scholarly journals Tendency towards being a “Morning person” increases risk of Parkinson’s disease: evidence from Mendelian randomisation

2018 ◽  
Author(s):  
AJ Noyce ◽  
DA Kia ◽  
K Heilbron ◽  
JEC Jepson ◽  
G Hemani ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Circadian Rhythm ◽  
Causal Relationship ◽  
Odds Ratio ◽  
Causal Effect ◽  
Coffee Consumption ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
Effect Estimate

AbstractBackgroundCircadian rhythm may play a role in neurodegenerative diseases such as Parkinson’s disease (PD). Chronotype is the behavioural manifestation of circadian rhythm and Mendelian randomisation (MR) involves the use of genetic variants to explore causal effects of exposures on outcomes. This study aimed to explore a causal relationship between chronotype and coffee consumption on risk of PD.MethodsTwo-sample MR was undertaken using publicly available GWAS data. Associations between genetic instrumental variables (IV) and “morning person” (one extreme of chronotype) were obtained from the personal genetics company 23andMe, Inc., and UK Biobank, and consisted of the per-allele odds ratio of being a “morning person” for 15 independent variants. The per-allele difference in log-odds of PD for each variant was estimated from a recent meta-analysis. The inverse variance weight method was used to estimate an odds ratio (OR) for the effect of being a “morning person” on PD. Additional MR methods were used to check for bias in the IVW estimate, arising through violation of MR assumptions. The results were compared to analyses employing a genetic instrument of coffee consumption, because coffee consumption has been previously inversely linked to PD.FindingsBeing a “morning person” was causally linked with risk of PD (OR 1⋅27; 95% confidence interval 1⋅06-1⋅51; p=0⋅012). Sensitivity analyses did not suggest that invalid instruments were biasing the effect estimate and there was no evidence for a reverse causal relationship between liability for PD and chronotype. There was no robust evidence for a causal effect of high coffee consumption using IV analysis, but the effect was imprecisely estimated (OR 1⋅12; 95% CI 0⋅89-1⋅42; p=0⋅22).InterpretationWe observed causal evidence to support the notion that being a “morning person”, a phenotype driven by the circadian clock, is associated with a higher risk of PD. Further work on the mechanisms is warranted and may lead to novel therapeutic targets.FundingNo specific funding source.

scholarly journals The Parkinson’s Disease Mendelian Randomization Research Portal

2019 ◽  
Author(s):  
Alastair J Noyce ◽  
Sara Bandres-Ciga ◽  
Jonggeol Kim ◽  
Karl Heilbron ◽  
Demis Kia ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
P Value ◽  
Phenotypic Traits ◽  
Genome Wide Association Studies ◽  
Summary Statistics

ABSTRACTBackgroundMendelian randomization (MR) is a method for exploring observational associations to find evidence of causality.ObjectiveTo apply MR between multiple risk factors/phenotypic traits (exposures) and Parkinson’s disease (PD) in a large, unbiased manner, and to create a public resource for research.MethodsWe used two-sample MR in which the summary statistics relating to SNPs from genome wide association studies (GWASes) of 5,839 exposures curated on MR Base were used to assess causal relationships with PD. We selected the highest quality exposure GWASes for this report (n=401). For the disease outcome, summary statistics from the largest published PD GWAS were used. For each exposure, the causal effect on PD was assessed using the inverse variance weighted (IVW) method, followed by a range of sensitivity analyses. We used a false discovery rate (FDR) corrected p-value of <0.05 from the IVW analysis to prioritize traits of interest.ResultsWe observed evidence for causal associations between twelve exposures and risk of PD. Of these, nine were causal effects related to increasing adiposity and decreasing risk of PD. The remaining top exposures that affected PD risk were tea drinking, time spent watching television and forced vital capacity, but the latter two appeared to be biased by violations of underlying MR assumptions.DiscussionWe present a new platform which offers MR analyses for a total of 5,839 GWASes versus the largest PD GWASes available (https://pdgenetics.shinyapps.io/pdgenetics/). Alongside, we report further evidence to support a causal role for adiposity on lowering the risk of PD.

scholarly journals Lack of Causal Effects or Genetic Correlation between Restless Legs Syndrome and Parkinson’s Disease

2021 ◽  
Author(s):  
Mehrdad A Estiar ◽  
Konstantin Senkevich ◽  
Eric Yu ◽  
Parizad Varghaei ◽  
Lynne Krohn ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Correlation ◽  
Causal Relationship ◽  
Restless Legs Syndrome ◽  
Causal Effect ◽  
Epidemiological Studies ◽  
Restless Legs ◽  
Inverse Variance ◽  
Effect Of Pd

