scholarly journals Bidirectional Mendelian randomization analysis of shared genetic signals between coexisting neurodegenerative disorders to decipher underlying causal pathways

2019 ◽  
Author(s):  
Sandeep Grover ◽  
Keyword(s):  
Multiple Sclerosis ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Macular Degeneration ◽  
Neurodegenerative Disorders ◽  
Mendelian Randomization ◽  
Age Related Macular Degeneration ◽  
European Ancestry ◽  
Age Related

ABSTRACTOBJECTIVETo investigate whether coexistence of various neurodegenerative disorders is coincidental or biologically connected.DESIGNTwo sample Mendelian randomization using summary effect estimatesSETTINGGenetic data taken on various neurodegenerative disorders from various cohorts comprising individuals predominantly of European ancestry.PARTICIPANTSInternational Genomics of Alzheimer’s patients (IGAP), project MinE, International Age-related Macular Degeneration Consortium (IAMDGC), International Multiple Sclerosis Genetics Consortium (IMSGC), International Parkinson’s Disease Genomics Consortium (IPDGC)MAIN OUTCOME MEASURESAlzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS), Age related macular degeneration (AMD), Multiple sclerosis (MS) and Parkinson’s disease (PD).RESULTSA Bonferroni corrected threshold of P=0.005 was considered to be significant, and P<0.05 was considered suggestive of evidence for a potential association. I observed a risky effect of PD on ALS (OR = 1.126, 95% CI = 1.059-1.198, P = 0.005). Using AD as exposure and PD as outcome, I observed a risky effect of AD on PD using all the MR methods with strongest results using MBE method (OR = 2.072, 95% CI = 1.006-4.028, P = 0.0416). Genetic predisposition to AD was further observed to be a risky for AMD (OR = 1.759, 95% CI = 1.040-1.974, P = 0.0363). On the contrary, AMD was observed to be strongly protective towards MS (OR = 0.861, 95% CI = 0.776-0.955, P = 0.0059).CONCLUSIONSMy findings are consistent with the previously observed relative occurrence of co-existing neurodegenerative diseases or overlapping symptoms among neurodegenerative diseases.

scholarly journals Sleep, pain, and neurodegeneration: A Mendelian randomization study

2021 ◽  
Author(s):  
Sandeep Grover ◽  
Manu Sharma ◽  
Keyword(s):  
Multiple Sclerosis ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Risk Factor ◽  
Macular Degeneration ◽  
Mendelian Randomization ◽  
Age Related Macular Degeneration ◽  
Suggestive Evidence ◽  
Age Related

AbstractObjectiveTo examine whether sleep and pain-related traits have a causal effect on the risk of neurodegeneration.DesignTwo-sample Mendelian randomization using an inverse-variance weighted (IVW) estimate of the summary effect estimates.SettingGenetic data on sleep and pain-related traits and neurodegenerative disorders (NDD) from various cohorts comprising individuals predominantly of European ancestry.ParticipantsParticipants from the International Sleep Genetic Epidemiology Consortium (ISGEC), UK Biobank sleep and chronotype research group, International Genomics of Alzheimer’s patients (IGAP), project MinE, International Age-related Macular Degeneration Consortium (IAMDGC), International Multiple Sclerosis Genetics Consortium (IMSGC), International Parkinson’s Disease Genomics Consortium (IPDGC)ExposuresSelf-reported chronotype (CHR), morning preference (MP), insomnia symptoms (INS), sleep duration (SP), short sleep (SS), long sleep (LS), and multisite chronic pain (MCP)Main outcome measuresAge-related macular degeneration (AMD), Alzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS), Multiple sclerosis (MS), and Parkinson’s disease (PD)ResultsWe considered a threshold of P=0.00142 as significant accounting for multiple testing, and P<0.05 was considered to be suggestive evidence for a potential association. Using direct MR, MP was observed as the strongest risk factor for AMD (ORIVW = 1.19, 95% CI 1.08, 1.32, P = 0.00073). We observed suggestive evidence of influence of different sleep traits on neurodegeneration: CHR on AMD (ORIVW = 1.27, 95% CI 1.08, 1.49, P = 0.0034), SS on AD (ORIVW 1.26, 95% CI 1.08, 1.46, P = 0.0044), and INS on ALS (ORIVW 1.55, 95% CI 1.12, 2.14, P = 0.0123). The association of SS with AD was, however, lost after the exclusion of overlapping UKB samples. Using pain as exposure, our study failed to observe any role of pain in neurodegeneration. Results were largely robust to reverse causal analyses and sensitivity analyses accounting for horizontal pleiotropy.ConclusionsOur study highlighted the role of morning preference as a risk factor for AMD and provided suggestive evidence of different sleep traits on a wide spectrum of neurodegenerative diseases.

