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The 20th century coronary heart disease pandemic remains a partial enigma. Here we focus on sex differences in mortality as an indicator of the disease during a time when classification of cause of death was uncertain. We suggest that cohorts born during a few decades around the turn of the century bore the brunt of the pandemic, and propose that the 1889-1895 Russian influenza epidemic may have contributed to this. That some evidence points to the introduction of a human seasonal coronavirus during the 1889-95 pandemic adds contemporary relevance to these speculations.

Background Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin-6 (IL-6). Genetic variants in IL6R known to downregulate IL-6 signalling are associated with improved COVID-19 outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RA). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. Methods and findings We performed a Mendelian randomisation analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. In the UK Biobank cohort (N=486,484, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of our primary outcome, sepsis (Odds ratio, OR = 0.80; 95% CI 0.66-0.96, per unit of natural log transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR=0.74; 95% CI 0.47-1.15); critical care admission with sepsis (OR=0.48, 95% CI 0.30-0.78) and critical care death with sepsis (OR=0.37, 95% CI 0.14 - 0.98). Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 - 0.97) and for sepsis survival in critical care (OR=0.22; 95% CI 0.04-1.31) in the GainS and GenOSept consortium, although this result had a large degree of imprecision. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR=0.69, 95% 0.57 - 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. These results are subject to the limitations and assumptions of Mendelian randomisation, which in this case reflects interpretation of these SNP effects as causally acting through blockade of IL6R, and reflect lifetime exposure to IL6R blockade, rather than the effect of therapeutic IL6R blockade. Conclusions IL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. This data suggests a randomised trial of IL-6 receptor antagonists in sepsis should be considered.

Epigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker.We conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (nine single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs), and GrimAge (4 SNPs) on multiple cancers (i.e. breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N = 34,710), and for cancer from the UK Biobank (N cases = 2671-13,879; N controls = 173,493-372,016), FinnGen (N cases = 719-8401; N controls = 74,685-174,006) and several international cancer genetic consortia (N cases = 11,348-122,977; N controls = 15,861-105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach.Meta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR = 1.12 per year increase in GrimAge acceleration, 95% CI 1.04-1.20, p = 0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR = 1.15, 95% CI 1.09-1.21, p = 0.006), than rectal cancer (IVW OR = 1.05, 95% CI 0.97-1.13, p = 0.24). Results were less consistent for associations between other epigenetic clocks and cancers.GrimAge acceleration may increase the risk of colorectal cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results.FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z which is part of grant 218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic's Operational Programme 'Competitiveness, EntrepreneurshipInnovation' (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019). RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5, respectively) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer's Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor's Research Fellow at the University of Bristol.Have you noticed that some people seem to get older faster than others? Scientists have previously found that a chemical tag on DNA known as DNA methylation can be used to predict an individual’s chronological age. However, age predicted using DNA methylation (also known as biological or epigenetic age) does not always perfectly correspond to chronological age. Indeed, some people’s biological age is higher than their years, while other people’s is lower. When an individual’s biological age is higher than their chronological age, they are said to be experiencing ‘epigenetic age acceleration’. This type of accelerated ageing, which can be measured with ‘epigenetic clocks’ based on DNA methylation, has been associated with several adverse health outcomes, including cancer. This means that epigenetic clocks may improve our ability to predict cancer risk and detect cancer early. However, it is still unclear whether accelerated biological ageing causes cancer, or whether it simply correlates with the disease. Morales-Berstein et al. wanted to investigate whether epigenetic age acceleration, as measured by epigenetic clocks, plays a role in the development of several cancers. To do so, they used an approach known as Mendelian randomization. Using genetic variants as natural experiments, they studied the effect of different measures of epigenetic age acceleration on cancer risk. Their work focused on five types of cancer: breast, colorectal, prostate, ovarian and lung cancer. They used genetic association data from people of European ancestry to determine whether genetic variants that are strongly associated with accelerated ageing are also strongly associated with cancer. The results showed that one of the DNA methylation markers used as an estimate of biological ageing could be directly related to the risk of developing colorectal cancer. This work provides new insights into the relationship between markers of biological ageing and cancer. Similar relationships should also be studied in other groups of people and for other cancer sites. The results suggest that reversing biological ageing by altering DNA methylation could prevent or delay the development of colorectal cancer.

