Biology subjects

Gill, D.

Publications and source records attributed to Gill, D..

At least 19 recordsLinked to original sources

bioRxiv2025

The relationship between sleep, mental health, and performance on tests of pattern separation in young adults

ObjectivesYoung adults experience the highest rates of mental health disorders of any age group. Given that mental health disorders are associated with sleep disturbances and cognitive impairments, we investigated whether sleep moderates the effects on cognition. MethodsUniversity students (N=89; aged 18-30 years) remotely monitored their sleep for seven consecutive days using wrist actigraphy and sleep diaries. On day seven, participants completed cognitive testing and mental health questionnaires. Cognitive tests included the Psychomotor Vigilance Task (PVT), Cambridge Neuropsychological Test Automated Battery (CANTAB), and the Mnemonic Similarity Task (MST). CANTABs Delayed Matching to Sample (DMS) and MST are designed to tax pattern separation, a computational mechanism supporting encoding of similar experiences as distinct representations. Becks Depression Inventory and Becks Anxiety Inventory assessed mental health. ResultsEighty participants (mean age: 20.13{+/-}2.00) were included in the analyses. Most participants reported mild to severe depressive and anxiety symptoms. Depressive symptoms were correlated with wake-up time ({rho}=.35, p=.002) as well as PVT ({rho}=.26, p=.02) and DMS ({rho}=.24, p=.04) performance. Bedtime was correlated with performance on MST (r=-.29, r=.02) and DMS ({rho}=.25, p=.03), while wake-up time was correlated with performance on MST (r=- .31, p=.01) and DMS ({rho}=.28, p=.01). Sleep did not moderate the effects of mental health on cognitive performance. ConclusionCognitive tests taxing pattern separation are sensitive to depressive symptoms and sleep timing. While students face a disproportionate burden of mental health disorders compromising cognitive functioning, improving sleep quality may offer a partial, though not moderating, pathway to alleviating these cognitive impairments.

neuroscience↗

bioRxiv2024

Embodied processing in whisker somatosensory cortex during exploratory behaviour in freely moving mice

Sensory systems have evolved to solve computational challenges that animals face during behaviour in their natural environments. To illuminate how sensory cortex operates under such conditions, we investigated the function of neurons in whisker-related Somatosensory Cortex (wS1) of freely moving mice, engaged in tactile exploratory behaviour. By recording neural activity from wS1 whilst tracking the mouse body in 3D, we found that wS1 neurons are substantially modulated by body state (configuration of individual body-parts and their derivatives), even in the absence of whisker afferent input. Most neurons were modulated by multiple dimensions of body state, with the most prominently encoded being the angle of the head to the body and locomotion speed. Overall, our data suggest that sensory cortex functions as an embodied representation, which integrates signals from its associated sense organ within a body schema.

neuroscience↗

bioRxiv2024

The relationship between sleep and cognitive performance on tests of pattern separation

Study objectivesSleep disturbances are considered both a risk factor and symptom of dementia. The present research aimed to identify cognitive tests in which performance is associated with objective sleep quality or quantity, focusing on cognitive tests designed to evaluate the earliest cognitive changes in dementia. MethodsWe recruited older adults (50 years of age or older) and remotely monitored their sleep patterns for 7 consecutive days using wrist actigraphy and sleep diaries. On day 7, participants completed a battery of cognitive tests, which included the Psychomotor Vigilance Task (PVT), the Prodromal Alzheimers and Mild Cognitive Impairment battery from the Cambridge Neuropsychological Test Automated Battery (CANTAB), and the Mnemonic Similarity Task (MST), designed to tax pattern separation. The participants were also assessed with the Montreal Cognitive Assessment (MoCA). ResultsThe final sample included 34 participants (mean age: 65.56, SD: 9.57). There were significant correlations between objective total sleep time and PVT and MST performance. MoCA scores were correlated with performance on CANTAB and MST. Objective total sleep time also predicted MST performance when controlling for age and gender. ConclusionsPerformance on cognitive tests designed to assess pattern separation are sensitive to older adults objective sleep duration and the early cognitive changes associated with dementia. MST should be evaluated for potential use as a clinical trial outcome measure for sleep-promoting treatments in older adults. Statement of SignificanceThere is growing emphasis on the importance of sleep as a potential therapeutic target for neurodegenerative diseases (e.g., Alzheimers disease). Identifying cognitive measures that are sensitive to both sleep and the earliest cognitive changes associated with dementia are needed for use as outcome measures in clinical trials evaluating the effectiveness of sleep-promoting interventions. Our research addresses this need by investigating the relationship between sleep patterns and performance on cognitive tests designed to assess the earliest cognitive changes in dementia. Our results suggest that cognitive tests designed to assess pattern separation are uniquely sensitive to sleep quantity in older adults.

