Evaluation of the Role of LRRK2 Gene in Parkinson’s Disease in an East Indian Cohort

Leucine rich repeat kinase 2 (LRRK2)gene defects cause Parkinson's disease (PD). Recently,LRRK2has also been shown by genome wide association (GWA) studies to be a susceptibility gene for the disease. In India mutations inLRRK2is a rare cause of PD. We, therefore, genotyped 64 SNPs acrossLRRK2in 161 control samples and finally studied 6 haplotype tagging SNPs for association-based study on 300 cases and 446 ethnically matched controls to explore the potential role ofLRRK2as a susceptibility gene in PD for East Indians. We did not find any significant allele/ genotype or haplotype associations with PD suggesting that common genetic variants withinLRRK2play limited role in modulating PD among East Indians. In addition, we also screened for the common mutations (viz. p.R1441C, p.R1441G, p.R1441H, p.Y1699C, p.G2019S), and a risk variant common among Asians (p.G2385R) but did not observe any of the above mentioned variants in our cohort. Our study, therefore, strongly suggests thatLRRK2has minimal role as a candidate and susceptibility gene in PD pathogenesis among East Indians.

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DEFINING CANDIDATE PARKINSON’S DISEASE GENES THROUGH THE ANALYSIS OF GENOME-WIDE HOMOZYGOSITY

10.1101/2020.11.23.20235671 ◽

2020 ◽

Author(s):

Steven J Lubbe ◽

Yvette C. Wong ◽

Bernabe Bustos ◽

Soojin Kim ◽

Jana Vandrovcova ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Autosomal Recessive Inheritance ◽

Homozygosity Mapping ◽

Disease Genes ◽

Compound Heterozygous ◽

Genome Wide ◽

Biallelic Mutations ◽

Functional Analyses

ABSTRACTEarly-onset Parkinson’s disease (EOPD) can be caused by biallelic mutations in PRKN, DJ1 and PINK1. However, while the identification of novel genes is becoming increasingly challenging, new insights into EOPD genetics have important relevance for understanding the pathways driving disease pathogenesis. Here, using extended runs of homozygosity (ROH) >8Mb as a marker for possible autosomal recessive inheritance, we identified 90 EOPD patients with extended ROH. Investigating rare, damaging homozygous variants to identify candidate genes for EOPD, 81 genes were prioritised. Through the assessment of biallelic (homozygous and compound heterozygous) variant frequencies in cases and controls from three independent cohorts totalling 3,381 PD patients and 2,463 controls, we identified two biallelic MIEF1 variant carriers among EOPD patients. We further investigated the role of disease-associated variants in MIEF1 which encodes for MID51, an outer mitochondrial membrane protein, and found that putative EOPD-associated variants in MID51 preferentially disrupted its oligomerization state. These findings provide further support for the role of mitochondrial dysfunction in the development of PD. Together, we have used genome-wide homozygosity mapping to identify potential EOPD genes, and future studies incorporating expanded datasets and further functional analyses will help to determine their roles in disease aetiology.

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

10.1101/2021.06.22.21259012 ◽

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.

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Exploring human-genome gut-microbiome interaction in Parkinson’s disease

npj Parkinson s Disease ◽

10.1038/s41531-021-00218-2 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Zachary D. Wallen ◽

William J. Stone ◽

Stewart A. Factor ◽

Eric Molho ◽

Cyrus P. Zabetian ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Gut Microbiome ◽

Alpha Synuclein ◽

Incomplete Penetrance ◽

Susceptibility Loci ◽

Opportunistic Pathogens ◽

Host Genotype ◽

Genome Wide

AbstractThe causes of complex diseases remain an enigma despite decades of epidemiologic research on environmental risks and genome-wide studies that have uncovered tens or hundreds of susceptibility loci for each disease. We hypothesize that the microbiome is the missing link. Genetic studies have shown that overexpression of alpha-synuclein, a key pathological protein in Parkinson’s disease (PD), can cause familial PD and variants at alpha-synuclein locus confer risk of idiopathic PD. Recently, dysbiosis of gut microbiome in PD was identified: altered abundances of three microbial clusters were found, one of which was composed of opportunistic pathogens. Using two large datasets, we found evidence that the overabundance of opportunistic pathogens in PD gut is influenced by the host genotype at the alpha-synuclein locus, and that the variants responsible modulate alpha-synuclein expression. Results put forth testable hypotheses on the role of gut microbiome in the pathogenesis of PD, the incomplete penetrance of PD susceptibility genes, and potential triggers of pathology in the gut.

