Biology subjects

Richmond, R.

Publications and source records attributed to Richmond, R..

12 recordsLinked to original sources

bioRxiv2023

Adolescent chronic sleep restriction promotes alcohol drinking in adulthood: evidence from epidemiological and preclinical data.

Epidemiological investigations have indicated that insufficient sleep is prevalent among adolescents, posing a globally underestimated health risk. Sleep fragmentation and sleep loss during adolescence have been linked to concurrent emotional dysregulation and an increase in impulsive, risk-taking behaviors, including a higher likelihood of substance abuse. Among the most widely used substances, alcohol stands as the primary risk factor for deaths and disability among individuals aged 15-49 worldwide. While the association between sleep loss and alcohol consumption during adolescence is well documented, the extent to which prior exposure to sleep loss in adolescence contributes to heightened alcohol use later in adulthood remains less clearly delineated. Here, we analyzed longitudinal epidemiological data spanning 9 years, from adolescence to adulthood, including 5497 participants of the Avon Longitudinal Study of Parents And Children cohort. Sleep and alcohol measures collected from interviews and questionnaires at 15 and 24 years of age were analyzed with multivariable linear regression and a cross-lagged autoregressive path model. Additionally, we employed a controlled preclinical experimental setting to investigate the causal relationship underlying the associations found in the human study and to assess comorbid behavioral alterations. Preclinical data were collected by sleep restricting Marchigian Sardinian alcohol preferring rats (msP, n=40) during adolescence and measuring voluntary alcohol drinking concurrently and in adulthood. Polysomnography was used to validate the efficacy of the sleep restriction procedure. Behavioral tests were used to assess anxiety, risky behavior, and despair. In humans, after adjusting for covariates, we found a cross-sectional association between all sleep parameters and alcohol consumption at 15 years of age but not at 24 years. Notably, alcohol consumption (Alcohol Use Disorder Identification Test for Consumption) at 24 years was predicted by insufficient sleep at 15 years whilst alcohol drinking at 15 years could not predict sleep problems at 24. In msP rats, adolescent chronic sleep restriction escalated alcohol consumption and led to increased propensity for risk-taking behavior in adolescence and adulthood. Our findings demonstrate that adolescent insufficient sleep causally contributes to higher adult alcohol consumption, potentially by promoting risky behavior.

neuroscience↗

bioRxiv2019

Mendelian randomisation for mediation analysis: current methods and challenges for implementation

Mediation analysis seeks to explain the pathway(s) through which an exposure affects an outcome. Mediation analysis experiences a number of methodological difficulties, including bias due to confounding and measurement error. Mendelian randomisation (MR) can be used to improve causal inference for mediation analysis. We describe two approaches that can be used for estimating mediation analysis with MR: multivariable Mendelian randomisation (MVMR) and two-step Mendelian randomisation. We outline the approaches and provide code to demonstrate how they can be used in mediation analysis. We review issues that can affect analyses, including confounding, measurement error, weak instrument bias, and analysis of multiple mediators. Description of the methods is supplemented by simulated and real data examples. Although Mendelian randomisation relies on large sample sizes and strong assumptions, such as having strong instruments and no horizontally pleiotropic pathways, our examples demonstrate that it is unlikely to be affected by confounders of the exposure or mediator and the outcome, reverse causality and non-differential measurement error of the exposure or mediator. Both MVMR and two-step MR can be implemented in both individual-level MR and summary data MR, and can improve causal inference in mediation analysis.

genetics↗

bioRxiv2019

Physiological and Molecular Responses Suggest Local Adaptation of the Lobe Coral Porites lobata to the Nearshore Environment