neuroscience↗

bioRxiv2024

Mendelian randomization for multiple exposures and outcomes with Bayesian Directed Acyclic Graphs exploration and causal effects estimation

Current Mendelian randomization (MR) methods do not reflect complex relationships among multiple exposures and outcomes as is typical for real-life applications. We introduce MrDAG the first MR method to model dependency relations within the exposures, the outcomes, and between them to improve causal effects estimation. MrDAG combines three causal inference strategies in a unified manner. It uses genetic variation as instrumental variables to account for unmeasured confounders. It performs structure learning to detect and orientate the direction of the dependencies within exposures and outcomes. Finally, interventional calculus is employed to derive principled causal effect estimates. MrDAG was motivated to unravel how lifestyle and behavioural exposures impact mental health. It highlights education and smoking as key effective points of intervention given their down-stream effects on mental health. These insights would have been difficult to delineate without modelling the causal paths between multiple exposures and outcomes at once.

systems biology↗

bioRxiv2024

The chromosome-level genome of the ctenophore Mnemiopsis leidyi A. Agassiz, 1865 reveals a unique immune gene repertoire

Ctenophora are basal marine metazoans, the sister group of all other animals. Mnemiopsis leidyi is one of the most successful invasive species worldwide with intense ecological and evolutionary research interest. Here, we generated a chromosome-level genome assembly of M. leidyi with a focus on its immune gene repertoire. The genome was 247.97 Mb, with N50 16.84 Mb, and 84.7% completeness. Its karyotype was 13 chromosomes. In this genome and that of two other ctenophores, Bolinopsis microptera and Hormiphora californensis, we detected a high number of protein domains related to potential immune receptors. Among those, proteins containing Toll/interleukin-1(TIR2) domain, NACHT domain, Scavenger Receptor Cystein-Rich (SRCR) domain, or C-type Lectin domain (CTLD) were abundant and presented unique domain architectures in M. leidyi. M. leidyi seems to lack bona fide Toll like Receptors, but it does possess a repertoire of 15 TIR2-domain containing genes. Besides, we detected a bona fide NOD-like receptor and 38 NACHT-domain containing genes. In order to verify the function of those domain containing genes, we exposed M. leidyi to the pathogen Vibrio coralliilyticus. Among the differentially expressed genes, we identified potential immune receptors, including four TIR2-domain containing genes, all of which were upregulated in response to pathogen exposure. To conclude, many common immune receptor domains, highly conserved across metazoans, are already present in Ctenophora. These domains have large expansions and unique architectures in M. leidyi, findings consistent with the basal evolutionary position of this group, but still might have conserved functions in immunity and host-microbe interaction.

genomics↗

bioRxiv2023

Multi-response Mendelian randomization: Identification of shared and distinct exposures for multimorbidity and multiple related disease outcomes

