A Mendelian Randomization Study Of Factors Associated With Parkinson’s Disease

Observational studies have identified many factors associated with Parkinson’s disease(PD).However,conflicting results occur in some observational studies due to constraints within the study design,such as sample size and unmeasurable confounding factors.Inconsistency in evidence can lead to an incorrectly conducted randomized controlled trial(RCT),thus wasting both human and financial resources.Mendelian randomization(MR)study is an epidemiological method that uses genetic variation as an instrumental variable to infer causal association between exposure and outcome.The principle of MR is similar to that of RCT,and is therefore also known as a "natural RCT".Leveraging this advantage,MR studies can better avoid bias caused by confounding factors,thereby providing evidence of a level higher than that of observational studies and hold special value in exploring the etiology of diseases and potential drug targets.Genetic loci and single nucleotide polymorphisms linked to PD risk,onset age,and progression were found,providing a chance to employ MR framework for causal analysis of exposure and PD association.In this thesis,three two-sample MR studies were conducted to analyze the causal associations between exposures and PD.The first part explored the causal association between the gut microbiotaderived metabolites trimethylamine N-oxide(TMAO)and its precursors betaine,carnitine,and choline and PD.This study has revealed suggestive evidence that suggest a negative causal effect of TMAO on the risk of motor fluctuations and carnitine on the risk of insomnia in PD.In contrast,betaine has shown a positive causal effect on the Hoehn-Yahr staging,the Unified Parkinson’s Disease Rating Scale(UPDRS)Part Ⅲscore and the risk of motor fluctuations in PD,as well as choline has shown a positive causal effect on the UPDRS Ⅳ score and the modified Schwab and England Activities of Daily Living Scale(SEADL)score in PD.The second part explored the causal association between epigenetic acceleration and PD.This study has revealed significant statistical evidence indicating a causal effect of epigenetic acceleration on reducing the risk of PD.There is suggestive statistical evidence that epigenetic acceleration may lead to higher risk of motor fluctuations,dementia,depression,and lower scores on Mini-Mental State Examination and modified SEADL in PD.The third part explored the causal association between retinal thickness and PD.This study has revealed significant statistical evidence indicating a causal effect between a decrease in retinal nerve fibre layer(RNFL)thickness and a decrease in the risk of constipation in PD.There is also suggestive statistical evidence of a causal effect between a decrease in RNFL thickness and a decrease in UPDRS total score,as well as a decrease in ganglion cell inner plexiform layer(GCIPL)thickness leading to a decrease in the risk of constipation,but an increase in the risks of insomnia,rapid eye movement sleep behavior disorder,and depression in PD.In conclusion,this thesis provides genetic evidence for a causal association between the gut microbiota-derived metabolites TMAO and its precursors,epigenetic acceleration,RNFL and GCIPL thickness and PD.