scholarly journals Increased risk of Parkinson’s disease among patients with age-related macular degeneration

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Po-Yu Jay Chen ◽  
Lei Wan ◽  
Jung-Nien Lai ◽  
Chih Sheng Chen ◽  
Jamie Jiin-Yi Chen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Macular Degeneration ◽  
Cox Regression ◽  
Age Related Macular Degeneration ◽  
Rank Test ◽  
Cox Regression Analysis ◽  
Age Related ◽  
Increased Risk

Abstract Background This study aimed to investigate the risk of Parkinson’s disease (PD) among patients with age-related macular degeneration (AMD) and its association with confounding comorbidities. Methods A population-based retrospective cohort study was conducted using Longitudinal Health Insurance Database 2000 (LHID2000). We established AMD and non-AMD cohorts from January 1, 2000 to December 31, 2012 to determine the diagnosis of PD. A total of 20,848 patients were enrolled, with 10,424 AMD patients and 10,424 controls matched for age, sex, and index year at a 1:1 ratio. The follow-up period was from the index date of AMD diagnosis to the diagnosis of PD, death, withdrawal from the insurance program, or end of 2013. Multivariable Cox regression analysis was performed to examine the hazard ratio (HR) and 95% confidence interval (CI) for the risk of PD between the AMD and non-AMD cohorts. Result After adjusting for potential confounders, there was a higher risk of developing PD in the AMD cohort than in the non-AMD cohort (adjusted HR = 1.35, 95% CI = 1.16–1.58). A significant association could be observed in both female (aHR = 1.42, 95% CI = 1.13–1.80) and male (aHR = 1.28, 95% CI = 1.05–1.57) patients, aged more than 60 years (60–69: aHR = 1.51, 95% CI = 1.09–2.09, 70–79: aHR = 1.30, 95% CI = 1.05–1.60; 80–100: aHR = 1.40, 95% CI = 1.01–1.95), and with more than one comorbidity (aHR = 1.40, 95% CI = 1.20–1.64). A significant association between increased risk of PD and AMD was observed among patients with comorbidities of osteoporosis (aHR = 1.68, 95% CI = 1.22–2.33), diabetes (aHR = 1.41, 95% CI = 1.12–1.78) and hypertension (aHR = 1.36, 95% CI = 1.15–1.62) and medications of statin (aHR = 1.42, 95% CI = 1.19–1.69) and calcium channel blocker (CCB) (aHR = 1.32, 95% CI = 1.11–1.58). The cumulative incidence of PD was significantly higher over the 12-year follow-up period in AMD cohort (log-rank test, p < 0.001). Conclusions Patients with AMD may exhibit a higher risk of PD than those without AMD.

New Drug Update 2020

2021 ◽  
Vol 36 (4) ◽  
pp. 176-186
Author(s):  
Daniel A. Hussar ◽  
Laura A. Finn
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Older People ◽  
Macular Degeneration ◽  
Age Related Macular Degeneration ◽  
New Drugs ◽  
Medical Problems ◽  
New Agents ◽  
New Drug ◽  
Age Related

Five new drugs marketed within the last year that are used for medical problems often experienced by older people have been selected for consideration in this review. The uses and most important properties of these agents are discussed, and a rating for each new drug is determined using the New Drug Comparison Rating (NDCR) system developed by the author (DAH). Advantages, disadvantages, and other important information regarding each new drug are identified and used as the basis for determining the rating. The drugs considered include new agents indicated for the treatment of patients with hypercholesterolemia, Parkinson's disease, insomnia, schizophrenia, and age-related macular degeneration.

scholarly journals Casual Effect of Serum Lipid Biomarkers On Early Age-Related Macular Degeneration Using Mendelian Randomization

