Role of circulating polyunsaturated fatty acids on cardiovascular diseases risk:analysis using Mendelian randomization and fatty acid genetic association data from over 114,000 UK Biobank participants

BACKGROUND: Despite early interest in the health effects of polyunsaturated fatty acids (PUFA), there is still substantial controversy and uncertainty on the evidence linking PUFA to cardiovascular diseases (CVDs). We investigated the effect of plasma concentration of omega-3 PUFA (i.e. docosahexaenoic acid (DHA) and total omega-3 PUFA) and omega-6 PUFA (i.e. linoleic acid and total omega-6 PUFA) on the risk of CVDs using Mendelian randomization. METHODS: We conducted the largest genome-wide association study (GWAS) of circulating PUFA to date including a sample of 114,999 individuals and incorporated these data in a two-sample Mendelian randomization framework to investigate the involvement of circulating PUFA on a wide range of CVDs in up to 1,153,768 individuals of European ancestry (i.e. coronary artery disease, ischemic stroke, haemorrhagic stroke, heart failure, atrial fibrillation, peripheral arterial disease, aortic aneurysm, venous thromboembolism and aortic valve stenosis). RESULTS: GWAS identified between 46 and 64 SNPs for the four PUFA traits, explaining 4.8–7.9% of circulating PUFA variance and with mean F statistics >100. Higher genetically predicted DHA (and total omega-3 fatty acids) concentration was related to higher risk of some cardiovascular endpoints; however, these findings did not pass our criteria for multiple testing correction and were attenuated when accounting for LDL-cholesterol through multivariable Mendelian randomization or excluding SNPs in the vicinity of the FADS locus. Estimates for the relation between higher genetically predicted linoleic acid (and total omega-6) concentration were inconsistent across different cardiovascular endpoints and Mendelian randomization methods. There was weak evidence of higher genetically predicted linoleic acid being related to lower risk of ischemic stroke and peripheral artery disease when accounting by LDL-cholesterol. CONCLUSIONS: We have conducted the largest GWAS of circulating PUFA to date and the most comprehensive Mendelian randomization analyses. Overall, our Mendelian randomization findings do not support a protective role of circulating PUFA concentration on the risk of CVDs. However, horizontal pleiotropy via lipoprotein-related traits could be a key source of bias in our analyses. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-022-02399-w

The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians:A Mendelian randomization study

Despite early interest, the evidence linking fatty acids to cardiovascular diseases (CVDs) remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the etiology of several CVD endpoints in up to 1 153 768 European (maximum 123 668 cases) and 212 453 East Asian (maximum 29 319 cases) ancestry individuals. As instruments, we selected single nucleotide polymorphisms mapping to genes with well-known roles in PUFA (i.e. FADS1/2 and ELOVL2) and MUFA (i.e. SCD) biosynthesis. Our findings suggest that higher PUFA biosynthesis rate (proxied by rs174576 near FADS1/2) is related to higher odds of multiple CVDs, particularly ischemic stroke, peripheral artery disease and venous thromboembolism, whereas higher MUFA biosynthesis rate (proxied by rs603424 near SCD) is related to lower odds of coronary artery disease among Europeans. Results were unclear for East Asians as most effect estimates were imprecise. By triangulating multiple approaches (i.e. uni-/multi-variable Mendelian randomization, a phenome-wide scan, genetic colocalization and within-sibling analyses), our results are compatible with higher low-density lipoprotein (LDL) cholesterol (and possibly glucose) being a downstream effect of higher PUFA biosynthesis rate. Our findings indicate that PUFA and MUFA biosynthesis are involved in the etiology of CVDs and suggest LDL cholesterol as a potential mediating trait between PUFA biosynthesis and CVDs risk

Understanding the consequences of education inequality on cardiovascular disease: mendelian randomisation study.