The existing framework of Mendelian randomization (MR) infers the causal effect of one or multiple exposures on one single outcome. It is not designed to jointly model multiple outcomes, as would be necessary to detect causes of more than one outcome and would be relevant to model multimorbidity or other related disease outcomes. Here, we introduce Multi-response Mendelian randomization (MR2), a novel MR method specifically designed for multiple outcomes to identify exposures that cause more than one outcome or, conversely, exposures that exert their effect on distinct responses. MR2 uses a sparse Bayesian Gaussian copula regression framework to detect causal effects while estimating the residual correlation between summary-level outcomes, i.e., the correlation that cannot be explained by the exposures, and viceversa. We show both theoretically and in a comprehensive simulation study how unmeasured shared pleiotropy induces residual correlation. We also reveal how non-genetic factors that affect more than one outcome contribute to their correlation. We demonstrate that by accounting for residual correlation, MR2 has higher power to detect shared exposures causing more than one outcome. It also provides more accurate causal effect estimates than existing methods that ignore the dependence between related responses. Finally, we illustrate how MR2 detects shared and distinct causal exposures for five cardiovascular diseases in two applications considering cardiometabolic and lipidomic exposures and uncovers residual correlation between summary-level outcomes reflecting known relationships between cardiovascular diseases.

genetics↗

bioRxiv2022

Ocean currents drive the worldwide colonization of the most widespread marine plant, eelgrass (Zostera marina)

Currents are unique drivers of oceanic phylogeography and so determine the distribution of marine coastal species, along with past glaciations and sea level changes. Here, we reconstruct the worldwide colonization history of eelgrass (Zostera marina L.), the most widely distributed marine flowering plant or seagrass from its origin in the Northwest Pacific, based on nuclear and chloroplast genomes. We identified two divergent Pacific clades with evidence for admixture along the East Pacific coast. Multiple west to east (trans-Pacific) colonization events support the key role of the North Pacific Current. Time-calibrated nuclear and chloroplast phylogenies yielded concordant estimates of the arrival of Z. marina in the Atlantic through the Canadian Arctic, suggesting that eelgrass-based ecosystems, hotspots of biodiversity and carbon sequestration, have only been present since [~]208 Kya (thousand years ago). Mediterranean populations were founded [~]53 Kya while extant distributions along western and eastern Atlantic shores coincide with the end of the Last Glacial Maximum ([~]20 Kya). The recent colonization and 5-to 7-fold lower genomic diversity of Atlantic compared to the Pacific populations raises concern and opportunity about how Atlantic eelgrass might respond to rapidly warming coastal oceans.

evolutionary biology↗

bioRxiv2022

The Ca2+-gated Cl- channel TMEM16A amplifies capillary pericyte contraction reducing cerebral blood flow after ischemia

Pericyte-mediated capillary constriction decreases cerebral blood flow in stroke after an occluded artery is unblocked. The determinants of pericyte tone are poorly understood. We show that a small rise in cytoplasmic Ca2+ concentration ([Ca2+]i) in pericytes activates chloride efflux through the Ca2+-gated anion channel TMEM16A, thus depolarizing the cell and opening voltage-gated calcium channels. This mechanism strongly amplifies the pericyte [Ca2+]i rise and capillary constriction evoked by contractile agonists and ischemia. In a rodent stroke model, TMEM16A inhibition slows the ischemia-evoked pericyte [Ca2+]i rise, capillary constriction and pericyte death, reduces neutrophil stalling and improves cerebrovascular reperfusion. Genetic analysis implicates altered TMEM16A expression in poor patient recovery from ischemic stroke. Thus, pericyte TMEM16A is a crucial regulator of cerebral capillary function, and a potential therapeutic target for stroke and possibly other disorders of impaired microvascular flow, such as Alzheimers disease and vascular dementia.

physiology↗

bioRxiv2022

Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming

The expression of the pluripotency factors OCT4, SOX2, KLF4 and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, cycles of brief OSKM expression do not change cell identity but can reverse markers of aging in cells and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome and metabolome in naturally aged mice subject to a single period of transient OSKM expression. We found that this is sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen and blood. Similarly, we observed reversion of transcriptional changes, especially regarding biological processes known to change during aging. Finally, some serum metabolites altered with aging were also restored to young levels upon transient reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic and metabolomic changes towards a younger configuration in multiple tissues and in the serum.