2021 ◽  
Author(s):  
Fen-Fen Li ◽  
Yuqin Wang ◽  
Qi Chen ◽  
Lue Xiang ◽  
Feng-Qin Rao ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Serum Lipid ◽  
Mendelian Randomization ◽  
Density Lipoprotein ◽  
Lipid Biomarkers ◽  
Age Related Macular Degeneration ◽  
Lipoprotein Cholesterol ◽  
European Ancestry ◽  
Age Related ◽  
Increased Risk

Abstract Background Age-related macular degeneration (AMD) is one of the major causes of vision loss. Early AMD needs to be taken seriously, whereas lipid biomarkers’ casual effects on early AMD remain unclear. Methods In this study, a two-sample Mendelian randomization (MR) analysis was performed to systematically assess the causal relationships between seven serum lipid biomarkers, consisting of apolipoprotein A (ApoA), apolipoprotein B (ApoB), total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), direct low-density lipoprotein cholesterol (LDL-C), lipoprotein A [Lp(a)], and triglycerides (TG), and the risk of early AMD. Totally, 14,034 cases and 91,214 controls of European ancestry were included in the analysis (Number of SNPs = 11,304,110). Results MR estimates showed that a higher HDL-C level was strongly associated with increased risk of early AMD (OR = 1.25, 95% CI: 1.15-1.35, P = 2.61 × 10−8). In addition, the level of ApoA was also positively associated with the risk of early AMD (OR = 2.04, 95% CI: 1.50-2.77, P = 6.27 × 10−6). Conversely, higher LDL-C levels significantly decreased the risk of early AMD (OR = 0.90, 95% CI: 0.85-0.96, P = 2.03 × 10−3). In addition to LDL-C, higher levels of ApoB and TG were found to be positively associated with early AMD risk. Sensitivity analyses further supported these associations. Moreover, multivariable MR analyses, adjusting for the effects of correlated lipid biomarkers yielded similar results. Conclusion This study addresses the question of causality relationships that elevated circulating HDL-C/ApoA levels and increased risk of early AMD, whereas LDL-C, ApoB, and TG specifically reduce the risk of early AMD. These findings contribute to our better understanding of the role of lipid metabolism in drusen formation, particularly in early AMD development.

scholarly journals Role of educational attainment, cognitive performance and intelligence in neurodegeneration: a bidirectional Mendelian randomization study

2019 ◽  
Author(s):  
Sandeep Grover ◽  
Keyword(s):  
Educational Attainment ◽  
Neurodegenerative Diseases ◽  
Cognitive Performance ◽  
Mendelian Randomization ◽  
Late Onset ◽  
Age Related Macular Degeneration ◽  
European Ancestry ◽  
Reverse Causality ◽  
Age Related

AbstractI examined the potential bi-directional causality between educational attainment (EA) (n = 766,345) and age related macular degeneration (AMD) (cases (n) =16144, controls (n) =17832) using the summary GWAS datasets on individuals with European ancestry. I used datasets on other late-onset neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD) as controls to validate the findings. A risky effect of EA on AMD was observed (OR=1.318, 95% CI=1.080 −1.610, P=0.0068) after ruling out potential pleiotropy and absence of reverse causality. I further replicated previously observed protective and risky causal associations of EA with AD and PD.

scholarly journals Causal Association between Periodontitis and Parkinson’s Disease: A Bidirectional Mendelian Randomization Study

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 772
Author(s):  
João Botelho ◽  
Vanessa Machado ◽  
José João Mendes ◽  
Paulo Mascarenhas
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Instrumental Variables ◽  
Mendelian Randomization ◽  
Association Studies ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genetic Liability ◽  
Bidirectional Association

The latest evidence revealed a possible association between periodontitis and Parkinson’s disease (PD). We explored the causal relationship of this bidirectional association through two-sample Mendelian randomization (MR) in European ancestry populations. To this end, we used openly accessible data of genome-wide association studies (GWAS) on periodontitis and PD. As instrumental variables for periodontitis, seventeen single-nucleotide polymorphisms (SNPs) from a GWAS of periodontitis (1817 periodontitis cases vs. 2215 controls) and eight non-overlapping SNPs of periodontitis from an additional GWAS for validation purposes. Instrumental variables to explore for the reverse causation included forty-five SNPs from a GWAS of PD (20,184 cases and 397,324 controls). Multiple approaches of MR were carried-out. There was no evidence of genetic liability of periodontitis being associated with a higher risk of PD (B = −0.0003, Standard Error [SE] 0.0003, p = 0.26). The eight independent SNPs (B = −0.0000, SE 0.0001, p = 0.99) validated this outcome. We also found no association of genetically primed PD towards periodontitis (B = −0.0001, SE 0.0001, p = 0.19). These MR study findings do not support a bidirectional causal genetic liability between periodontitis and PD. Further GWAS studies are needed to confirm the consistency of these results.

