation to the Main Risk Factors

Background: Many evidences suggest a pathological link between neurodegenerative diseases and cancer. In fact, several epidemiologic studies indicate a decreased incidence of most cancer types in Parkinson’s disease (PD) patients and some PD genes are involved in cancer networks. Objective: The aim of this study is to assess the influence of several factors in the risk of cancer in a cohort of 753 PD patients and to study how these variables interact with each other. Methods: We analyzed the effect of gender, tobacco, alcohol, type of PD (genetic or idiopathic PD), and two genetic variants, previously associated with cancer, rs5848-GRN and rs1042522-TP53. Results: A higher age at PD onset was observed in patients who develop cancer before PD (p < 0.001). Alcohol consumption was a risk factor to develop cancer in PD patients (p = 0.011), while smoking was not a cancer risk factor in our cohort (p = 0.098). Among the genetic factors, the genotype TT GRN-rs5848 was statistically more frequent in PD patients without cancer (p = 0.05). Conclusions: Our study identified several factors, genetic and nongenetic, which contribute to the risk for cancer in PD.

Narcolepsy in Parkinson's disease with insulin resistance

Background: Parkinson’s disease (PD) is characterized by its progression of motor-related symptoms such as tremors, rigidity, slowness of movement, and difficulty with walking and balance. Comorbid conditions in PD individuals include insulin resistance (IR) and narcolepsy-like sleep patterns. The intersecting sleep symptoms of both conditions include excessive daytime sleepiness, hallucinations, insomnia, and falling into REM sleep more quickly than an average person. Understanding of the biological basis and relationship of these comorbid disorders with PD may help with early detection and intervention strategies to improve quality of life. Methods: In this study, an integrative genomics and systems biology approach was used to analyze gene expression patterns associated with PD, IR, and narcolepsy in order to identify genes and pathways that may shed light on how these disorders are interrelated. A correlation analysis with known genes associated with these disorders (LRRK2, HLA-DQB1, and HCRT) was used to query microarray data corresponding to brain regions known to be involved in PD and narcolepsy. This includes the hypothalamus, dorsal thalamus, pons, and subcoeruleus nucleus. Risk factor genes for PD, IR, and narcolepsy were also incorporated into the analysis. Results: The PD and narcolepsy signaling networks are connected through insulin and immune system pathways. Important genes and pathways that link PD, narcolepsy, and IR are CACNA1C, CAMK1D, BHLHE41, HMGB1, and AGE-RAGE. Conclusions: We have identified the genetic signatures that link PD with its comorbid disorders, narcolepsy and insulin resistance, from the convergence and intersection of dopaminergic, insulin, and immune system related signaling pathways. These findings may aid in the design of early intervention strategies and treatment regimes for non-motor symptoms in PD patients as well as individuals with diabetes and narcolepsy.

Rare Variants Analysis of Lysosomal Related Genes in Early-Onset and Familial Parkinson's Disease in a Chinese Cohort.

Genetic studies have indicated that variants in several lysosomal genes are risk factors for idiopathic Parkinson's disease (PD). However, the role of lysosomal genes in PD in Asian populations is largely unknown. This study aimed to analyze rare variants in lysosomal related genes in Chinese population with early-onset and familial PD. In total, 1,136 participants, including 536 and 600 patients with sporadic early-onset PD (SEOPD) and familial PD, respectively, underwent whole-exome sequencing to assess the genetic etiology. Rare variants in PD were investigated in 67 candidate lysosomal related genes (LRGs), including 15 lysosomal function-related genes and 52 lysosomal storage disorder genes. Compared with the autosomal dominant PD (ADPD) or SEOPD cohorts, a much higher proportion of patients with multiple rare damaging variants of LRGs were found in the autosomal recessive PD (ARPD) cohort. At a gene level, rare damaging variants in GBA and MAN2B1 were enriched in PD, but in SCARB2, MCOLN1, LYST, VPS16, and VPS13C were much less in patients. At an allele level, GBA p. Leu483Pro was found to increase the risk of PD. Genotype-phenotype correlation showed no significance in the clinical features among patients carrying a discrepant number of rare variants in LRGs. Our study suggests rare variants in LRGs might be more important in the pathogenicity of ARPD cases compared with ADPD or SEOPD. We further confirm rare variants in GBA are involve in PD pathogenecity and other genes associated with PD identified in this study should be supported with more evidence.

The PINK1 repertoire: Not just a one trick pony.

