Association between telomere length and Parkinson's disease: a Mendelian randomization study.

In this study, we examined the potential association of telomere length with Parkinson's disease (PD) using the publicly available genome-wide association study summary statistics from the International Parkinson's Disease Genomics Consortium involving up to 37,688 patients with PD and 449,056 controls in Mendelian randomization framework. The Mendelian randomization approach has the potential to investigate a causal relationship between a risk factor and a disease, avoiding confounding and reverse causation that often present in conventional epidemiological studies. We did not find that longer telomeres were associated with higher risks of PD (odds ratio: 1.18, 95% confidence interval: 0.94, 1.48, p = 0.15). Our study, therefore, did not provide evidence to support a potential causal relationship between telomere length and PD.

Chen R ，Zhan Y 《-》

Exploring the Causal Pathway From Telomere Length to Coronary Heart Disease: A Network Mendelian Randomization Study.

Observational studies have found shorter leukocyte telomere length (TL) to be a risk factor for coronary heart disease (CHD), and recently the association was suggested to be causal. However, the relationship between TL and common metabolic risk factors for CHD is not well understood. Whether these risk factors could explain pathways from TL to CHD warrants further attention. To examine whether metabolic risk factors for CHD mediate the causal pathway from short TL to increased risk of CHD using a network Mendelian randomization design. Summary statistics from several genome-wide association studies were used in a 2-sample Mendelian randomization study design. Network Mendelian randomization analysis-an approach using genetic variants as the instrumental variables for both the exposure and mediator to infer causality-was performed to examine the causal association between telomeres and CHD and metabolic risk factors. Summary statistics from the ENGAGE Telomere Consortium were used (n=37 684) as a TL genetic instrument, CARDIoGRAMplusC4D Consortium data were used (case=22 233 and control=64 762) for CHD, and other consortia data were used for metabolic traits (fasting insulin, triglyceride, total cholesterol, low-density lipoprotein cholesterol, fasting glucose, diabetes mellitus, glycohemoglobin, body mass index, waist circumference, and waist:hip ratio). One-unit increase of genetically determined TL was associated with -0.07 (95% confidence interval, -0.01 to -0.12; P=0.01) lower log-transformed fasting insulin (pmol/L) and 21% lower odds (95% confidence interval, 3-35; P=0.02) of CHD. Higher genetically determined log-transformed fasting insulin level was associated with higher CHD risk (odds ratio, 1.86; 95% confidence interval, 1.01-3.41; P=0.04). Overall, our findings support a role of insulin as a mediator on the causal pathway from shorter telomeres to CHD pathogenesis.

Zhan Y ，Karlsson IK ，Karlsson R ，Tillander A ，Reynolds CA ，Pedersen NL ，Hägg S ... -  《-》

Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.

Telomeres Mendelian Randomization Collaboration ，Haycock PC ，Burgess S ，Nounu A ，Zheng J ，Okoli GN ，Bowden J ，Wade KH ，Timpson NJ ，Evans DM ，Willeit P ，Aviv A ，Gaunt TR ，Hemani G ，Mangino M ，Ellis HP ，Kurian KM ，Pooley KA ，Eeles RA ，Lee JE ，Fang S ，Chen WV ，Law MH ，Bowdler LM ，Iles MM ，Yang Q ，Worrall BB ，Markus HS ，Hung RJ ，Amos CI ，Spurdle AB ，Thompson DJ ，O'Mara TA ，Wolpin B ，Amundadottir L ，Stolzenberg-Solomon R ，Trichopoulou A ，Onland-Moret NC ，Lund E ，Duell EJ ，Canzian F ，Severi G ，Overvad K ，Gunter MJ ，Tumino R ，Svenson U ，van Rij A ，Baas AF ，Bown MJ ，Samani NJ ，van t'Hof FNG ，Tromp G ，Jones GT ，Kuivaniemi H ，Elmore JR ，Johansson M ，Mckay J ，Scelo G ，Carreras-Torres R ，Gaborieau V ，Brennan P ，Bracci PM ，Neale RE ，Olson SH ，Gallinger S ，Li D ，Petersen GM ，Risch HA ，Klein AP ，Han J ，Abnet CC ，Freedman ND ，Taylor PR ，Maris JM ，Aben KK ，Kiemeney LA ，Vermeulen SH ，Wiencke JK ，Walsh KM ，Wrensch M ，Rice T ，Turnbull C ，Litchfield K ，Paternoster L ，Standl M ，Abecasis GR ，SanGiovanni JP ，Li Y ，Mijatovic V ，Sapkota Y ，Low SK ，Zondervan KT ，Montgomery GW ，Nyholt DR ，van Heel DA ，Hunt K ，Arking DE ，Ashar FN ，Sotoodehnia N ，Woo D ，Rosand J ，Comeau ME ，Brown WM ，Silverman EK ，Hokanson JE ，Cho MH ，Hui J ，Ferreira MA ，Thompson PJ ，Morrison AC ，Felix JF ，Smith NL ，Christiano AM ，Petukhova L ，Betz RC ，Fan X ，Zhang X ，Zhu C ，Langefeld CD ，Thompson SD ，Wang F ，Lin X ，Schwartz DA ，Fingerlin T ，Rotter JI ，Cotch MF ，Jensen RA ，Munz M ，Dommisch H ，Schaefer AS ，Han F ，Ollila HM ，Hillary RP ，Albagha O ，Ralston SH ，Zeng C ，Zheng W ，Shu XO ，Reis A ，Uebe S ，Hüffmeier U ，Kawamura Y ，Otowa T ，Sasaki T ，Hibberd ML ，Davila S ，Xie G ，Siminovitch K ，Bei JX ，Zeng YX ，Försti A ，Chen B ，Landi S ，Franke A ，Fischer A ，Ellinghaus D ，Flores C ，Noth I ，Ma SF ，Foo JN ，Liu J ，Kim JW ，Cox DG ，Delattre O ，Mirabeau O ，Skibola CF ，Tang CS ，Garcia-Barcelo M ，Chang KP ，Su WH ，Chang YS ，Martin NG ，Gordon S ，Wade TD ，Lee C ，Kubo M ，Cha PC ，Nakamura Y ，Levy D ，Kimura M ，Hwang SJ ，Hunt S ，Spector T ，Soranzo N ，Manichaikul AW ，Barr RG ，Kahali B ，Speliotes E ，Yerges-Armstrong LM ，Cheng CY ，Jonas JB ，Wong TY ，Fogh I ，Lin K ，Powell JF ，Rice K ，Relton CL ，Martin RM ，Davey Smith G ... -  《-》

