PARK16 locus: Differential effects of the non-coding rs823114 on Parkinson’s disease risk, RNA expression, and DNA methylation

Goldstein, Orly; Gana‐Weisz, Mali; Casey, Fergal; Meltzer-Fridrich, Hila; Yaacov, Or; Waldman, Yedael Y.; Lin, Dongdong; Mordechai, Yael; Zhu, Jing; Cullen, Patrick; Omer, Nurit; Shiner, Tamara; Thaler, Avner; Bar‐Shira, Anat; Mirelman, Anat; John, Sally; Giladi, Nir; Orr‐Urtreger, Avi

doi:10.1016/j.jgg.2020.10.010

Cited by 5 publications

(4 citation statements)

References 19 publications

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“…Furthermore, the risk alleles previously identified using GWAS by us and others [1,12] can have a different effect size in subgroups of PD. For example, we demonstrated that the PARK16 locus, in which rs823114 had a significant association with PD protection among LRRK2-G2019S carriers, with a large effect size, was not protective among GBA1 carriers, suggesting a stratified effect based on mutation carrier status [13].…”

Section: Introductionmentioning

confidence: 87%

MAPT Locus in Parkinson’s Disease Patients of Ashkenazi Origin: A Stratified Analysis

Shani,

Gana-Weisz,

Bar-Shira

et al. 2023

Genes

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Introduction: MAPT locus is associated with Parkinson’s disease (PD), which is located within a large inversion region of high linkage disequilibrium (LD). We aimed to determine whether the H2-haplotype protective effect and its effect size depends on the GBA1 or LRRK2 risk allele carrier status, and to further characterize genetic alterations that might contribute to its effect. Methods: LD analysis was performed using whole-genome sequencing data of 202 unrelated Ashkenazi Jewish (AJ) PDs. A haplotype-divergent variant was genotyped in a cohort of 1200 consecutively recruited AJ-PDs. The odd ratios were calculated using AJ-non-neuro cases from the gnomAD database as the controls in an un-stratified and a stratified manner according to the mutation carrier status, and the effect on the Age at Motor Symptom Onset (AMSO) was examined. Expression and splicing quantitative trait locus (eQTL and sQTL) analyses were carried out using brain tissues from a database. Results: The H2 haplotype exhibited significant association with PD protection, with a similar effect size in GBA1 carriers, LRRK2-G2019S carriers, and non-carriers (OR = 0.77, 0.69, and 0.82, respectively), and there was no effect on AMSO. The LD interval was narrowed to approximately 1.2 Mb. The H2 haplotype carried potential variants in candidate genes (MAPT and SPPL2C); structural deletions and segmental duplication (KANSL1); and variants affecting gene expression and intron excision ratio in brain tissues (LRRC37A/2). Conclusions: Our results demonstrate that H2 is associated with PD and its protective effect is not influenced by the GBA1/LRRK2 risk allele carrier status. This effect may be genetically complex, resulting from different levels of variations such as missense mutations in relevant genes, structural variations, epigenetic modifications, and RNA expression changes, which may operate independently or in synergy.

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Section: Introductionmentioning

confidence: 87%

MAPT Locus in Parkinson’s Disease Patients of Ashkenazi Origin: A Stratified Analysis

Shani,

Gana-Weisz,

Bar-Shira

et al. 2023

Genes

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“…In the last few years, various studies have shown that physical activity induces epigenetic changes that affect the CNS plasticity. Among the genes mostly affected by epigenetic regulation, it is important to mention synuclein α ( SNCA , 4q22.1); parkin RBR E3 ubiquitin protein ligase ( PARK2 , 6q26); Parkinson disease 16 ( PARK16 , 1q32) and leucine-rich repeat kinase 2 ( LRRK2 , 12q12); [ 69 , 70 , 71 , 72 , 73 , 74 , 75 ].…”