PTEN-induced kinase 1 (PINK1) is a Parkinson's disease gene that acts as a sensor for mitochondrial damage. Its best understood role involves phosphorylating ubiquitin and the E3 ligase Parkin (PRKN) to trigger a ubiquitylation cascade that results in selective clearance of damaged mitochondria through mitophagy. Here we focus on other physiological roles of PINK1. Some of these also lie upstream of Parkin but others represent autonomous functions, for which alternative substrates have been identified. We argue that PINK1 orchestrates a multi-arm response to mitochondrial damage that impacts on mitochondrial architecture and biogenesis, calcium handling, transcription and translation. We further discuss a role for PINK1 in immune signalling co-ordinated at mitochondria and consider the significance of a freely diffusible cleavage product, that is constitutively generated and degraded under basal conditions.

Parkinson Disease: Translating Insights from Molecular Mechanisms to Neuroprotection.

Parkinson disease (PD) used to be considered a nongenetic condition. However, the identification of several autosomal dominant and recessive mutations linked to monogenic PD has changed this view. Clinically manifest PD is then thought to occur through a complex interplay between genetic mutations, many of which have incomplete penetrance, and environmental factors, both neuroprotective and increasing susceptibility, which variably interact to reach a threshold over which PD becomes clinically manifested. Functional studies of PD gene products have identified many cellular and molecular pathways, providing crucial insights into the nature and causes of PD. PD originates from multiple causes and a range of pathogenic processes at play, ultimately culminating in nigral dopaminergic loss and motor dysfunction. An in-depth understanding of these complex and possibly convergent pathways will pave the way for therapeutic approaches to alleviate the disease symptoms and neuroprotective strategies to prevent disease manifestations. This review is aimed at providing a comprehensive understanding of advances made in PD research based on leveraging genetic insights into the pathogenesis of PD. It further discusses novel perspectives to facilitate identification of critical molecular pathways that are central to neurodegeneration that hold the potential to develop neuroprotective and/or neurorestorative therapeutic strategies for PD. SIGNIFICANCE STATEMENT: A comprehensive review of PD pathophysiology is provided on the complex interplay of genetic and environmental factors and biologic processes that contribute to PD pathogenesis. This knowledge identifies new targets that could be leveraged into disease-modifying therapies to prevent or slow neurodegeneration in PD.

Narcolepsy in Parkinson's disease with insulin resistance

Background: Parkinson’s disease (PD) is characterized by its progression of motor-related symptoms such as tremors, rigidity, slowness of movement, and difficulty with walking and balance. Comorbid conditions in PD individuals include insulin resistance (IR) and narcolepsy-like sleep patterns. The intersecting sleep symptoms of both conditions include excessive daytime sleepiness, hallucinations, insomnia, and falling into REM sleep more quickly than an average person. Understanding of the biological basis and relationship of these comorbid disorders with PD may help with early detection and intervention strategies to improve quality of life. Methods: In this study, an integrative genomics and systems biology approach was used to analyze gene expression patterns associated with PD, IR, and narcolepsy in order to identify genes and pathways that may shed light on how these disorders are interrelated. A correlation analysis with known genes associated with these disorders (LRRK2, HLA-DQB1, and HCRT) was used to query microarray data corresponding to brain regions known to be involved in PD and narcolepsy. This includes the hypothalamus, dorsal thalamus, pons, and subcoeruleus nucleus. Risk factor genes for PD, IR, and narcolepsy were also incorporated into the analysis. Results: The PD and narcolepsy signaling networks are connected through insulin and immune system pathways. Important genes and pathways that link PD, narcolepsy, and IR are CACNA1C, CAMK1D, BHLHE41, HMGB1, and AGE-RAGE. Conclusions: We have identified the genetic signatures that link PD with its comorbid disorders, narcolepsy and insulin resistance, from the convergence and intersection of dopaminergic, insulin, and immune system related signaling pathways. These findings may aid in the design of early intervention strategies and treatment regimes for non-motor symptoms in PD patients as well as individuals with diabetes and narcolepsy.

A systematic review of molecular approaches that link mitochondrial dysfunction and neuroinflammation in Parkinson's disease.