AbstractBackgroundEpidemiological studies have reported association between Parkinson’s disease (PD) and restless legs syndrome (RLS).ObjectivesWe aimed to use genetic data to study whether these two disorders are causally linked or share genetic architecture.MethodsWe performed two-sample Mendelian randomization (MR) and linkage disequilibrium score regression (LDSC) using summary statistics from recent genome-wide meta-analyses of PD and RLS.ResultsWe found no evidence for a causal relationship between RLS (as the exposure) and PD (as the outcome, inverse variance-weighted; b=-0.003, se=0.031, p=0.916, F-statistic=217.5). Reverse MR also did not demonstrate any causal effect of PD on RLS (inverse variance-weighted; b=-0.012, se=0.023, p=0.592, F-statistic=191.7). LDSC analysis demonstrated lack of genetic correlation between RLS and PD (rg=-0.028, se=0.042, p=0.507).ConclusionsThere was no evidence for a causal relationship or genetic correlation between RLS and PD. The associations observed in epidemiological studies could be, in part, attributed to confounding or non-genetic determinants.

scholarly journals Bias in two-sample Mendelian randomization when using heritable covariable-adjusted summary associations

2021 ◽  
Author(s):  
Fernando Pires Hartwig ◽  
Kate Tilling ◽  
George Davey Smith ◽  
Deborah A Lawlor ◽  
Maria Carolina Borges
Keyword(s):  
Waist Circumference ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Real Data ◽  
Sensitivity Analyses ◽  
Effect Estimate ◽  
Genome Wide Association Studies ◽  
Residual Confounding

Abstract Background Two-sample Mendelian randomization (MR) allows the use of freely accessible summary association results from genome-wide association studies (GWAS) to estimate causal effects of modifiable exposures on outcomes. Some GWAS adjust for heritable covariables in an attempt to estimate direct effects of genetic variants on the trait of interest. One, both or neither of the exposure GWAS and outcome GWAS may have been adjusted for covariables. Methods We performed a simulation study comprising different scenarios that could motivate covariable adjustment in a GWAS and analysed real data to assess the influence of using covariable-adjusted summary association results in two-sample MR. Results In the absence of residual confounding between exposure and covariable, between exposure and outcome, and between covariable and outcome, using covariable-adjusted summary associations for two-sample MR eliminated bias due to horizontal pleiotropy. However, covariable adjustment led to bias in the presence of residual confounding (especially between the covariable and the outcome), even in the absence of horizontal pleiotropy (when the genetic variants would be valid instruments without covariable adjustment). In an analysis using real data from the Genetic Investigation of ANthropometric Traits (GIANT) consortium and UK Biobank, the causal effect estimate of waist circumference on blood pressure changed direction upon adjustment of waist circumference for body mass index. Conclusions Our findings indicate that using covariable-adjusted summary associations in MR should generally be avoided. When that is not possible, careful consideration of the causal relationships underlying the data (including potentially unmeasured confounders) is required to direct sensitivity analyses and interpret results with appropriate caution.

scholarly journals Genetic evidence for a causative effect of airflow obstruction on left ventricular filling: a Mendelian randomisation study

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Lars Harbaum ◽  
Jan K. Hennigs ◽  
Marcel Simon ◽  
Tim Oqueka ◽  
Henrik Watz ◽  
...  
Keyword(s):  
General Population ◽  
Genetic Variants ◽  
Airflow Obstruction ◽  
Left Ventricular ◽  
Sensitivity Analyses ◽  
Weighted Regression ◽  
Mendelian Randomisation ◽  
Effect Estimate ◽  
Genome Wide Association Studies ◽  
Inverse Variance

Abstract Background Observational studies on the general population have suggested that airflow obstruction associates with left ventricular (LV) filling. To limit the influence of environmental risk factors/exposures, we used a Mendelian randomisation (MR) approach based on common genetic variations and tested whether a causative relation between airflow obstruction and LV filling can be detected. Methods We used summary statistics from large genome-wide association studies (GWAS) on the ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) measured by spirometry and the LV end-diastolic volume (LVEDV) as assessed by cardiac magnetic resonance imaging. The primary MR was based on an inverse variance weighted regression. Various complementary MR methods and subsets of the instrument variables were used to assess the plausibility of the findings. Results We obtained consistent evidence in our primary MR analysis and subsequent sensitivity analyses that reducing airflow obstruction leads to increased inflow to the LV (odds ratio [OR] from inverse variance weighted regression 1.05, 95% confidence interval [CI] 1.01–1.09, P = 0.0172). Sensitivity analyses indicated a certain extent of negative horizontal pleiotropy and the estimate from biased-corrected MR-Egger was adjusted upward (OR 1.2, 95% CI 1.09–1.31, P < 0.001). Prioritisation of single genetic variants revealed rs995758, rs2070600 and rs7733410 as major contributors to the MR result. Conclusion Our findings indicate a causal relationship between airflow obstruction and LV filling in the general population providing genetic context to observational associations. The results suggest that targeting (even subclinical) airflow obstruction can lead to direct cardiac improvements, demonstrated by an increase in LVEDV. Functional annotation of single genetic variants contributing most to the causal effect estimate could help to prioritise biological underpinnings.