Section: Genetic and Epigenetic Factors Involved In Nutrients Metabol...mentioning

confidence: 99%

Relationship between Nutrition, Lifestyle, and Neurodegenerative Disease: Lessons from ADH1B, CYP1A2 and MTHFR

Barati

Fabrizio

Strafella

et al. 2022

Genes

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In the present review, the main features involved in the susceptibility and progression of neurodegenerative disorders (NDDs) have been discussed, with the purpose of highlighting their potential application for promoting the management and treatment of patients with NDDs. In particular, the impact of genetic and epigenetic factors, nutrients, and lifestyle will be presented, with particular emphasis on Alzheimer’s disease (AD) and Parkinson’s disease (PD). Metabolism, dietary habits, physical exercise and microbiota are part of a complex network that is crucial for brain function and preservation. This complex equilibrium can be disrupted by genetic, epigenetic, and environmental factors causing perturbations in central nervous system homeostasis, contributing thereby to neuroinflammation and neurodegeneration. Diet and physical activity can directly act on epigenetic modifications, which, in turn, alter the expression of specific genes involved in NDDs onset and progression. On this subject, the introduction of nutrigenomics shed light on the main molecular players involved in the modulation of health and disease status. In particular, the review presents data concerning the impact of ADH1B, CYP1A2, and MTHFR on the susceptibility and progression of NDDs (especially AD and PD) and how they may be exploited for developing precision medicine strategies for the disease treatment and management.

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“…There is one report of hypermethylation of PM20D1 in PD [82] . Additionally, several studies have focused on genetic variants that correlate with the expression level of the gene.…”

Section: Parkinson'smentioning

confidence: 99%

“…In the same tissues, the risk PD variant rs823118-T, located between RAB29 and NUCKS1, increases PM20D1 methylation and affects the expression of RAB29 and NUCKS1 [64] . Goldstein et al (2021) found evidence suggesting that the risk non-coding variant rs823114-A, located upstream of the NUCKS1 gene, has an eQTL and mQTL effect on PM20D1 and other genes in the PARK16 locus [83] . Additionally, Cibulka et al (2022) reported that minor allele A for rs708727 in SLC41A1 is associated with PD in the Slovak population [37] .…”

Section: Parkinson'smentioning

confidence: 99%

The many roles of the Alzheimer-associated gene PM20D1

Garro-Núñez¹,

Mora-Cubillo²,

Fonseca-Bone³

et al. 2022

J Transl Genet Genom

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PM20D1 is a little studied enzyme until recently, belonging to the mammalian M20 peptidase family, which catalyzes both the synthesis and hydrolysis of N-acyl amino acids (NAAs). NAAs are bioactive lipids biosynthesized from free fatty acids and free amino acids. These molecules have been associated with many biological functions; however, most of the biochemical mechanisms have not yet been described. The best-known biochemical mechanism is the one involved in thermogenesis, which also has implications for reactive oxygen species levels and cell preservation. In the last few years, genetic variation in PM20D1, as well as changes in its methylation and expression levels, have been reported to be associated with several disease phenotypes, including Alzheimer’s disease. In this review, we explore the current knowledge regarding the PM20D1 gene, including aspects such as its biology, potential functions, regulation of its expression, and role in different phenotypes such as Alzheimer’s disease, obesity, Parkinson’s disease, and several other disorders.

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PARK16 locus: Differential effects of the non-coding rs823114 on Parkinson’s disease risk, RNA expression, and DNA methylation

Cited by 5 publications

References 19 publications

MAPT Locus in Parkinson’s Disease Patients of Ashkenazi Origin: A Stratified Analysis

MAPT Locus in Parkinson’s Disease Patients of Ashkenazi Origin: A Stratified Analysis

Relationship between Nutrition, Lifestyle, and Neurodegenerative Disease: Lessons from ADH1B, CYP1A2 and MTHFR

The many roles of the Alzheimer-associated gene PM20D1

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