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder that affects 1% of the population worldwide. Etiology of PD is likely to be multi-factorial such as protein misfolding, mitochondrial dysfunction, oxidative stress, and neuroinflammation that contributes to the pathology of Parkinson's disease (PD), numerous studies have shown that mitochondrial dysfunction may play a key role in the dopaminergic neuronal loss. In multiple ways, the two most important are the activation of neuroinflammation and mitochondrial dysfunction, while mitochondrial dysfunction could cause neuroinflammation and vice versa. Thus, the mitochondrial proteins are the highly promising target for the development of PD. However, the limited amount of dopaminergic neurons prevented the detailed investigation of Parkinson's disease with regard to mitochondrial dysfunction. Both genetic and environmental factors are also associated with mitochondrial dysfunction and PD pathogenesis. The induction of PD by neurotoxins that inhibit mitochondrial complex I provide direct evidence linking mitochondrial dysfunction to PD. A decrease of mitochondrial complex I activity is observed in PD brain and in neurotoxin- or genetic factor-inducedin vitroandin vivomodels. Moreover, PINK1, Parkin, DJ-1 and LRRK2 mitochondrial PD gene products have important roles in mitophagy, a cellular process that clear damaged mitochondria.This review paper would discuss the evidence for the mitochondrial dysfunction and neuroinflammation in PD.

Modelling the functional genomics of Parkinson's disease in Caenorhabditis elegans: LRRK2 and beyond.

For decades, Parkinson’s disease (PD) cases have been genetically categorised into familial, when caused by mutations in single genes with a clear inheritance pattern in affected families, or idiopathic, in the absence of an evident monogenic determinant. Recently, genome-wide association studies (GWAS) have revealed how common genetic variability can explain up to 36% of PD heritability and that PD manifestation is often determined by multiple variants at different genetic loci. Thus, one of the current challenges in PD research stands in modelling the complex genetic architecture of this condition and translating this into functional studies. Caenorhabditis elegans provide a profound advantage as a reductionist, economical model for PD research, with a short lifecycle, straightforward genome engineering and high conservation of PD relevant neural, cellular and molecular pathways. Functional models of PD genes utilising C. elegans show many phenotypes recapitulating pathologies observed in PD. When contrasted with mammalian in vivo and in vitro models, these are frequently validated, suggesting relevance of C. elegans in the development of novel PD functional models. This review will discuss how the nematode C. elegans PD models have contributed to the uncovering of molecular and cellular mechanisms of disease, with a focus on the genes most commonly found as causative in familial PD and risk factors in idiopathic PD. Specifically, we will examine the current knowledge on a central player in both familial and idiopathic PD, Leucine-rich repeat kinase 2 (LRRK2) and how it connects to multiple PD associated GWAS candidates and Mendelian disease-causing genes.

Generation of integration-free human iPSC line LCPHi001-A from a Parkinson's disease patient carrying the RecNciI mutation in GBA gene

Parkinson’s disease (PD) is a neurodegenerative disease caused by environmental and genetic factors. The identified PD genes include SNCA, LRRK2, Parkin, DJ-1, PINK1, and ATP13A2. Mutations in the glucocerebrosidase (GBA) gene were reported to be associated with PD in different ethnic populations. Here we generated a novel induced pluripotent stem cell (iPSC) line LCPHi001-A from a PD patient carrying RecNciI mutation (c.1448 T > C, c.1483G > C, and c.1497G > C) in GBA by non-integrative episomal plasmids. The LCPHi001-A line expressed pluripotency markers, displayed differentiation capacity to three germ layers in vivo, and had the normal karyotype.

Genetic and epigenetic disease modifiers in an Italian C9orf72 family expressing ALS, FTD or PD clinical phenotypes

Objective: The presence of the hexanucleotide repeat expansion (HRE) in C9orf72 gene is associated to the ALS/FTD spectrum, but also to parkinsonisms. We here describe an Italian family with the father diagnosed with Parkinson disease (PD) at the age of 67 and the two daughters developing FTD and ALS at 45 years of age. We searched for C9orf72 HRE with possible genetic and epigenetic modifiers to account for the intrafamilial phenotypic variability. Methods: C9orf72 mutational analysis was performed by fragment length analysis, Repeat-primed PCR and Southern blot. Targeted next generation sequencing was used to analyze 48 genes associated to neurodegenerative diseases. Promoter methylation was analyzed by bisulfite sequencing. Results: Genetic analysis identified C9orf72 HRE in all the affected members with a similar repeat expansion size. Both the father and the FTD daughter also carried the heterozygous p.Ile946Phe variant in ATP13A2 gene, associated to PD. In addition, the father also showed a heterozygous EIF4G1 variant (p.Ala13Pro), that might increase his susceptibility to develop PD. The DNA methylation analysis showed that all the 26 CpG sites within C9orf72 promoter were unmethylated in all family members. Conclusions: Neither C9orf72 HRE size nor promoter methylation act as disease modifiers within this family, at least in blood, not excluding HRE mosaicism and a different methylation pattern in the brain. However, the presence of rare genetic variants in PD genes suggests that they may influence the clinical manifestation in the father. Other genetic and/or epigenetic modifiers must be responsible for disease variability in this C9orf72 family case.

