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Background Evidence for the impact of body size and composition on cancer risk is limited. This mendelian randomisation (MR) study investigates evidence supporting causal relationships of body mass index (BMI), fat mass index (FMI), fat-free mass index (FFMI), and height with cancer risk. Methods and findings Single nucleotide polymorphisms (SNPs) were used as instrumental variables for BMI (312 SNPs), FMI (577 SNPs), FFMI (577 SNPs), and height (293 SNPs). Associations of the genetic variants with 22 site-specific cancers and overall cancer were estimated in 367,561 individuals from the UK Biobank (UKBB) and with lung, breast, ovarian, uterine, and prostate cancer in large international consortia. In the UKBB, genetically predicted BMI was positively associated with overall cancer (odds ratio [OR] per 1 kg/m2 increase 1.01, 95% confidence interval [CI] 1.00–1.02; p = 0.043); several digestive system cancers: stomach (OR 1.13, 95% CI 1.06–1.21; p < 0.001), esophagus (OR 1.10, 95% CI 1.03, 1.17; p = 0.003), liver (OR 1.13, 95% CI 1.03–1.25; p = 0.012), and pancreas (OR 1.06, 95% CI 1.01–1.12; p = 0.016); and lung cancer (OR 1.08, 95% CI 1.04–1.12; p < 0.001). For sex-specific cancers, genetically predicted elevated BMI was associated with an increased risk of uterine cancer (OR 1.10, 95% CI 1.05–1.15; p < 0.001) and with a lower risk of prostate cancer (OR 0.97, 95% CI 0.94–0.99; p = 0.009). When dividing cancers into digestive system versus non-digestive system, genetically predicted BMI was positively associated with digestive system cancers (OR 1.04, 95% CI 1.02–1.06; p < 0.001) but not with non-digestive system cancers (OR 1.01, 95% CI 0.99–1.02; p = 0.369). Genetically predicted FMI was positively associated with liver, pancreatic, and lung cancer and inversely associated with melanoma and prostate cancer. Genetically predicted FFMI was positively associated with non-Hodgkin lymphoma and melanoma. Genetically predicted height was associated with increased risk of overall cancer (OR per 1 standard deviation increase 1.09; 95% CI 1.05–1.12; p < 0.001) and multiple site-specific cancers. Similar results were observed in analyses using the weighted median and MR–Egger methods. Results based on consortium data confirmed the positive associations between BMI and lung and uterine cancer risk as well as the inverse association between BMI and prostate cancer, and, additionally, showed an inverse association between genetically predicted BMI and breast cancer. The main limitations are the assumption that genetic associations with cancer outcomes are mediated via the proposed risk factors and that estimates for some lower frequency cancer types are subject to low precision. Conclusions Our results show that the evidence for BMI as a causal risk factor for cancer is mixed. We find that BMI has a consistent causal role in increasing risk of digestive system cancers and a role for sex-specific cancers with inconsistent directions of effect. In contrast, increased height appears to have a consistent risk-increasing effect on overall and site-specific cancers., Mathew Vithayathil and colleagues study associations of body mass index and other measures with incidence of specific cancers., Author summary Why was this study done? The causal relevance of body size and composition as risk factors for specific cancers is unclear based on traditional observational studies. By considering the relationships between genetically predicted values of body size and composition with cancer risk, our estimates are less influenced by confounding variables, and, hence, more reliably reflect the underlying causal relationships between these measures and cancer risk. What did the researchers do and find? We assessed the associations between genetically predicted body mass index (BMI), fat mass index (FMI), fat-free mass index (FFMI), and height with 22 specific cancers in the UK Biobank (UKBB), a population-based sample of the United Kingdom residents. Although genetically predicted height was consistently associated with increased risk of site-specific cancers, genetically predicted BMI was associated with an increased risk of certain digestive system cancers (esophageal, stomach, liver, and pancreas), plus lung and uterine cancer, but a decreased risk of breast and prostate cancer. When dividing cancers into digestive system cancers versus non-digestive system cancers, genetically predicted BMI was associated with increased risk of digestive system cancers, but not associated with non-digestive system cancers. What do these findings mean? Our findings suggest that BMI is a causal risk factor for some cancers, but is not a generic risk factor for all cancers. Body fat may play a role in development of specific cancers and should be studied further to identify future targets to prevent cancer. Public health strategies should focus on reducing obesity as a risk factor for cancer, but should be clear that benefit may be limited to certain cancers.