cell biology↗

bioRxiv2021

Noise-augmented directional clustering of genetic association data identifies distinct mechanisms underlying obesity

Clustering genetic variants based on their associations with different traits can provide insight into their underlying biological mechanisms. Existing clustering approaches typically group variants based on the similarity of their association estimates for various traits. We present a new procedure for clustering variants based on their proportional associations with different traits, which is more reflective of the underlying mechanisms to which they relate. The method is based on a mixture model approach for directional clustering and includes a noise cluster that provides robustness to outliers. The procedure performs well across a range of simulation scenarios. In an applied setting, clustering genetic variants associated with body mass index generates groups reflective of distinct biological pathways. Mendelian randomization analyses support that the clusters vary in their effect on coronary heart disease, including one cluster that represents elevated body mass index with a favourable metabolic profile and reduced coronary heart disease risk. Analysis of the biological pathways underlying this cluster identifies inflammation as playing a key role in mediating the effects of increased body mass index on coronary heart disease.

genetics↗

bioRxiv2021

Lower Vibrio spp. abundances in Zostera marina leaf canopies suggest a novel ecosystem function for temperate seagrass beds

Seagrasses, a polyphyletic group of about 60 marine angiosperm species, are the foundation of diverse and functionally important marine habitats along sheltered sedimentary coasts. As a novel ecological function with high societal relevance, a role of the leaf canopy for reducing potentially harmful bacteria has recently been hypothesized. Accordingly, we tested whether or not the abundance of general bacteria and more specifically, those belonging to the genus Vibrio were reduced within temperate Zostera marina (eelgrass) meadows compared to adjacent sand flats and sampled 5 sites in the south-western Baltic Sea using SCUBA. Compared to non-vegetated area, we found an average reduction of 39% for all Vibrio and 63% for the potentially harmful V. vulnificus/cholerae subtype based on robust plate counting data on Vibrio selective agar. The underlying mechanism is currently elusive and clearly merits further study. Our results underline the critical importance of seagrasses in maintaining shallow water ecosystem functioning including water quality and provide further motivation for their protection and restoration.

ecology↗

bioRxiv2021

Polygenic Prediction of Type 2 Diabetes in Continental Africa

ObjectivePolygenic prediction of type 2 diabetes in continental Africans is adversely affected by the limited number of genome-wide association studies (GWAS) of type 2 diabetes from Africa, and the poor transferability of European derived polygenic risk scores (PRS) in diverse ethnicities. We set out to evaluate if African American or multi-ethnic derived PRSs would improve polygenic prediction in continental Africans. Research Design and MethodsUsing the PRSice software, ethnic-specific PRSs were computed with weights from the type 2 diabetes GWAS of the Million Veteran Program (MVP) study. The South African Zulu study (1602 cases and 976 controls) was used as the target data set. Replication and assessment of the best predictive PRS association with age at diagnosis was done in the Africa America Diabetes Mellitus (AADM) study (1031 cases and 738 controls). ResultsThe African American derived PRS was more predictive of type 2 diabetes compared to the European and multi-ethnic derived scores. Notably, participants in the 10th decile of this PRS had a 3.19-fold greater risk (OR 3.19; 95%CI (1.94-5.29), p = 5.33 x10-6) of developing diabetes and were diagnosed 2.6 years earlier compared to those in the first decile. ConclusionsAfrican American derived PRS enhances polygenic prediction of type 2 diabetes in continental Africans. Improved representation of non-Europeans populations (including Africans) in GWAS, promises to provide better tools for precision medicine interventions in type 2 diabetes.

genetics↗

bioRxiv2021

Multi-omic rejuvenation of human cells by maturation phase transient reprogramming