Genetic analysis of TRIM family genes for early-onset Parkinson's disease in Chinese population

IntroductionAmounting evidence has suggested the Tripartite Motif (TRIM) family proteins as related to Parkinson's disease (PD). However, many of the risk genes were still awaiting further explorations, and their genetic role in PD has not been investigated yet. MethodsHere, we aimed to systematically evaluate the genetic associations of TRIMs with PD in a large Chinese early-onset PD (EOPD, age at onset < 50 years) cohort. We identified rare variants (minor allele frequency < 0.01) in 743 unrelated EOPD patients using whole exome sequencing, and evaluated the association between rare variants and EOPD at allele and gene levels. ResultsTotally 123 rare variants were identified in 13 TRIM protein family members, including TRIM3, TRIM6, TRIM8, TRIM9, TRIM10, TRIM11, TRIM17, TRIM24, TRIM27, TRIM28, TRIM34, TRIM40 and TRIM41. At the allele level, three variants were nominally associated with PD, namely p.R65H in TRIM10, p.P467S in TRIM11, and p.I425V in TRIM24. Gene-based burden analysis showed a clear enrichment of rare variants of TRIM24 in EOPD. ConclusionThese results demonstrate TRIM24 as a potential risk gene for PD, provide a better understanding for the genetic involvement of TRIM protein family members in EOPD and broaden the current mutation spectrum of PD.

Clinical and Genetic Analysis of Costa Rican Patients With Parkinson's Disease.

Background: Most research in genomics of Parkinson's disease (PD) has been done in subjects of European ancestry, leading to sampling bias and leaving Latin American populations underrepresented. We sought to clinically characterize PD patients of Costa Rican origin and to sequence familial PD and atypical parkinsonism-associated genes in cases and controls.Methods: We enrolled 118 PD patients with 97 unrelated controls. Collected information included demographics, exposure to risk and protective factors, and motor and cognitive assessments. We sequenced coding and untranslated regions in familial PD and atypical parkinsonism-associated genes including GBA, SNCA, VPS35, LRRK2, GCH1, PRKN, PINK1, DJ-1, VPS13C, and ATP13A2.Results: Mean age of PD probands was 62.12 ± 13.51 years; 57.6% were male. The frequency of risk and protective factors averaged ~45%. Physical activity significantly correlated with better motor performance despite years of disease. Increased years of education were significantly associated with better cognitive function, whereas hallucinations, falls, mood disorders, and coffee consumption correlated with worse cognitive performance. We did not identify an association between tested genes and PD or any damaging homozygous or compound heterozygous variants. Rare variants in LRRK2 were nominally associated with PD; six were located between amino acids p.1620 and 1623 in the C-terminal-of-ROC (COR) domain of Lrrk2. Non-synonymous GBA variants (p.T369M, p.N370S, and p.L444P) were identified in three healthy individuals. One PD patient carried a pathogenic GCH1 variant, p.K224R.Discussion: This is the first study that describes sociodemographics, risk factors, clinical presentation, and genetics of Costa Rican patients with PD, adding information to genomics research in a Latino population.

Identification of Parkinson's Disease-Causing Genes via Omics Data.

Parkinson’s disease (PD) is the second most frequent neurogenic disease after Alzheimer’s disease. The clinical manifestations include mostly motor disorders, such as bradykinesia, myotonia, and static tremors. Since the cause of this pathological features remain unclear, there is currently no radical treatment for PD. Environmental and genetic factors are thought to contribute to the pathology of PD. To identify the genetic factors, some studies employed the Genome-Wide Association Studies (GWAS) method and detected certain genes closely related to PD. However, the functions of these gene mutants in the development of PD are unknown. Combining GWAS and expression Quantitative Trait Loci (eQTL) analysis, the biological meaning of mutation could be explained to some extent. Therefore, the present investigation used Summary data-based Mendelian Randomization (SMR) analysis to integrate of two PD GWAS datasets and four eQTL datasets with the objective of identifying casual genes. Using this strategy, we found six Single Nucleotide Polymorphism (SNP) loci which could cause the development of PD through altering the susceptibility gene expression, and three risk genes: Synuclein Alpha (SNCA), Mitochondrial Poly(A) Polymerase (MTPAP), and RP11-305E6.4. We proved the accuracy of results through case studies and inferred the functions of these genes in PD. Overall, this study provides insights into the genetic mechanism behind PD, which is crucial for the study of the development of this disease and its diagnosis and treatment.