Background Epigenetic clocks are biomarkers of ageing derived from DNA methylation levels at a subset of CpG sites. The difference between age predicted by these clocks and chronological age, termed “epigenetic age acceleration”, has been shown to predict age-related disease and mortality. We aimed to assess the prognostic value of epigenetic age acceleration and a DNA methylation-based mortality risk score with all-cause mortality in a prospective clinical cohort of individuals with head and neck cancer: Head and Neck 5000. We investigated two markers of intrinsic epigenetic age acceleration (IEAAHorvath and IEAAHannum), one marker of extrinsic epigenetic age acceleration (EEAA), one optimised to predict physiological dysregulation (AgeAccelPheno), one optimised to predict lifespan (AgeAccelGrim) and a DNA methylation-based predictor of mortality (ZhangScore). Cox regression models were first used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations of epigenetic age acceleration with all-cause mortality in people with oropharyngeal cancer (n = 408; 105 deaths). The added prognostic value of epigenetic markers compared to a clinical model including age, sex, TNM stage and HPV status was then evaluated. Results IEAAHannum and AgeAccelGrim were associated with mortality risk after adjustment for clinical and lifestyle factors (HRs per standard deviation [SD] increase in age acceleration = 1.30 [95% CI 1.07, 1.57; p = 0.007] and 1.40 [95% CI 1.06, 1.83; p = 0.016], respectively). There was weak evidence that the addition of AgeAccelGrim to the clinical model improved 3-year mortality prediction (area under the receiver operating characteristic curve: 0.80 vs. 0.77; p value for difference = 0.069). Conclusion In the setting of a large, clinical cohort of individuals with head and neck cancer, our study demonstrates the potential of epigenetic markers of ageing to enhance survival prediction in people with oropharyngeal cancer, beyond established prognostic factors. Our findings have potential uses in both clinical and non-clinical contexts: to aid treatment planning and improve patient stratification.

Accurate measurement of the effects of disease status on healthcare costs is important in the pragmatic evaluation of interventions but is complicated by endogeneity bias. Mendelian Randomization, the use of random perturbations in germline genetic variation as instrumental variables, can avoid these limitations. We used a novel Mendelian Randomization analysis to model the causal impact on inpatient hospital costs of liability to six prevalent diseases and health conditions: asthma, eczema, migraine, coronary heart disease, Type 2 diabetes, and depression. We identified genetic variants from replicated genome-wide associations studies and estimated their association with inpatient hospital costs on over 300,000 individuals. There was concordance of findings across varieties of sensitivity analyses, including stratification by sex and methods robust to violations of the exclusion restriction. Results overall were imprecise and we could not rule out large effects of liability to disease on healthcare costs. In particular, genetic liability to coronary heart disease had substantial impacts on costs.

Studies suggest that adiposity in childhood may reduce the risk of breast cancer in later life. The biological mechanism underlying this effect is unclear but is likely to be independent of body size in adulthood. Using a Mendelian randomization framework, we investigated 18 hypothesised mediators of the protective effect of childhood adiposity on later-life breast cancer, including hormonal, reproductive, physical, and glycaemic traits.Our results indicate that, while most of the hypothesised mediators are affected by childhood body size, only IGF-1, testosterone, age at menarche and age at menopause influenced breast cancer risk. However, accounting for those traits in multivariable Mendelian randomization showed that the protective effect of childhood body size still remained. This suggests either a direct effect of childhood body size on breast cancer risk or mediation via other pathways not considered.Our work presents a framework for the systematic exploration of potential biological mediators of disease in Mendelian randomization analysis.

ImportanceEvidence linking parental diagnoses of inflammatory bowel disease (IBD) with offspring autism is inconclusive.ObjectiveTo investigate associations between parental diagnoses of IBD and offspring autism and elucidate their underlying aetiology by conducting four complementary studies.Design, Setting and Participants(1) Nationwide population-based cohort study using Swedish registers to examine associations between parental IBD diagnoses and autism diagnoses in offspring, (2) Linkage disequilibrium (LD)-score regression to estimate the genetic correlation between the phenotypes. (3) Polygenic risk score (PRS) analyses in the Avon Longitudinal Study of Parents and Children (ALSPAC) to investigate associations between maternal genetic liability to IBD and autism factor mean score in offspring. (4) Two-sample Mendelian randomization (MR) to assess bidirectional causal links between genetic liability to IBD and autism.ResultsObservational analyses provided evidence of an association between parental IBD diagnoses and offspring autism diagnosis in mutually adjusted models (maternal: OR= 1.32; 95% CI: 1.25 to 1.40; pPRS= 0.02; 95%CI: 0.003 to 0.05; p= 0.02; R2=0.06; Crohn’s: βPRS= 0.03; 95%CI: 0.01 to 0.05; p= 0.004; R2= 0.06; n= 7357, 50.3% male). MR analyses provided evidence of a potential causal effect of genetic liability for IBD, especially ulcerative colitis, on autism (ORMR= 1.03; 95%CI: 1.01 to 1.06). There was little evidence to suggest a causal effect of genetic liability to autism on risk of IBD, or a genetic correlation between the two conditions.Conclusions and relevanceTriangulating evidence from a nationwide register-based cohort study, genetic correlation, polygenic risk score analyses and MR, we found evidence of a potentially causal link between parental, particularly maternal, diagnoses and genetic liability to IBD and offspring autism. Perinatal immune system dysregulation, micronutrient malabsorption and anaemia may be implicated.