OBJECTIVES: To investigate the role of body mass index (BMI), systolic blood pressure, and smoking behaviour in explaining the effect of education on the risk of cardiovascular disease outcomes. DESIGN: Mendelian randomisation study. SETTING: UK Biobank and international genome-wide association study data. PARTICIPANTS: Predominantly participants of European ancestry. EXPOSURE: Educational attainment, BMI, systolic blood pressure, and smoking behaviour in observational analysis, and randomly allocated genetic variants to instrument these traits in mendelian randomisation. MAIN OUTCOMES MEASURE: The risk of coronary heart disease, stroke, myocardial infarction, and cardiovascular disease (all subtypes; all measured in odds ratio), and the degree to which this is mediated through BMI, systolic blood pressure, and smoking behaviour respectively. RESULTS: Each additional standard deviation of education (3.6 years) was associated with a 13% lower risk of coronary heart disease (odds ratio 0.86, 95% confidence interval 0.84 to 0.89) in observational analysis and a 37% lower risk (0.63, 0.60 to 0.67) in mendelian randomisation analysis. As a proportion of the total risk reduction, BMI was estimated to mediate 15% (95% confidence interval 13% to 17%) and 18% (14% to 23%) in the observational and mendelian randomisation estimates, respectively. Corresponding estimates were 11% (9% to 13%) and 21% (15% to 27%) for systolic blood pressure and 19% (15% to 22%) and 34% (17% to 50%) for smoking behaviour. All three risk factors combined were estimated to mediate 42% (36% to 48%) and 36% (5% to 68%) of the effect of education on coronary heart disease in observational and mendelian randomisation analyses, respectively. Similar results were obtained when investigating the risk of stroke, myocardial infarction, and cardiovascular disease. CONCLUSIONS: BMI, systolic blood pressure, and smoking behaviour mediate a substantial proportion of the protective effect of education on the risk of cardiovascular outcomes and intervening on these would lead to reductions in cases of cardiovascular disease attributable to lower levels of education. However, more than half of the protective effect of education remains unexplained and requires further investigation.Includes MRC, ESRC, Wellcome Trust and NIHR

Regulation of Motor Function and Behavior by Atypical Chemokine Receptor 1

The final publication is available at Springer via http://dx.doi.org/10.1007/s10519-014-9665-7Atypical Chemokine Receptor 1 (ACKR1), previously known as the Duffy Antigen Receptor for Chemokines, stands out among chemokine receptors for its high selective expression on Purkinje cells of the cerebellum, consistent with the ability of ACKR1 ligands to activate Purkinje cells in vitro. Nevertheless, evidence for ACKR1 regulation of brain function in vivo has been lacking. Here we demonstrate that Ackr1−/− mice have markedly impaired balance and ataxia when placed on a rotating rod and increased tremor when injected with harmaline, a drug that induces whole-body tremor by activating Purkinje cells. Ackr1−/− mice also exhibited impaired exploratory behavior, increased anxiety-like behavior and frequent episodes of marked hypoactivity under low-stress conditions. The behavioral phenotype of Ackr1−/− mice was the opposite of the phenotype occurring in mice with cerebellar degeneration and the defects persisted when Ackr1 was deficient only on non-hematopoietic cells. We conclude that normal motor function and behavior depend in part on negative regulation of Purkinje cell activity by Ackr1

Additional file 1 of Role of circulating polyunsaturated fatty acids on cardiovascular diseases risk: analysis using Mendelian randomization and fatty acid genetic association data from over 114,000 UK Biobank participants

Additional file 1: Supplementary Tables S1–S11

Understanding the consequences of education inequality on cardiovascular disease: mendelian randomisation study.

OBJECTIVES: To investigate the role of body mass index (BMI), systolic blood pressure, and smoking behaviour in explaining the effect of education on the risk of cardiovascular disease outcomes. DESIGN: Mendelian randomisation study. SETTING: UK Biobank and international genome-wide association study data. PARTICIPANTS: Predominantly participants of European ancestry. EXPOSURE: Educational attainment, BMI, systolic blood pressure, and smoking behaviour in observational analysis, and randomly allocated genetic variants to instrument these traits in mendelian randomisation. MAIN OUTCOMES MEASURE: The risk of coronary heart disease, stroke, myocardial infarction, and cardiovascular disease (all subtypes; all measured in odds ratio), and the degree to which this is mediated through BMI, systolic blood pressure, and smoking behaviour respectively. RESULTS: Each additional standard deviation of education (3.6 years) was associated with a 13% lower risk of coronary heart disease (odds ratio 0.86, 95% confidence interval 0.84 to 0.89) in observational analysis and a 37% lower risk (0.63, 0.60 to 0.67) in mendelian randomisation analysis. As a proportion of the total risk reduction, BMI was estimated to mediate 15% (95% confidence interval 13% to 17%) and 18% (14% to 23%) in the observational and mendelian randomisation estimates, respectively. Corresponding estimates were 11% (9% to 13%) and 21% (15% to 27%) for systolic blood pressure and 19% (15% to 22%) and 34% (17% to 50%) for smoking behaviour. All three risk factors combined were estimated to mediate 42% (36% to 48%) and 36% (5% to 68%) of the effect of education on coronary heart disease in observational and mendelian randomisation analyses, respectively. Similar results were obtained when investigating the risk of stroke, myocardial infarction, and cardiovascular disease. CONCLUSIONS: BMI, systolic blood pressure, and smoking behaviour mediate a substantial proportion of the protective effect of education on the risk of cardiovascular outcomes and intervening on these would lead to reductions in cases of cardiovascular disease attributable to lower levels of education. However, more than half of the protective effect of education remains unexplained and requires further investigation.Includes MRC, ESRC, Wellcome Trust and NIHR