scholarly journals Effect of Basal Metabolic Rate on Cancer: A Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Jack C. M. Ng ◽  
C. Mary Schooling
Keyword(s):  
Growth Factor ◽  
Cancer Risk ◽  
Confidence Interval ◽  
Metabolic Rate ◽  
Basal Metabolic Rate ◽  
Odds Ratio ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Sensitivity Analyses ◽  
Insulin Like Growth Factor

Background: Basal metabolic rate is associated with cancer, but these observations are open to confounding. Limited evidence from Mendelian randomization studies exists, with inconclusive results. Moreover, whether basal metabolic rate has a similar role in cancer for men and women independent of insulin-like growth factor 1 increasing cancer risk has not been investigated.Methods: We conducted a two-sample Mendelian randomization study using summary data from the UK Biobank to estimate the causal effect of basal metabolic rate on cancer. Overall and sex-specific analysis and multiple sensitivity analyses were performed including multivariable Mendelian randomization to control for insulin-like growth factor 1.Results: We obtained 782 genetic variants strongly (p-value &lt; 5 × 10–8) and independently (r2 &lt; 0.01) predicting basal metabolic rate. Genetically predicted higher basal metabolic rate was associated with an increase in cancer risk overall (odds ratio, 1.06; 95% confidence interval, 1.02–1.10) with similar estimates by sex (odds ratio for men, 1.07; 95% confidence interval, 1.002–1.14; odds ratio for women, 1.06; 95% confidence interval, 0.995–1.12). Sensitivity analyses including adjustment for insulin-like growth factor 1 showed directionally consistent results.Conclusion: Higher basal metabolic rate might increase cancer risk. Basal metabolic rate as a potential modifiable target of cancer prevention warrants further study.

Chronic coffee consumption and striatal DAT-SPECT findings in Parkinson’s disease

2018 ◽  
Vol 39 (3) ◽  
pp. 551-555 ◽  
Author(s):  
Angelo Fabio Gigante ◽  
Artor Niccoli Asabella ◽  
Giovanni Iliceto ◽  
Tommaso Martino ◽  
Cristina Ferrari ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Coffee Consumption ◽  
Dat Spect

Physical activity and Parkinson’s disease: a two-sample Mendelian randomisation study

2020 ◽  
pp. jnnp-2020-324515
Author(s):  
Sebastian Baumeister ◽  
Christa Meisinger ◽  
Michael Leitzmann ◽  
Alexander Teumer ◽  
Martin Bahls ◽  
...  
Keyword(s):  
Physical Activity ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mendelian Randomisation

scholarly journals Prospective study of coffee consumption and risk of Parkinson's disease

2007 ◽  
Vol 62 (7) ◽  
pp. 908-915 ◽  
Author(s):  
K Sääksjärvi ◽  
P Knekt ◽  
H Rissanen ◽  
M A Laaksonen ◽  
A Reunanen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Prospective Study ◽  
Coffee Consumption

Rotigotine Improves Abnormal Circadian Rhythm of Blood Pressure in Parkinson’s Disease

2018 ◽  
Vol 79 (5-6) ◽  
pp. 281-286 ◽  
Author(s):  
Hisayoshi Oka ◽  
Atuso Nakahara ◽  
Tadashi Umehara
Keyword(s):  
Blood Pressure ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Circadian Rhythm ◽  
Time Course ◽  
Autonomic Failure ◽  
Not Given ◽  
Daily Lives ◽  
Dopaminergic Drugs ◽  
Autonomic Responses

Introduction: Cardiovascular autonomic failure is commonly associated with Parkinson’s disease (PD), affecting the daily lives of patients. Rotigotine was recently reported not to influence cardiovascular autonomic responses in contrast to other dopaminergic drugs. The effect of rotigotine on daily blood pressure (BP) fluctuations might reflect autonomic failure in patients with PD. Methods: Twenty-five PD patients who were receiving rotigotine and 12 patients not receiving rotigotine were recruited. Systolic BP during the daytime and nighttime was measured by 24-h BP monitoring at an interval of 2 years. The patients were divided into 3 groups according to the BP fluctuation type: dippers (nocturnal fall in BP ≥10%), non-dippers (0–10%), and risers (< 0%). The time course of BP was compared between the patients given rotigotine and those not given rotigotine. Results: Among the 25 patients who received rotigotine, the BP type worsened in 2 patients, was unchanged in 16 patients, and improved in 7 patients. Among the 12 patients who were not receiving rotigotine, the BP type worsened in 5 patients, was unchanged in 4 patients, and improved only in 3 patients (p = 0.042). Conclusion: Rotigotine improves the abnormal circadian rhythm of BP in patients with PD. Rotigotine was suggested to have favorable effects on cardiovascular autonomic responses and circadian rhythm in patients with PD.

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