Alzheimer’s disease is a progressive and fatal neurodegenerative disease affecting 50 million people worldwide, characterized by memory loss and neuronal degeneration. Current treatments have limited efficacy and there is no cure. Alzheimer's is likely caused by a combination of factors, providing several potential therapeutic targets. One area of interest is the epigenetic regulation of gene expression within the brain. Epigenetic marks, including DNA methylation and histone modifications, show consistent changes with age and in those with Alzheimer’s. Some epigenetic regulation has been linked to disease pathology and progression and are the focus of current research. Epigenetic regulators might make promising therapeutic targets yet challenges need to be overcome to generate an efficacious drug lacking deleterious side effects.

Objective: The objective of this study was to explore the potential causal associations of body mass index, height, weight, fat mass, fat percentage and non-fat mass in the whole body, arms, legs and trunk (henceforth, ‘anthropometric measures’) with multiple sclerosis (MS) risk and severity. We also investigated the potential for reverse causation between anthropometric measures and MS risk. Methods: We conducted a two-sample univariable, multivariable and bidirectional Mendelian randomisation (MR) analysis. Results: A range of features linked to obesity (body mass index, weight, fat mass and fat percentage) were risk factors for MS development and worsened the disease’s severity in MS patients. Interestingly, we were able to demonstrate that height and non-fat mass have no association with MS risk or MS severity. We demonstrated that the association between anthropometric measures and MS is not subject to bias from reverse causation. Conclusions: Our findings provide evidence from human genetics that a range of features linked to obesity is an important contributor to MS development and MS severity, but height and non-fat mass are not. Importantly, these findings also identify a potentially modifiable factor that may reduce the accumulation of further disability and ameliorate MS severity.

Background Parkinson's disease (PD) is a common neurodegenerative movement disorder. Observational studies suggest higher levels of plasma urate may protect against Parkinson's risk and progression; however, causality cannot be established. Objectives This study set out to determine whether there is a true causal association between urate levels and PD age at onset (AAO) and progression severity using recently released PD AAO and progression genome‐wide association study (GWAS) data. Methods A large two‐sample Mendelian randomization design was employed, using genetic variants underlying urate levels and the latest GWAS data for PD outcomes. Results This study found no causal association between urate levels and Parkinson's risk, AAO, or progression severity. Conclusions Our results predict increasing urate levels as a therapeutic strategy is unlikely to benefit PD patients. © 2021 International Parkinson and Movement Disorder Society

Background There has been considerable interest in statins due to their pleiotropic effects beyond their lipid-lowering properties. Many of these pleiotropic effects are predominantly ascribed to their capacity to inhibit the isoprenylation of Rho small guanosine triphosphatases (Rho GTPases). We aimed to genetically investigate the role of lipids and statin interventions on multiple sclerosis (MS) risk and severity. Method We employed two-sample Mendelian randomization (MR) to: (1) investigate the causal role of lipids (high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG)) levels in MS risk and severity, (2) genetically mimic both cholesterol-dependent (via low-density lipoprotein cholesterol (LDL-C) and cholesterol biosynthesis pathway) and cholesterol-independent (via Rho GTPases) effects of statins on MS risk and MS severity. Results The results of MR using the inverse variance weighted method show that lifelong higher HDL-C (OR 1.14 (95% CI 1.04 to1.26), p-value 7.94E-03) increase MS risk, but LDL-C and TG were not. MR results also show that genetically predicted RAC2 (OR 0.86 (95% CI 0.78 to 0.95), p-value 3.80E-03) is implicated causally in reducing MS risk. Furthermore, we found no evidence for the causal role of lipids and genetically mimicked statins on MS severity. There is no evidence of reverse causation between MS risk and lipids. Conclusions Evidence from this study suggests that HDL-C is a risk factor for MS development. The MR findings suggest that RAC2 (a member of Rho GTPases) is a potent genetic modifier of MS risk. Since RAC2 has been reported to mediate some of the pleiotropic effects of statins, we suggest that statins reduce MS risk via a RAC2-related mechanism(s) (i.e., cholesterol-independent pathway).