Mendelian Randomization Study Using Dopaminergic Neuron‐Specific <scp>eQTL</scp> Nominates Potential Causal Genes for Parkinson's Disease

Dang, Xinglun; Zhang, Zhijun; Luo, Xiong-Jian

doi:10.1002/mds.29239

Cited by 16 publications

(12 citation statements)

References 41 publications

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“…This important issue can be addressed by complementing GWAS data with quantitative trait loci (QTL) datasets correlating risk genotypes with gene expression, methylation, and proteomic data (i.e., Mendelian randomization studies—MRS); this knowledge of the molecular mechanisms by which genetic variants localized in PD risk loci increase the disease risk is a key step to translating genetic evidence into possible therapeutic targets. Remarkably, the link between endolysosomal impairment and synaptic dysfunction within PD derives also from these approaches, which have recently confirmed the causal role of several “lysosomal” and “synaptic” genetic hits (i.e., ARSA , CTSB , GALC , IDUA , RAB29 , RAB7L1 , SH3GL2 , SMPD1 , STX1B , TMEM175 , VAMP42 , and ZSWIM7 ) [ 333 , 343 , 345 , 346 , 347 , 348 , 349 ].…”

Section: Genetic Risk Factors For Pd Associated With Endolysosomal Dy...mentioning

confidence: 95%

Genetic Evidence for Endolysosomal Dysfunction in Parkinson’s Disease: A Critical Overview

Yahya

Fonzo

Monfrini

2023

IJMS

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the aging population, and no disease-modifying therapy has been approved to date. The pathogenesis of PD has been related to many dysfunctional cellular mechanisms, however, most of its monogenic forms are caused by pathogenic variants in genes involved in endolysosomal function (LRRK2, VPS35, VPS13C, and ATP13A2) and synaptic vesicle trafficking (SNCA, RAB39B, SYNJ1, and DNAJC6). Moreover, an extensive search for PD risk variants revealed strong risk variants in several lysosomal genes (e.g., GBA1, SMPD1, TMEM175, and SCARB2) highlighting the key role of lysosomal dysfunction in PD pathogenesis. Furthermore, large genetic studies revealed that PD status is associated with the overall “lysosomal genetic burden”, namely the cumulative effect of strong and weak risk variants affecting lysosomal genes. In this context, understanding the complex mechanisms of impaired vesicular trafficking and dysfunctional endolysosomes in dopaminergic neurons of PD patients is a fundamental step to identifying precise therapeutic targets and developing effective drugs to modify the neurodegenerative process in PD.

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Section: Genetic Risk Factors For Pd Associated With Endolysosomal Dy...mentioning

confidence: 95%

Genetic Evidence for Endolysosomal Dysfunction in Parkinson’s Disease: A Critical Overview

Yahya

Fonzo

Monfrini

2023

IJMS

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“…This was downloaded within the TwoSampleMR package from the IEU Open GWAS Project (Elsworth et al). After harmonising the exposure and outcome data, genes with one eQTL associated with it underwent 2SMR using the Wald test whilst those with multiple eQTLs underwent 2SMR using MR Egger regression and inverse variance weighted methods (Dang et al 2022). A Bonferroni correction was used to adjust the p-value threshold to correct for multiple tests.…”

Section: Two Sample Mendelian Randomisationmentioning

confidence: 99%

An unbiasedde novonetwork analysis uncovering causal genes and the developmental intersection between autism and co-occurring traits