Corals in nearshore marine environments are increasingly exposed to reduced water quality, which is the primary local threat to Hawaiian coral reefs. It is unclear if corals surviving in such conditions have adapted to withstand sedimentation, pollutants, and other environmental stressors. Lobe coral populations from Maunalua Bay, Hawaii showed clear genetic differentiation between the polluted, high-stress nearshore site and the lower-stress offshore site. To understand the driving force of the observed genetic partitioning, reciprocal transplant and common-garden experiments were conducted to assess phenotypic differences between these two populations. Physiological responses were significantly different between the populations, revealing more stress-resilient traits in the nearshore corals. Changes in protein profiles between the two populations highlighted the inherent differences in the cellular metabolic processes and activities; nearshore corals did not significantly alter their proteome between the sites, while offshore corals responded to nearshore transplantation with increased abundances of proteins associated with detoxification, antioxidant defense, and regulation of cellular metabolic processes. The response differences across multiple phenotypes between the populations suggest local adaptation of nearshore corals to reduced water quality. Our results provide insight into corals adaptive potential and its underlying processes, and reveal potential protein biomarkers that could be used to predict resiliency.

ecology↗

bioRxiv2019

Identifying epigenetic biomarkers of established prognostic factors and survival in a clinical cohort of individuals with oropharyngeal cancer

Smoking status, alcohol consumption and HPV infection (acquired through sexual activity) are the predominant risk factors for oropharyngeal cancer and are thought to alter the prognosis of the disease. Here, we conduct epigenome-wide association studies (EWAS) of these factors and [~]3-year survival using Illumina Methylation EPIC blood DNA methylation profiles from 409 individuals in the Head and Neck 5000 (HN5000) study. CpG site associations below our multiple-testing threshold (PBonferroni < 0.05) with both a prognostic factor and with survival were observed in four gene regions: SPEG (smoking), GFI1 (smoking), PPT2 (smoking), and KHD3CL (alcohol consumption). These were further analysed using 2-step Mendelian randomization to assess whether methylation may be a causal mediator of cancer survival. Evidence for mediation was observed only in the SPEG gene region, showing an association with decreased survival (mortality HR: 1.28, 95% CI: 1.14 to 1.43, P: 2.12x10-05). Replication in data from independent datasets, and from HN5000 participants with longer follow-up times is needed to confirm these findings.

epidemiology↗

bioRxiv2019

Validation and characterization of a DNA methylation alcohol biomarker across the life course

Recently, an alcohol predictor was developed using DNA methylation at 144 CpG sites (DNAm-Alc) as a biomarker for improved clinical or epidemiologic assessment of alcohol-related ill health. We validate the performance and characterize the drivers of this DNAm-Alc for the first time in independent populations. In N=1,049 parents from the Avon Longitudinal Study of Parents and Children (ALSPAC) Accessible Resource for Integrated Epigenomic Studies (ARIES) at midlife, we found DNAm-Alc explained 7.6% of the variation in alcohol intake, roughly half of what had been reported previously, and interestingly explained a larger 9.8% of AUDIT score, a scale of alcohol use disorder. Explanatory capacity in participants from the offspring generation of ARIES measured during adolescence was much lower. However, DNAm-Alc explained 14.3% of the variation in replication using the Head and Neck 5000 (HN5000) clinical cohort that had higher average alcohol consumption. To investigate whether this relationship was being driven by genetic and/or earlier environment confounding we examined how earlier vs. concurrent DNAm-Alc measures predicted AUDIT scores. In both ARIES parental and offspring generations, we observed associations between AUDIT and concurrent, but not earlier DNAm-Alc, suggesting independence from genetic and stable environmental contributions. The stronger relationship between DNAm-Alcs and AUDIT in parents at midlife compared to adolescents despite similar levels of consumption suggests that DNAm-Alc likely reflects long-term patterns of alcohol abuse. Such biomarkers may have potential applications for biomonitoring and risk prediction, especially in cases where reporting bias is a concern.

epidemiology↗

bioRxiv2018

DNA methylation links prenatal smoking exposure to later life health outcomes in offspring.

