Identifying the potential causal role of insomnia symptoms on 11,409 health-related outcomes: a phenome-wide Mendelian randomisation analysis in UK Biobank.

BACKGROUND: Insomnia symptoms are widespread in the population and might have effects on many chronic conditions and their risk factors but previous research has focused on select hypothesised associations/effects rather than taking a systematic hypothesis-free approach across many health outcomes. METHODS: We performed a Mendelian randomisation (MR) phenome-wide association study (PheWAS) in 336,975 unrelated white-British UK Biobank participants. Self-reported insomnia symptoms were instrumented by a genetic risk score (GRS) created from 129 single-nucleotide polymorphisms (SNPs). A total of 11,409 outcomes from UK Biobank were extracted and processed by an automated pipeline (PHESANT) for the MR-PheWAS. Potential causal effects (those passing a Bonferroni-corrected significance threshold) were followed up with two-sample MR in MR-Base, where possible. RESULTS: Four hundred thirty-seven potential causal effects of insomnia symptoms were observed for a diverse range of outcomes, including anxiety, depression, pain, body composition, respiratory, musculoskeletal and cardiovascular traits. We were able to undertake two-sample MR for 71 of these 437 and found evidence of causal effects (with directionally concordant effect estimates across main and sensitivity analyses) for 30 of these. These included novel findings (by which we mean not extensively explored in conventional observational studies and not previously explored using MR based on a systematic search) of an adverse effect on risk of spondylosis (OR [95%CI] = 1.55 [1.33, 1.81]) and bronchitis (OR [95%CI] = 1.12 [1.03, 1.22]), among others. CONCLUSIONS: Insomnia symptoms potentially cause a wide range of adverse health-related outcomes and behaviours. This has implications for developing interventions to prevent and treat a number of diseases in order to reduce multimorbidity and associated polypharmacy.

Reporting and methodological quality of studies that use Mendelian randomisation in UK Biobank: a meta-epidemiological study.

OBJECTIVES: To identify whether Mendelian randomisation (MR) studies are appropriately conducted and reported in enough detail for other researchers to accurately replicate and interpret them. DESIGN: Cross-sectional meta-epidemiological study. DATA SOURCES: Web of Science, EMBASE, PubMed and PsycINFO were searched on 15 July 2022 for literature. ELIGIBILITY CRITERIA: Full research articles that conducted an MR analysis exclusively using individual-level UK Biobank data to obtain a causal estimate of the exposure-outcome relationship (for no more than ten exposures or outcomes). METHODS AND ANALYSIS: Data were extracted using a 25-item checklist relating to reporting and methodological quality (based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)-MR reporting guidelines and the guidelines for performing MR investigations). Article characteristics, such as 2021 Journal Impact Factor, publication year, journal word limit/recommendation, whether the MR analysis was the primary analysis, open access status and whether reporting guidelines were followed, were also extracted. Descriptive statistics were calculated for each item, and whether article characteristics predicted overall article completeness was investigated with linear regression. RESULTS: 116 articles were included in this review. The proportion of articles which reported complete information/adequate methodology ranged from 3% to 100% across the different items. Palindromic variants, variant replication, missing data, associations of the instrumental variable with the exposure or outcome and bias introduced by two-sample methods used on a single sample were often not completely addressed (<11%). There was no clear evidence that article characteristics predicted overall completeness except for primary analysis status. CONCLUSIONS: The results identify areas in which the reporting and conducting of MR studies needs to be improved and also suggest researchers do not make use of supplementary materials to sufficiently report secondary analyses. Future research should focus on the quality of code and analyses, attempt direct replications and investigate the impact of the STROBE-MR specifically. STUDY REGISTRATION: https://osf.io/nwrdj.

Detection of oligomeric forms of alpha-synuclein protein in human plasma as a potential biomarker for Parkinson's disease.

To date there is no accepted clinical diagnostic test for Parkinson's disease (PD) based on biochemical analysis of blood or cerebrospinal fluid (CSF). alpha-Synuclein (alpha-syn) protein has been linked to the pathogenesis of PD with the discovery of mutations in the gene encoding alpha-syn in familial cases with early-onset PD. Lewy bodies and Lewy neurites, which constitute the main pathological features in the brains of patients with sporadic PD and dementia with Lewy bodies, are formed by the conversion of soluble monomers of alpha-syn into insoluble aggregates. We recently reported the presence of alpha-syn in normal human blood plasma and in postmortem CSF. Here, we investigated whether alpha-syn can be used as a biomarker for PD. We have developed a novel ELISA method that detects only oligomeric "soluble aggregates" of alpha-syn. Using this ELISA, we report the presence of significantly elevated (P=0.002) levels of oligomeric forms of alpha-syn in plasma samples obtained from 34 PD patients compared with 27 controls; 52% (95% confidence intervals 0.353-0.687) of the PD patients displayed signals >0.5 OD with our ELISA assay in comparison to only 14.8% (95% confidence intervals 0.014-0.281) for the control cases. An analysis of the test's diagnostic value revealed a specificity of 0.852 (95% confidence intervals 0.662-0.958), sensitivity of 0.529 (95% confidence intervals 0.351-0.702) and a positive predictive value of 0.818 (95% confidence intervals 0.597-0.948). These observations offer new opportunities for developing diagnostic tests for PD and related diseases and for testing therapeutic agents aimed at preventing or reversing the aggregation of alpha-syn.

Alpha-synuclein implicated in Parkinson's disease is present in extracellular biological fluids, including human plasma.

Parkinson's disease (PD) and other related disorders are characterized by the accumulation of fibrillar aggregates of alpha-synuclein protein (alpha-syn) inside brain cells. It is likely that the formation of alpha-syn aggregates plays a seminal role in the pathogenesis of at least some of these diseases, because two different mutations in the gene encoding alpha-syn have been found in inherited forms of PD. alpha-Syn is mainly expressed by neuronal cells and is generally considered to exist as a cytoplasmic protein. Here, we report the unexpected identification of alpha-syn in conditioned culture media from untransfected and alpha-syn-transfected human neuroblastoma cells, as well as in human cerebrospinal fluid and blood plasma. The method used was immunocapture by using anti-alpha-syn antibodies coupled to magnetic beads, followed by detection on Western blots. In all cases, alpha-syn was identified as a single 15 kDa band, which co-migrated with a recombinant form of the protein and reacted with five different antibodies to alpha-syn. Our findings suggest that cells normally secrete alpha-syn into their surrounding media, both in vitro and in vivo. The detection of extracellular alpha-syn and/or its modified forms in body fluids, particularly in human plasma, offers new opportunities for the development of diagnostic tests for PD and related diseases.