Epigenome-wide Association Studies and the Interpretation of Disease -Omics

Epigenome-wide association studies represent one means of applying genome-wide assays to identify molecular events that could be associated with human phenotypes. The epigenome is especially intriguing as a target for study, as epigenetic regulatory processes are, by definition, heritable from parent to daughter cells and are found to have transcriptional regulatory properties. As such, the epigenome is an attractive candidate for mediating long-term responses to cellular stimuli, such as environmental effects modifying disease risk. Such epigenomic studies represent a broader category of disease -omics, which suffer from multiple problems in design and execution that severely limit their interpretability. Here we define many of the problems with current epigenomic studies and propose solutions that can be applied to allow this and other disease -omics studies to achieve their potential for generating valuable insights

Folic acid in pregnancy and mortality from cancer and cardiovascular disease : further follow-up of the Aberdeen folic acid supplementation trial

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions. Acknowledgements The authors wish to acknowledge Professor Marion Hall, who set up the original randomised trial of folic acid supplementation. The authors also thank Ms Katie Wilde and the Data Management Team, University of Aberdeen, for their help with the extraction and linking of data and the data analysts from ISD Scotland.Peer reviewedPublisher PD

Woolf et als GWAS by subtraction is not useful for cross-generational Mendelian randomization studies

Mendelian randomization (MR) is an epidemiological method that can be used to strengthen causal inference regarding the relationship between a modifiable environmental exposure and a medically relevant trait and to estimate the magnitude of this relationship1. Recently, there has been considerable interest in using MR to examine potential causal relationships between parental phenotypes and outcomes amongst their offspring. In a recent issue of BMC Research Notes, Woolf et al (2023) present a new method, GWAS by subtraction, to derive genome-wide summary statistics for paternal smoking and other paternal phenotypes with the goal that these estimates can then be used in downstream (including two sample) MR studies. Whilst a potentially useful goal, Woolf et al. (2023) focus on the wrong parameter of interest for useful genome-wide association studies (GWAS) and downstream cross-generational MR studies, and the estimator that they derive is neither efficient nor appropriate for such use.Comment: 8 pages, 0 figure

The Midspan studies

No abstract available

Association of plasma uric acid with ischaemic heart disease and blood pressure: mendelian randomisation analysis of two large cohorts

Objectives: To assess the associations between both uric acid levels and hyperuricaemia, with ischaemic heart disease and blood pressure, and to explore the potentially confounding role of body mass index. Design: Mendelian randomisation analysis, using variation at specific genes (SLC2A9 (rs7442295) as an instrument for uric acid; and FTO (rs9939609), MC4R (rs17782313), and TMEM18 (rs6548238) for body mass index). Setting: Two large, prospective cohort studies in Denmark. Participants: We measured levels of uric acid and related covariables in 58 072 participants from the Copenhagen General Population Study and 10 602 from the Copenhagen City Heart Study, comprising 4890 and 2282 cases of ischaemic heart disease, respectively. Main outcome: Blood pressure and prospectively assessed ischaemic heart disease. Results: Estimates confirmed known observational associations between plasma uric acid and hyperuricaemia with risk of ischaemic heart disease and diastolic and systolic blood pressure. However, when using genotypic instruments for uric acid and hyperuricaemia, we saw no evidence for causal associations between uric acid, ischaemic heart disease, and blood pressure. We used genetic instruments to investigate body mass index as a potentially confounding factor in observational associations, and saw a causal effect on uric acid levels. Every four unit increase of body mass index saw a rise in uric acid of 0.03 mmol/L (95% confidence interval 0.02 to 0.04), and an increase in risk of hyperuricaemia of 7.5% (3.9% to 11.1%). Conclusion: By contrast with observational findings, there is no strong evidence for causal associations between uric acid and ischaemic heart disease or blood pressure. However, evidence supports a causal effect between body mass index and uric acid level and hyperuricaemia. This finding strongly suggests body mass index as a confounder in observational associations, and suggests a role for elevated body mass index or obesity in the development of uric acid related conditions

Grindr Users Take More Risks, but Are More Open to Human Immunodeficiency Virus (HIV) Pre-exposure Prophylaxis: Could This Dating App Provide a Platform for HIV Prevention Outreach?

BackgroundTechnology has changed the way that men who have sex with men (MSM) seek sex. More than 60% of MSM in the United States use the internet and/or smartphone-based geospatial networking apps to find sex partners. We correlated use of the most popular app (Grindr) with sexual risk and prevention behavior among MSM.MethodsA nested cohort study was conducted between September 2018 and June 2019 among MSM receiving community-based human immunodeficiency virus (HIV) and sexually transmitted infection (STI) screening in central San Diego. During the testing encounter, participants were surveyed for demographics, substance use, risk behavior (previous 3 months), HIV pre-exposure prophylaxis (PrEP) use, and Grindr usage. Participants who tested negative for HIV and who were not on PrEP were offered immediate PrEP.ResultsThe study included 1256 MSM, 1090 of whom (86.8%) were not taking PrEP. Overall, 580 of 1256 (46%) participants indicated that they used Grindr in the previous 7 days. Grindr users reported significantly higher risk behavior (greater number of male partners and condomless sex) and were more likely to test positive for chlamydia or gonorrhea (8.6% vs 4.7% of nonusers; P = .005). Grindr users were also more likely to be on PrEP (18.7% vs 8.7% of nonusers; P < .001) and had fewer newly diagnosed HIV infections (9 vs 26 among nonusers; P = .014). Grindr users were also nearly twice as likely as nonusers to initiate PrEP (24.6% vs 14%; P < .001).ConclusionsGiven the higher risk behavior and greater acceptance of PrEP among MSM who used Grindr, Grindr may provide a useful platform to promote HIV and STI testing and increase PrEP uptake

Exploring the Developmental Overnutrition Hypothesis Using Parental–Offspring Associations and FTO as an Instrumental Variable

Using parental-offspring associations and theFTO gene as an instrumental variable for maternal adiposity, Debbie Lawlor and colleagues found that greater maternal BMI during offspring development does not appear to have a marked effect on offspring fat mass at age 9-11

Intergenerational social mobility and mid-life status attainment: influences of childhood intelligence, childhood social factors, and education

We examined the influences of childhood social background, childhood cognitive ability, and education on intergenerational social mobility and social status attainment at midlife. The subjects were men born in 1921 and who participated in the Scottish Mental Survey of 1932 and thereafter in the Midspan Collaborative study in Scotland between 1970 and 1973. In logistic regression analyses, childhood cognitive ability and height were associated with upward and downward change from father's social class to participant's social class at mid-life. Education significantly influenced upward social mobility. Number of siblings had no significant effect on social mobility. These effects were also examined after adjusting for the other variables. In structural equation modelling analyses, father's social class and childhood cognitive ability influenced social status attainment at midlife, with education and occupational status in young adulthood as partially mediating factors. It was noteworthy that childhood cognitive ability related more strongly to occupation in midlife than to first occupation. These data add to the relatively few studies that track the process of status attainment in adulthood, they provide information from a new geographical setting, and they contain information from a greater proportion of the lifecourse than do most existing studies