Maternal smoking during pregnancy is associated with adverse offspring health outcomes across their life course. We hypothesize that DNA methylation is a potential mediator of this relationship. To test this, we examined the association of prenatal maternal smoking with DNA methylation in 2,821 individuals (age 16 to 48 years) from five prospective birth cohort studies and perform Mendelian randomization and mediation analyses to assess, whether methylation markers have causal effects on disease outcomes in the offspring. We identify 69 differentially methylated CpGs in 36 genomic regions (P < 1x10-7), and show that DNA methylation may represent a biological mechanism through which maternal smoking is associated with increased risk of psychiatric morbidity in the exposed offspring.

epidemiology↗

bioRxiv2018

The effect of body mass index on smoking behaviour and nicotine metabolism: a Mendelian randomization study

BackgroundGiven clear evidence that smoking lowers weight, it is possible that individuals with higher body mass index (BMI) smoke in order to lose or maintain their weight.\n\nMethods and FindingsWe undertook Mendelian randomization analyses using 97 genetic variants associated with BMI. We performed two sample Mendelian randomization analyses of the effects of BMI on smoking behaviour in UK Biobank (N=335,921) and the Tobacco and Genetics consortium genomewide association study (GWAS) (N[≤]74,035) respectively, and two sample Mendelian randomization analyses of the effects of BMI on cotinine levels (N[≤]4,548) and nicotine metabolite ratio (N[≤]1,518) in published GWAS, and smoking-related DNA methylation in the Avon Longitudinal Study of Parents and Children (N[≤]846).\n\nIn inverse variance weighted Mendelian randomization analysis, there was evidence that higher BMI was causally associated with smoking initiation (OR for ever vs never smoking per one SD increase in BMI: 1.19, 95% CI: 1.11 to 1.27) and smoking heaviness (1.45 additional cigarettes smoked per day per SD increase in BMI, 95% CI: 1.03 to 1.86), but little evidence for a causal effect with smoking cessation. Results were broadly similar using pleiotropy robust methods (MR-Egger, median and weighted mode regression). These results were supported by evidence for a causal effect of BMI on DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) locus. There was no strong evidence that BMI was causally associated with cotinine, but suggestive evidence for a causal negative association with the nicotine metabolite ratio.\n\nConclusionsThere is a causal bidirectional association between BMI and smoking, but the relationship is likely to be complex due to opposing effects on behaviour and metabolism. It may be useful to consider BMI and smoking together when designing prevention strategies to minimise the effects of these risk factors on health outcomes.

epidemiology↗

bioRxiv2018

Appraising the causal relevance of DNA methylation for risk of lung cancer

DNA methylation changes in peripheral blood have been identified in relation to lung cancer risk. However, the causal nature of these associations remains to be fully elucidated. Meta-analysis of four epigenome-wide association studies (918 cases, 918 controls) revealed differential methylation at 16 CpG sites (FDR < 0.05) in relation to lung cancer risk. A two-sample Mendelian randomization analysis, using genetic instruments for methylation at 14 of the 16 CpG sites, and 29,863 cases and 55,586 controls from the TRICL-ILCCO lung cancer consortium, was performed to appraise the causal role of methylation at these sites on lung cancer. This approach provided little evidence that DNA methylation in peripheral blood at the 14 CpG sites play a causal role in lung cancer development, including for cg05575921 AHRR, where methylation is strongly associated with lung cancer risk. Further studies are needed to investigate the causal role played by DNA methylation in lung tissue.

epidemiology↗

bioRxiv2017

Investigating the role of insulin in increased adiposity: Bi-directional Mendelian randomization study

Insulin may serve as a key causal agent which regulates fat accumulation in the body. Here we assessed the causal relationship between fasting insulin and adiposity using publicly-available results from two large-scale genome-wide association studies for body mass index and fasting insulin levels in a two-sample, bidirectional Mendelian Randomized approach. This approach is only valid on the condition that the two instruments are independent of one another. In analysis excluding overlapping loci, there was an increase of 0.20 (0.17, 0.23) log pmol/L fasting insulin per SD increase in BMI (P= 2.80 x 10-36), while there was a null effect of fasting insulin on BMI, with a 0.01 (-0.39, 0.38) SD decrease in BMI per log pmol/L increase in fasting insulin (P= 0.98). Furthermore, a high degree of heterogeneity in the causal estimates was obtained from the insulin-related variants, which may be attributed to varying mechanisms of action of the insulin-associated variants. Results were largely consistent when an Egger regression technique and weighted median and mode estimators were applied. Findings suggest that the positive correlation between adiposity and fasting insulin levels are at least in part explained by the causal effect of adiposity on increasing insulin, rather than vice versa.