Ageing is the gradual decline in organismal fitness that occurs over time leading to tissue dysfunction and disease. At the cellular level, ageing is associated with reduced function, altered gene expression and a perturbed epigenome. Somatic cell reprogramming, the process of converting somatic cells to induced pluripotent stem cells (iPSCs), can reverse these age-associated changes. However, during iPSC reprogramming somatic cell identity is lost, and can be difficult to reacquire as re-differentiated iPSCs often resemble foetal rather than mature adult cells. Recent work has demonstrated that the epigenome is already rejuvenated by the maturation phase of reprogramming, which suggests full iPSC reprogramming is not required to reverse ageing of somatic cells. Here we have developed the first "maturation phase transient reprogramming" (MPTR) method, where reprogramming factors are expressed until this rejuvenation point followed by withdrawal of their induction. Using dermal fibroblasts from middle age donors, we found that cells reacquire their fibroblast identity following MPTR, possibly as a result of persisting epigenetic memory at enhancers. Excitingly, our method substantially rejuvenated multiple cellular attributes including the transcriptome, which was rejuvenated by around 30 years as measured by a novel transcriptome clock. The epigenome, including H3K9me3 histone methylation levels and the DNA methylation ageing clock, was rejuvenated to a similar extent. The magnitude of rejuvenation instigated by MTPR is substantially greater than that achieved in previous transient reprogramming protocols. MPTR fibroblasts produced youthful levels of collagen proteins, suggesting functional rejuvenation. Overall, our work demonstrates that it is possible to separate rejuvenation from pluripotency reprogramming, which should facilitate the discovery of novel anti-ageing genes and therapies. HighlightsO_LIWe developed a novel method by which human fibroblasts are reprogrammed until the maturation phase of iPSCs and are then returned to fibroblast identity C_LIO_LIDNA methylation memory in fibroblast enhancers may allow recovery of cell identity when fibroblast gene expression programmes are already extinct C_LIO_LIMolecular measures of ageing including transcriptome and DNA methylation clocks and H3K9me3 levels reveal robust and substantial rejuvenation C_LIO_LIFunctional rejuvenation of fibroblasts by MPTR is suggested by reacquisition of youthful levels of collagen proteins C_LI

molecular biology↗

bioRxiv2020

Coffee consumption and risk of breast cancer: a Mendelian Randomization study

BackgroundObservational studies have reported either null or weak protective associations for coffee consumption and risk of breast cancer. MethodsWe conducted a two-sample Mendelian randomization randomization (MR) analysis to evaluate the relationship between coffee consumption and breast cancer risk using 33 single-nucleotide polymorphisms (SNPs) associated with coffee consumption from a genome-wide association (GWA) study on 212,119 female UK Biobank participants of White British ancestry. Risk estimates for breast cancer were retrieved from publicly available GWA summary statistics from the Breast Cancer Association Consortium (BCAC) on 122,977 cases (of which 69,501 were estrogen receptor (ER)-positive, 21,468 ER-negative) and 105,974 controls of European ancestry. Random-effects inverse variance weighted (IVW) MR analyses were performed along with several sensitivity analyses to assess the impact of potential MR assumption violations. ResultsOne cup per day increase in genetically predicted coffee consumption in women was not associated with risk of total (IVW random-effects; odds ratio (OR): 0.91, 95% confidence intervals (CI): 0.80-1.02, P: 0.12, P for instrument heterogeneity: 7.17e-13), ER-positive (OR=0.90, 95% CI: 0.79-1.02, P: 0.09) and ER-negative breast cancer (OR: 0.88, 95% CI: 0.75-1.03, P: 0.12). Null associations were also found in the sensitivity analyses using MR-Egger (total breast cancer; OR: 1.00, 95% CI: 0.80-1.25), weighted median (OR: 0.97, 95% CI: 0.89-1.05) and weighted mode (OR: 1.00, CI: 0.93-1.07). ConclusionsThe results of this large MR study do not support an association of genetically predicted coffee consumption on breast cancer risk, but we cannot rule out existence of a weak inverse association.