BackgroundThe causal impact of excess adiposity on systemic metabolism is unclear. We used multivariable Mendelian randomization to compare the direct effects of total adiposity (using body mass index (BMI)) and abdominal adiposity (using waist-to-hip-ratio (WHR)) on circulating lipoproteins, lipids, and metabolites with a five-fold increase in sample size over previous studies.MethodsWe used new metabolic data on 109,532 UK Biobank participants. BMI and WHR were measured in 2006-2010, during which EDTA plasma was collected. Plasma samples were used in 2019-2020 to quantify 249 metabolic traits with high-throughput nuclear magnetic resonance spectroscopy including subclass-specific lipoprotein concentrations, apolipoprotein B, cholesterol and triglycerides, plus pre-glycemic and inflammatory metabolites. We used two-stage least squares regression models with genetic risk scores for BMI and WHR as instruments to estimate the total (unadjusted) and direct (mutually adjusted) effects of BMI and WHR on metabolic traits. We also estimated the effects of BMI and WHR on statin use, and examined interaction of main effects by sex, statin use, and age as a proxy for medication use.ResultsHigher BMI (per standard deviation (SD) or 4.8 kg/m2) was estimated to moderately decrease apolipoprotein B and low-density lipoprotein (LDL) cholesterol before and after adjustment for WHR, whilst higher BMI increased triglycerides before but not after WHR adjustment. Estimated effects of higher WHR (per SD, or 0.090 ratio-unit) on lipoproteins, lipids, and metabolites were often larger than those of BMI, but null for LDL cholesterol, and attenuations were minimal upon adjustment for BMI. Patterns of effect estimates differed by sex, e.g., only BMI independently increased triglycerides among men, whereas only WHR independently increased triglycerides among women. Higher BMI and WHR (per SD) were each estimated to directly increase the relative odds of using statins (by 3.49 (95% CI = 3.42, 3.57) times higher for WHR). These patterns were most pronounced among women, and there was strong evidence that the effects of BMI and WHR on metabolic traits differed by statin use and age. Among the youngest adults (38-53 years, statin use 5%), higher BMI and WHR (per SD) each modestly increased LDL cholesterol (0.04 SD, 95% CI = -0.01, 0.08 for total effect of BMI and 0.10 SD, 95% CI = 0.02, 0.17 for total effect of WHR). This estimate for BMI fully attenuated, and the estimate for WHR remained unchanged, upon mutual adjustment. These direct effects on LDL cholesterol were more inverse for BMI and less positive for WHR at intermediate ages (54-62 years, statins 17%) and older ages (63-73 years, statins 29%) where the mutually adjusted effects of BMI and WHR on LDL cholesterol had reversed to -0.19 SD (95% CI = -0.27, -0.11) and -0.05 SD (95% CI = -0.16, 0.06), respectively.ConclusionsOur results suggest that abdominal adiposity has a dominant role in driving the metabolic harms of excess adiposity, particularly among women. Our findings also suggest that apparent effects of adiposity on lowering LDL cholesterol are explained by an effect of adiposity on statin use.

In the version of this article originally published, the e-mail address of corresponding author Patricia B. Munroe was incorrect. The error has been corrected in the HTML and PDF versions of the article.

Objectives: This study characterized the determinants of carotid intima-media thickness (cIMT) in a large (n > 4,000) longitudinal cohort of healthy young people age 9 to 21 years. Background: Greater cIMT is commonly used in the young as a marker of subclinical atherosclerosis, but its evolution at this age is still poorly understood. Methods: Associations between cardiovascular risk factors and cIMT were investigated in both longitudinal (ages 9 to 17 years) and cross-sectional (ages 17 and 21 years) analyses, with the latter also related to other measures of carotid structure and stress. Additional use of ultra-high frequency ultrasound in the radial artery at age 21 years allowed investigation of the distinct layers (i.e., intima or media) that may underlie observed differences. Results: Fat-free mass (FFM) and systolic blood pressure were the only modifiable risk factors positively associated with cIMT (e.g., mean difference in cIMT per 1-SD increase in FFM at age 17: 0.007 mm: 95% confidence interval [CI]: 0.004 to 0.010; p < 0.001), whereas fat mass was negatively associated with cIMT (difference: −0.0032; 95% CI: 0.004 to −0.001; p = 0.001). Similar results were obtained when investigating cumulative exposure to these factors throughout adolescence. An increase in cIMT maintained circumferential wall stress in the face of increased mean arterial pressure when increases in body mass were attributable to increased FFM, but not fat mass. Risk factor−associated differences in the radial artery occurred in the media alone, and there was little evidence of a relationship between intimal thickness and any risk factor. Conclusions: Subtle changes in cIMT in the young may predominantly involve the media and represent physiological adaptations as opposed to subclinical atherosclerosis. Other vascular measures may be more appropriate for the identification of arterial disease before adulthood. © 2021 The Authors

This paper provides guidelines for performing Mendelian randomization investigations. It is aimed at practitioners seeking to undertake analyses and write up their findings, and at journal editors and reviewers seeking to assess Mendelian randomization manuscripts. The guidelines are divided into nine sections: motivation and scope, data sources, choice of genetic variants, variant harmonization, primary analysis, supplementary and sensitivity analyses (one section on robust statistical methods and one on other approaches), data presentation, and interpretation. These guidelines will be updated based on feedback from the community and advances in the field. Updates will be made periodically as needed, and at least every 18 months.

Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson’s disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P