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Targeted sequencing of Parkinson’s disease loci genes highlights SYT11, FGF20 and other associations

Brain ◽

10.1093/brain/awaa401 ◽

2020 ◽

Author(s):

Uladzislau Rudakou ◽

Eric Yu ◽

Lynne Krohn ◽

Jennifer A Ruskey ◽

Farnaz Asayesh ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Linkage Disequilibrium ◽

Rare Variants ◽

Association Studies ◽

Strong Linkage Disequilibrium ◽

Genome Wide Association Studies ◽

Common Variants ◽

Common Genetic Variants

Abstract Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson’s disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson’s disease in 2657 patients and 3647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency < 0.01) using optimized sequence Kernel association tests. The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants in SYT11, FGF20 and GCH1 associated with Parkinson’s disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that the SYT11 GWAS association is driven by variants in the nearby GBA gene. However, the association of SYT11 was mainly driven by a rare 3′ UTR variant (rs945006601) and was independent of GBA variants (P = 5.23 × 10−5 after exclusion of all GBA variant carriers). The association of FGF20 was driven by a rare 5′ UTR variant (rs1034608171) located in the promoter region. The previously reported association of GCH1 with Parkinson’s disease is driven by rare non-synonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified two LRRK2 variants, p.Arg793Met and p.Gln1353Lys, in 10 and eight controls, respectively, but not in patients. We identified common variants associated with Parkinson’s disease in MAPT, TMEM175, BST1, SNCA and GPNMB, which are all in strong linkage disequilibrium with known GWAS hits in their respective loci. A common coding PM20D1 variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson’s disease (odds ratio 0.73, 95% confidence interval 0.60–0.89, P = 1.161 × 10−3). This variant is not in linkage disequilibrium with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest that SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB should be considered for future studies as possible Parkinson’s disease-related genes.

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The role of pharmacogenomics in the personalization of Parkinson's disease treatment

Pharmacogenomics ◽

10.2217/pgs-2020-0031 ◽

2020 ◽

Vol 21 (14) ◽

pp. 1033-1043

Author(s):

Sara Redenšek ◽

Vita Dolžan

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Adverse Events ◽

Genetic Markers ◽

Response To Treatment ◽

Disease Treatment ◽

Genetic Biomarkers ◽

Genome Wide ◽

Treatment Integration

Parkinson's disease (PD)-related phenotypes can vary among patients substantially, including response to dopaminergic treatment in terms of efficacy and occurrence of adverse events. Many pharmacogenetic studies have already been conducted to find genetic markers of response to dopaminergic treatment. Integration of genetic and clinical data has already resulted in construction of clinical pharmacogenetic models for prediction of adverse events. However, the results of pharmacogenetic studies are inconsistent. More comprehensive genome-wide approaches are needed to find genetic biomarkers of PD-related phenotypes to better explain the variability in response to treatment. These genetic markers should be integrated with clinical, environmental, imaging, and other omics data to build clinically useful algorithms for personalization of PD management.

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Parkinson’s Disease-Overview

Journal of Regenerative Biology and Medicine ◽

10.37191/mapsci-2582-385x-3(6)-092 ◽

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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Targeted sequencing of Parkinson's disease loci genes highlights SYT11, FGF20 and other associations

10.1101/2020.05.29.20116111 ◽

2020 ◽

Author(s):

Uladzislau Rudakou ◽

Eric Yu ◽

Lynne M Krohn ◽

Jennifer A Ruskey ◽

Farnaz Asayesh ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Rare Variants ◽

Association Studies ◽

Meta Analysis ◽

Strong Linkage Disequilibrium ◽

Genome Wide Association Studies ◽

Common Variants ◽

Common Genetic Variants

Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson's disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson's disease in 2,657 patients and 3,647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency < 0.01) using optimized sequence Kernel association tests (SKAT-O). The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants in SYT11, FGF20 and GCH1 associated with Parkinson's disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that the SYT11 GWAS association is driven by variants in the nearby GBA gene. However, the association of SYT11 was mainly driven by a rare 3' UTR variant (rs945006601) and was independent of GBA variants (p=5.23E-05 after exclusion of all GBA variant carriers). The association of FGF20 was driven by a rare 5' UTR variant (rs1034608171) located in the promoter region. The previously reported association of GCH1 with Parkinson's Disease is driven by rare nonsynonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified two LRRK2 variants, p.Arg793Met and p.Gln1353Lys, in ten and eight controls, respectively, but not in patients. We identified common variants associated with Parkinson's disease in MAPT, TMEM175, BST1, SNCA and GPNMB which are all in strong linkage disequilibrium (LD) with known GWAS hits in their respective loci. A common coding PM20D1 variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson's disease (OR 0.73, 95% CI 0.60-0.89, p=1.161E-03). This variant is not in LD with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest that SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB should be considered for future studies as possible Parkinson's disease-related genes.

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Assessment of LIN28A variants in Parkinson’s disease

10.1101/2020.06.10.20103291 ◽

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.

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