cancer biology↗

bioRxiv2020

Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation

Adult skeletal muscles are maintained during homeostasis and regenerated upon injury by muscle stem cells (MuSCs). A heterogeneity in self-renewal, differentiation and regeneration properties has been reported for MuSCs based on their anatomical location. Although MuSCs derived from extraocular muscles (EOM) have a higher regenerative capacity than those derived from limb muscles, the molecular determinants that govern these differences remain undefined. Here we show that EOM and limb MuSCs have distinct DNA methylation signatures associated with enhancers of location-specific genes, and that the EOM transcriptome is reprogrammed following transplantation into a limb muscle environment. Notably, EOM MuSCs expressed host-site specific positional Hox codes after engraftment and self-renewal within the host muscle. However, about 10% of EOM-specific genes showed engraftment-resistant expression, pointing to cell-intrinsic molecular determinants of the higher engraftment potential of EOM MuSCs. Our results underscore the molecular diversity of distinct MuSC populations and molecularly define their plasticity in response to microenvironmental cues. These findings provide insights into strategies designed to improve the functional capacity of MuSCs in the context of regenerative medicine.

molecular biology↗

bioRxiv2019

Circulating concentrations of micro-nutrients and risk of breast cancer: A Mendelian randomization study

BackgroundThe epidemiological literature reports inconsistent associations between consumption or circulating concentrations of micro-nutrients and breast cancer risk. We investigated associations between genetically determined concentrations of 11 micro-nutrients (beta-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B6, vitamin B12 and zinc) and breast cancer risk using Mendelian randomization (MR).\n\nMaterials and methodsA two-sample MR study was conducted using 122,977 women with breast cancer, of whom 69,501 were estrogen receptor positive (ER+ve) and 21,468 were ER-ve, and 105,974 controls from the Breast Cancer Association Consortium. MR analyses were conducted using the inverse variance weighted approach, and sensitivity analyses were conducted to assess the impact of potential violations of MR assumptions.\n\nResultsOne standard deviation (SD: 0.08 mmol/L) higher genetically determined concentration of magnesium was associated with a 17% (odds ratio [OR]: 1.17, 95% confidence interval [CI]: 1.10 to 1.25, P=9.1 x 10-7) and 20% (OR: 1.20, 95% CI: 1.11 to 1.30, P=3.17 x 10-6) higher risk of overall and ER+ve breast cancer, respectively. An inverse association was observed for a SD (0.5 mg/dL) higher genetically determined phosphorus concentration and ER-ve breast cancer (OR: 0.84, 95% CI: 0.72 to 0.98, P=0.03). A suggestive inverse association was observed for a SD (0.48 mg/dL) higher genetically determined calcium concentration with overall breast cancer (OR: 0.91, 95% CI: 0.83 to 1.00, P=0.06). There was little evidence that any of the other nutrients were associated with breast cancer. The results for magnesium were robust under all sensitivity analyses.\n\nConclusionsHigher circulating concentrations of magnesium, phosphorus and calcium may affect breast cancer risk. Further work is required to replicate these findings and investigate underlying mechanisms.\n\nkey messageWe conducted a Mendelian randomization study to investigate whether concentrations of 11 micro-nutrients are associated with risk of breast cancer. An increased risk of overall and oestrogen-receptor positive disease was observed for genetically higher concentrations of magnesium and inverse associations were observed for phosphorus and calcium concentrations\n\nWhere authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization.

epidemiology↗

bioRxiv2019

Genetic determinants of lipids and cardiovascular disease outcomes: a wide-angled Mendelian randomization investigation