Miller

Golovina

Wicker

et al. 2023

Preprint

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Autism is a complex neurodevelopmental condition that manifests in various ways. Autism is often accompanied by other neurological disorders, such as ADHD, anxiety, and schizophrenia, which can complicate diagnosis and management. While research has investigated the role of specific genes in autism, their relationship with co-occurring traits is not fully understood. To address this gap, we conducted a two-sample Mendelian Randomisation analysis and identified four genes located at the 17q21.31 locus that are causally linked to autism in fetal cortical tissue (i.e. LINC02210, LRRC37A4P, RP11-259G18.1, RP11-798G7.6). LINC02210 was also identified as being causally related to autism in adult cortical tissue. By integrating data from expression quantitative trait loci [eQTLs], genes, and protein interactions we identified that the 17q21.31 locus contributes to the intersection between autism and other neurological traits and conditions in fetal cortical tissue. We also identified an additional distinct cluster of co-occurring traits, including cognition and worry, linked to genetic loci at 3p21.1. Our results support the hypothesis that an individual's autism phenotype is partially determined by their genetic risk for co-occurring conditions. Overall, our findings provide insights into the complex relationship between autism and co-occurring conditions, which could be used to develop predictive models for more accurate diagnosis and better clinical management.

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“…The sceQTL-gene association statistics from the BC-GRN were used as the exposure dataset while SNP-disease association statistics from Nalls et al 23 PD meta-GWAS were used as the outcome data for a MR analysis using the TwoSampleMR package (v0.5.6) 24 . We included sceQTLs with association p-value (< 1 × 10 − 5 ) 13,25,26 to minimise weak instrument bias while retaining su cient numbers of IVs for MR analysis. Independent IVs were identi ed using the ld_clump() function using default settings (r 2 < 0.001 and 10Mb window).…”

Section: Identi Cation Of Pd Causal Genes In Bc-grn Using Mendelian R...mentioning

confidence: 99%

“…Given its association with non-motor and motor symptoms in PD, the question remains whether genetic changes in the cortex can be causally linked to the development of PD? Mendelian Randomization (MR) is a powerful approach that determines the causal relationship between modi able gene expression and disease outcomes using genetic variants associated with gene expression as instrumental variables (IVs) 13 . MR has previously been used to identify genes whose expression changes in dopaminergic neurons have a causal role in PD 13 .…”

Section: Introductionmentioning

confidence: 99%

“…Mendelian Randomization (MR) is a powerful approach that determines the causal relationship between modi able gene expression and disease outcomes using genetic variants associated with gene expression as instrumental variables (IVs) 13 . MR has previously been used to identify genes whose expression changes in dopaminergic neurons have a causal role in PD 13 . However, given that gene expression and its regulation is predominantly tissue speci c, the identi cation of cortical risk genes for PD would contribute to improving our understanding of the disease mechanisms underlying non-motor symptoms of PD.…”

Section: Introductionmentioning

confidence: 99%

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Identifying the genetic links between Parkinson’s disease and non-motor symptoms: novel insights into disease mechanisms

O'Sullivan,

Gokuladhas,

Fadason

et al. 2023

Preprint

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Understanding the biological mechanisms that underlie the non-motor symptoms of Parkinson’s disease (PD) requires comprehensive frameworks that unravel the complex interplay of genetic risk factors. Here, we used a disease-agnostic brain cortex gene regulatory network integrated with Mendelian Randomization analyses to identify 19 genes whose changes in expression are causal for PD. We further used the network to identify genes that are regulated by PD-associated genome-wide association study (GWAS) SNPs. Extended protein interaction networks derived from both the causal genes and PD-associated SNPs identified convergent impacts on biological pathways and phenoytpes, connecting PD with established co-occurring traits, including non-motor symptoms. These findings hold promise for therapeutic development. In conclusion, while distinct sets of genes likely influence PD risk and outcomes, the existence of genes in common and intersecting pathways suggests that they may contribute to both increased disease risk and symptom heterogeneity observed in people with Parkinson’s.

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Mendelian Randomization Study Using Dopaminergic Neuron‐Specific eQTL Nominates Potential Causal Genes for Parkinson's Disease

Cited by 16 publications

References 41 publications

Genetic Evidence for Endolysosomal Dysfunction in Parkinson’s Disease: A Critical Overview

Genetic Evidence for Endolysosomal Dysfunction in Parkinson’s Disease: A Critical Overview

An unbiasedde novonetwork analysis uncovering causal genes and the developmental intersection between autism and co-occurring traits

Identifying the genetic links between Parkinson’s disease and non-motor symptoms: novel insights into disease mechanisms

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