The EWAS Catalog: a database of epigenome-wide association studies

Epigenome-wide association studies (EWAS) seek to quantify associations between traits/exposures and DNA methylation measured at thousands or millions of CpG sites across the genome. In recent years, the increase in availability of DNA methylation measures in population-based cohorts and case-control studies has resulted in a dramatic expansion of the number of EWAS being performed and pub-lished. To make this rich source of results more accessible, we have manually curated a database of CpG-trait associations (with p<1x10-4) from published EWAS, each assaying over 100,000 CpGs in at least 100 individuals. From 2021-01-29, The EWAS Catalog contained 1,045,303 associations from over 1000 EWAS. This includes 652,530 associations from 264 peer-reviewed publications. In addi-tion, it also contains summary statistics for 392,773 associations from 428 EWAS, performed in data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Gene Expression Om-nibus (GEO). The database is accompanied by a web-based tool and R package, giving researchers the opportunity to quickly and easily query EWAS associations and gain insight into the molecular under-pinnings of disease as well as the impact of traits and exposures on the DNA methylome. The EWAS Catalog is available at: http://www.ewascatalog.org

Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases.

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( https://www.epigraphdb.org/pqtl/ ). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.This publication is the work of the authors and Jie Zheng will serve as guarantor for the contents of this paper. JZ is funded by a Vice-Chancellor Fellowship from the University of Bristol. This research was also funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/1 and MC_UU_00011/4), GlaxoSmithKline, Biogen and the Cancer Research Integrative Cancer Epidemiology Programme (C18281/A19169). The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). GH is funded by the Wellcome Trust and the Royal Society [208806/Z/17/Z]. MVH is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre. This study was funded/supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol (GDS and TRG). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care. This work was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol and the Medical Research Council Proximity to Discovery Award. PE is supported by CRUK [C18281/A19169]. SL is funded by the Bau Tsu Zung Bau Kwan Yeun Hing Research and Clinical Fellowship (*200008682.920006.20006.400.01) from the University of Hong Kong. JD is funded by the National Institute for Health Research [Senior Investigator Award]. JD sits on the International Cardiovascular and Metabolic Advisory Board for Novartis (since 2010), the Steering Committee of UK Biobank (since 2011), the MRC International Advisory Group (ING) member, London (since 2013), the MRC High Throughput Science ‘Omics Panel Member, London (since 2013), the Scientific Advisory Committee for Sanofi (since 2013), the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis and the Astra Zeneca Genomics Advisory Board (2018). Participants in the INTERVAL randomised controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (www.nhsbt.nhs.uk), which has supported field work and other elements of the trial. DNA extraction and genotyping was co-funded by the National Institute for Health Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk) and the NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust] [*]. The academic coordinating centre for INTERVAL was supported by core funding from: NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), UK Medical Research Council (MR/L003120/1), British Heart Foundation (SP/09/002; RG/13/13/30194; RG/18/13/33946) and the NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust] [*]. A complete list of the investigators and contributors to the INTERVAL trial is provided in reference [**]. The academic coordinating centre would like to thank blood donor centre staff and blood donors for participating in the INTERVAL trial

Temporal Links in Daily Activity Patterns between Coral Reef Predators and Their Prey

Few studies have documented the activity patterns of both predators and their common prey over 24 h diel cycles. This study documents the temporal periodicity of two common resident predators of juvenile reef fishes, Cephalopholis cyanostigma (rockcod) and Pseudochromis fuscus (dottyback) and compares these to the activity and foraging pattern of a common prey species, juvenile Pomacentrus moluccensis (lemon damselfish). Detailed observations of activity in the field and using 24 h infrared video in the laboratory revealed that the two predators had very different activity patterns. C. cyanostigma was active over the whole 24 h period, with a peak in feeding strikes at dusk and increased activity at both dawn and dusk, while P. fuscus was not active at night and had its highest strike rates at midday. The activity and foraging pattern of P. moluccensis directly opposes that of C. cyanostigma with individuals reducing strike rate and intraspecific aggression at both dawn and dusk, and reducing distance from shelter and boldness at dusk only. Juveniles examined were just outside the size-selection window of P. fuscus. We suggest that the relatively predictable diel behaviour of coral reef predators results from physiological factors such as visual sensory abilities, circadian rhythmicity, variation in hunting profitability, and predation risk at different times of the day. Our study suggests that the diel periodicity of P. moluccensis behaviour may represent a response to increased predation risk at times when both the ability to efficiently capture food and visually detect predators is reduced