AimsTo systematically investigate causal relationships between circulating lipids and cardiovascular outcomes, using a Mendelian randomization approach.\n\nMethods and ResultsIn the primary analysis, we performed two-sample multivariable Mendelian randomization using data from participants of European ancestry. We also conducted univariable analyses using inverse-variance weighted and robust methods, and gene-specific analyses using variants that can be considered as proxies for specific lipid-lowering medications. We obtained associations with lipid fractions from the Global Lipids Genetics Consortium, a meta-analysis of 188,577 participants, and genetic associations with cardiovascular outcomes from 367,703 participants in UK Biobank.\n\nFor LDL-cholesterol, in addition to the expected positive associations with coronary artery disease (CAD) risk (odds ratio per 1 standard deviation increase [OR], 1.45; 95% confidence interval [95%CI] 1.35-1.57) and other atheromatous outcomes (ischemic cerebrovascular disease and peripheral vascular disease), we found independent associations of genetically-predicted LDL-cholesterol with abdominal aortic aneurysm (OR 1.75; 95%CI 1.40-2.17), and aortic valve stenosis (OR 1.46; 95%CI 1.25-1.70). Genetically-predicted triglyceride levels were positively associated with CAD (OR 1.25; 95%CI 1.12-1.40), aortic valve stenosis (OR 1.29; 95%CI 1.04-1.61), and hypertension (OR 1.17; 95%CI 1.07-1.27), but inversely associated with venous thromboembolism (OR 0.79; 95%CI 0.67-0.93). The positive associations of genetically-predicted LDL-cholesterol and triglycerides with heart failure and aortic stenosis appeared to be mediated by CAD.\n\nConclusionLowering LDL-cholesterol is likely to prevent abdominal aortic aneurysm and aortic stenosis, in addition to CAD and other atheromatous cardiovascular outcomes. Lowering triglycerides is likely to prevent CAD and aortic valve stenosis, but may increase risk of thromboembolism.

epidemiology↗

bioRxiv2018

What explains the effect of education on cardiovascular disease? Applying Mendelian randomization to identify the consequences of education inequality

Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the role of body mass index, systolic blood pressure and smoking in mediating the effect of education on cardiovascular disease risk?\n\nFindingWe find consistent evidence that body mass index, systolic blood pressure and smoking mediate the effect of education, explaining up to 18%, 27% and 33% respectively. Including all three risk factors in a model together explains around 40% of the effect of education.\n\nMeaningIntervening on body mass index, systolic blood pressure and smoking would lead to reductions in cases of CVD attributable to lower levels of education. Over half of the effect of education on risk of cardiovascular disease is not mediated through these risk factors.\n\nImportanceLower levels of education are causally related to higher cardiovascular risk, but the extent to which this is driven by modifiable risk factors also associated with education is unknown.\n\nObjectiveTo investigate the role of body mass index, systolic blood pressure and smoking in explaining the effect of education on risk of cardiovascular disease outcomes.\n\nDesignMultivariable regression analysis of observational data and Mendelian randomization (MR) analysis of genetic data.\n\nSettingUK Biobank and international genome-wide association study consortia.\n\nParticipantsPredominantly individuals of European ancestry.\n\nMain outcomes and measuresThe effects of education (per 1-standard deviation increase, equivalent to 3.6 years) on coronary heart disease, cardiovascular disease (all subtypes), myocardial infarction and stroke risk (all measured in odds ratio, OR), and the degree to which this is mediated through body mass index, systolic blood pressure and smoking.\n\nResultsEach additional standard deviation of education associated with 13% lower risk of coronary heart disease (OR 0.87, 95% confidence interval [CI] 0.84 to 0.89) in observational analysis and 37% lower risk (OR 0.63, 95% CI 0.60 to 0.67) in Mendelian randomization analysis. As a proportion of the total risk reduction, body mass index mediated 15% (95% CI 13% to 17%) and 18% (95% CI 14% to 23%) in the observational and Mendelian randomization estimates, respectively. Corresponding estimates for systolic blood pressure were 11% (95% CI 9% to 13%) and 21% (95% CI 15% to 27%), and for smoking, 19% (15% to 22%) and 33% (95% CI 17% to 49%). All three risk factors combined mediated 42% (95% CI 36% to 48%) and 36% (95 % CI 16% to 63%) of the effect of education on coronary heart disease in observational and Mendelian randomization respectively. Similar results were obtained when investigating risk of stroke, myocardial infarction and all-cause cardiovascular disease.\n\nConclusions and relevanceBMI, SBP and smoking mediate a substantial proportion of the protective effect of education on risk of cardiovascular outcomes and intervening on these would lead to reductions in cases of CVD attributable to lower levels of education. However, more than half of the protective effect of education remains unexplained and requires further investigation.

epidemiology↗