epidemiology↗

bioRxiv2017

Epigenome-Wide Association Study Of Asthma And Wheeze In Childhood And Adolescence

Asthma heritability has only been partially explained by genetic variants and is known to be sensitive to environmental factors, implicating epigenetic modifications such as DNA methylation in its pathogenesis.\n\nUsing data collected in the Avon Longitudinal Study of Parents and Children (ALSPAC), we assessed associations of asthma and wheeze with DNA methylation at 7.5 years and 16.5 years, at over 450,000 CpG sites in DNA from the peripheral blood of approx. 1000 participants. We used Mendelian randomization (MR), a method of causal inference that uses genetic variants as instrumental variables, to infer the direction of association between DNA methylation and asthma.\n\nWe identified 302 CpGs associated with current asthma status (FDR-adjusted P-value <0.05) and 445 with current wheeze status at 7.5 years, with substantial overlap between the two. Genes annotated to the 302 associated CpGs were enriched for pathways related to movement of cellular/subcellular components, locomotion, interleukin-4 production and eosinophil migration. All associations attenuated when adjusted for eosinophil and neutrophil cell count estimates. At 16.5 years, two sites were associated with current asthma after adjustment for cell counts. The CpGs mapped to the AP2A2 and IL5RA genes, with a -2.32 [95% CI -1.47,-3.18] and -2.49 [95% CI -1.56,-3.43] change in percentage methylation in asthma cases respectively. Two-sample bi-directional MR indicated a causal effect of asthma on DNA methylation at several CpG sites at 7.5 years. However, associations did not persist after adjustment for multiple testing. There was no evidence of a causal effect of asthma on DNA methylation at either of the two CpG sites at 16.5 years.\n\nThe majority of observed associations are driven by higher eosinophil cell counts in asthma cases, acting as an intermediate phenotype, with important implications for future studies of DNA methylation in atopic diseases.

epidemiology↗

bioRxiv2017

DNA Methylation As A Marker For Prenatal Smoke Exposure In Adults

Prenatal cigarette smoke is an environmental stressor that has a profound effect on DNA methylation in the exposed offspring. We have previously shown that some of these effects persist throughout childhood and into adolescence. Of interest is whether these signals persist into adulthood.\n\nWe conducted an analysis to investigate associations between reported maternal smoking in pregnancy and DNA methylation in peripheral blood of women in the Avon Longitudinal Study of Parents and Children (ALSPAC) (n=754; mean age 30 years). We observed associations at 15 CpG sites in 11 gene regions, MYO1G, FRMD4A, CYP1A1, CNTNAP2, ARL4C, AHRR, TIFAB, MDM4, AX748264, DRD1, FTO (FDR < 5%). All but two of these CpG sites have previously been identified in relation to prenatal smoke exposure in the offspring at birth and the majority showed persistent hypermethylation among the offspring of smokers.\n\nWe confirmed that most of these associations were not driven by own smoking and that they were still present 18 years later (N = 656; mean age 48 years). In addition, we replicated findings of a persistent methylation signal related to prenatal smoke exposure in peripheral blood among men in the ALSPAC cohort (N = 230; mean age 53 years). For both participant groups, there was a strong signal of association above that expected by chance at CpG sites previously associated with prenatal smoke exposure in newborns (Wilcoxon rank sum p-value < 2.2 x 10-4). Furthermore, we found that a prenatal smoking score, derived by combining methylation values at these CpG sites, could predict whether the mothers of the ALSPAC women smoked during pregnancy with an AUC 0.69 (95% 0.67, 0.73).

epidemiology↗

bioRxiv2017

Maternal and fetal genetic contribution to gestational weight gain

BackgroundClinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG.\n\nParticipants and MethodsA genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10,543 mothers and up to 16,317 offspring of European origin, with replication in 10,660 mothers and 7,561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (e.g. maternal BMI and glucose, birthweight).\n\nResultsWe found that approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and that the fetal genome made a surprisingly minor contribution to explaining variation in GWG. We were unable to identify any genetic variants that reached genome-wide levels of significance (P<5x10-8) and replicated. Some established maternal variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birthweight variants were largely unrelated to GWG.\n\nConclusionWe found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.

genetics↗