The Parkinson's Disease Mendelian Randomization Research Portal.

Mendelian randomization is a method for exploring observational associations to find evidence of causality. To apply Mendelian randomization between risk factors/phenotypic traits (exposures) and PD in a large, unbiased manner, and to create a public resource for research. We used two-sample Mendelian randomization in which the summary statistics relating to single-nucleotide polymorphisms from 5,839 genome-wide association studies of exposures were used to assess causal relationships with PD. We selected the highest-quality exposure genome-wide association studies for this report (n = 401). For the disease outcome, summary statistics from the largest published PD genome-wide association studies were used. For each exposure, the causal effect on PD was assessed using the inverse variance weighted method, followed by a range of sensitivity analyses. We used a false discovery rate of 5% from the inverse variance weighted analysis to prioritize exposures of interest. We observed evidence for causal associations between 12 exposures and risk of PD. Of these, nine were effects related to increasing adiposity and decreasing risk of PD. The remaining top three exposures that affected PD risk were tea drinking, time spent watching television, and forced vital capacity, but these may have been biased and were less convincing. Other exposures at nominal statistical significance included inverse effects of smoking and alcohol. We present a new platform which offers Mendelian randomization analyses for a total of 5,839 genome-wide association studies versus the largest PD genome-wide association studies available (https://pdgenetics.shinyapps.io/MRportal/). Alongside, we report further evidence to support a causal role for adiposity on lowering the risk of PD. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Noyce AJ ，Bandres-Ciga S ，Kim J ，Heilbron K ，Kia D ，Hemani G ，Xue A ，Lawlor DA ，Smith GD ，Duran R ，Gan-Or Z ，Blauwendraat C ，Gibbs JR ，23andMe Research Team5, International Parkinson's Disease Genomics Consortium (IPDGC) ，Hinds DA ，Yang J ，Visscher P ，Cuzick J ，Morris H ，Hardy J ，Wood NW ，Nalls MA ，Singleton AB ... -  《-》

A Mendelian randomization study investigating the causal role of inflammation on Parkinson's disease.

There is increasing evidence for inflammation as a determinant in the pathogenesis of Parkinson's disease, but its role in parkinsonian neurodegeneration remains elusive. It is not clear whether inflammatory cascades are causes or consequences of dopamine neuron death. In the present study, we aim to perform an in-depth statistical investigation of the causal relationship between inflammation and Parkinson's disease using a two-sample Mendelian randomization design. Genetic instruments were selected using summary-level data from the largest genome-wide association studies to date (sample size ranging from 13 955 to 204 402 individuals) conducted on a European population for the following inflammation biomarkers: C-reactive protein, interleukin-6, interleukin 1 receptor antagonist and tumour necrosis factor α. Genetic association data on Parkinson's disease (56 306 cases and 1 417 791 controls) and age at onset of Parkinson's disease (28 568 cases) were obtained from the International Parkinson's Disease Genomics Consortium. On primary analysis, causal associations were estimated on sets of strong (P-value < 5 × 10-8; F-statistic > 10) and independent (linkage disequilibrium r2 < 0.001) genetic instruments using the inverse-variance weighted method. In sensitivity analysis, we estimated causal effects using robust Mendelian randomization methods and after removing pleiotropic genetic variants. Reverse causation was also explored. We repeated the analysis on different data sources for inflammatory biomarkers to check the consistency of the findings. In all the three data sources selected for interleukin-6, we found statistical evidence for an earlier age at onset of Parkinson's disease associated with increased interleukin-6 concentration [years difference per 1 log-unit increase = -2.364, 95% confidence interval (CI) = -4.789-0.060; years difference per 1 log-unit increase = -2.011, 95% CI = -3.706 to -0.317; years difference per 1 log-unit increase = -1.569, 95% CI = -2.891 to -0.247]. We did not observe any statistical evidence for causal effects of C-reactive protein, interleukin 1 receptor antagonist and tumour necrosis factor α on both Parkinson's disease and its age at onset. Results after excluding possible pleiotropic genetic variants were consistent with findings from primary analyses. When investigating reverse causation, we did not find evidence for a causal effect of Parkinson's disease or age at onset on any biomarkers of inflammation. We found evidence for a causal association between the onset of Parkinson's disease and interleukin-6. The findings of this study suggest that the pro-inflammatory activity of the interleukin-6 cytokine could be a determinant of prodromal Parkinson's disease.

Bottigliengo D ，Foco L ，Seibler P ，Klein C ，König IR ，Del Greco M F ... -  《-》