The effects of eight serum lipid biomarkers on age-related macular degeneration risk: a Mendelian randomization study

2020 ◽  
Author(s):  
Xikun Han ◽  
Jue-Sheng Ong ◽  
Alex W Hewitt ◽  
Puya Gharahkhani ◽  
Stuart MacGregor
Keyword(s):  
Macular Degeneration ◽  
Serum Lipid ◽  
Mendelian Randomization ◽  
Density Lipoprotein ◽  
Lipid Biomarkers ◽  
Age Related Macular Degeneration ◽  
Apolipoprotein A1 ◽  
Lipoprotein Cholesterol ◽  
European Descent ◽  
Age Related

Abstract Background Age-related macular degeneration (AMD) is a leading cause of vision loss. Whereas lipids have been studied extensively to understand their effects on cardiovascular diseases, their relationship with AMD remains unclear. Methods Two-sample Mendelian randomization (MR) analyses were performed to systematically evaluate the causal relationships between eight serum lipid biomarkers, consisting of apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), direct low-density lipoprotein cholesterol (LDL-C), lipoprotein A [Lp(a)], triglycerides (TG) and non-HDL cholesterol (non-HDL-C), and the risk of different AMD stages and subtypes. We derived 64–407 genetic instruments for eight serum lipid biomarkers in 419 649 participants of European descent from the UK Biobank cohort. We conducted genome-wide association studies (GWAS) for 12 711 advanced AMD cases [8544 choroidal neovascularization (CNV) and 2656 geographic atrophy (GA) specific AMD subtypes] and 5336 intermediate AMD cases with 14 590 controls of European descent from the International AMD Genomics Consortium. Results Higher genetically predicted HDL-C and ApoA1 levels increased the risk of all AMD subtypes. LDL-C, ApoB, CHOL and non-HDL-C levels were associated with decreased risk of intermediate and GA AMD but not with CNV. Genetically predicted TG levels were associated with decreased risk of different AMD subtypes. Sensitivity analyses revealed no evidence for directional pleiotropy effects. In our multivariable MR analyses, adjusting for the effects of correlated lipid biomarkers yielded similar results. Conclusion These results suggest the role of lipid metabolism in drusen formation and particularly in AMD development at the early and intermediate stages. Mechanistic studies are warranted to investigate the utility of lipid pathways for therapeutic treatment in preventing AMD.

scholarly journals Pink1/Parkin link inflammation, mitochondrial stress, and neurodegeneration

2018 ◽  
Vol 217 (10) ◽  
pp. 3327-3329 ◽  
Author(s):  
Laura E. Newman ◽  
Gerald S. Shadel
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dna ◽  
Neurodegenerative Diseases ◽  
Mitochondrial Stress ◽  
Mitochondrial Dna Mutations ◽  
Dna Mutations ◽  
Age Related ◽  
Sting Pathway

What causes inflammation in age-related neurodegenerative diseases remains a mystery. Sliter et al. (2018. Nature. https://doi.org/10.1038/s41586-018-0448-9) show that, when damaged mitochondria cannot be removed by mitophagy, stress from exercise or mitochondrial DNA mutations activates the proinflammatory cGAS–STING pathway that may contribute to Parkinson’s disease.

scholarly journals Brain Aging and Gut–Brain Axis

Nutrients ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 424 ◽  
Author(s):  
M. Mohajeri
Keyword(s):  
Multiple Sclerosis ◽  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Brain Development ◽  
Neurodegenerative Disorders ◽  
Gut Microbiome ◽  
Brain Aging ◽  
And Function

In the last decade, the microbiome in general and the gut microbiome in particular have been associated not only to brain development and function, but also to the pathophysiology of brain aging and to neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), depression, or multiple sclerosis (MS) [...]

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