Funder: Karolinska Institute, The present study aimed to determine the associations between insomnia and cardiovascular diseases (CVDs) using Mendelian randomisation (MR) analysis. As instrumental variables, we used 208 independent single-nucleotide polymorphisms associated with insomnia at the genome-wide significance threshold in a meta-analysis of genome-wide association studies in the UK Biobank and 23andMe including a total of 397 959 self-reported insomnia cases and 933 057 non-cases. Summary-level data for nine CVDs were obtained from the UK Biobank including 367 586 individuals of European ancestry. After correction for multiple testing, genetic liability to insomnia was associated with higher odds of six CVDs, including peripheral arterial disease (odd ratio (OR) 1.22; 95% confidence interval (CI), 1.21, 1.33), heart failure (OR 1.21; 95% CI, 1.13, 1.30), coronary artery disease (OR 1.19; 95% CI, 1.14, 1.25), ischaemic stroke (OR 1.15; 95% CI, 1.06, 1.25), venous thromboembolism (OR 1.13; 95% CI, 1.07, 1.19) and atrial fibrillation (OR 1.10; 95% CI, 1.05, 1.15). There were suggestive associations for aortic valve stenosis (OR, 1.17; 95% CI, 1.04, 1.32) and haemorrhagic stroke (OR 1.14; 95% CI, 1.00, 1.29) but no association for abdominal aortic aneurysm (OR, 1.14, 95% CI, 0.98, 1.33). The patterns of associations remained with mild attenuation in multivariable MR analyses adjusting for genetically correlated phenotypes and potential mediators, including sleep duration, depression, body mass index, type 2 diabetes and smoking. The present MR study suggests potential causal associations of genetic liability to insomnia with increased risk of a broad range of CVDs.

Funder: United Kingdom Research and Innovation Future Leaders Fellowship (MR/T043202/1), Funder: EC‐Innovative Medicines Initiative (BigData@Heart), Funder: Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z), Background: Folate, vitamin B6 and vitamin B12 have been associated with digestive system cancers. We conducted a two-sample Mendelian randomisation study to assess the causality of these associations. Methods: Two, one and 14 independent single nucleotide polymorphisms associated with serum folate, vitamin B6 and vitamin B12 at the genome-wide significance threshold were selected as genetic instruments. Summary-level data for the associations of the vitamin-associated genetic variants with cancer were obtained from the UK Biobank study including 367,561 individuals and FinnGen consortium comprising up to 176,899 participants. Results: Genetically predicted folate and vitamin B6 concentrations were not associated with overall cancer, overall digestive system cancer or oesophageal, gastric, colorectal or pancreatic cancer. Genetically predicted vitamin B12 concentrations were positively associated with overall digestive system cancer (ORSD, 1.12; 95% CI 1.04, 1.21, p = 0.003) and colorectal cancer (ORSD 1.16; 95% CI 1.06, 1.26, p = 0.001) in UK Biobank. Results for colorectal cancer were consistent in FinnGen and the combined ORSD was 1.16 (95% CI 1.08, 1.25, p < 0.001). There was no association of genetically predicted vitamin B12 with any other site-specific digestive system cancers or overall cancer. Conclusions: These results provide evidence to suggest that elevated serum vitamin B12 concentrations are associated with colorectal cancer.

Background Insulin resistance predisposes to cardiometabolic disorders, which are commonly comorbid with schizophrenia and are key contributors to the significant excess mortality in schizophrenia. Mechanisms for the comorbidity remain unclear, but observational studies have implicated inflammation in both schizophrenia and cardiometabolic disorders separately. We aimed to examine whether there is genetic evidence that insulin resistance and 7 related cardiometabolic traits may be causally associated with schizophrenia, and whether evidence supports inflammation as a common mechanism for cardiometabolic disorders and schizophrenia. Methods and findings We used summary data from genome-wide association studies of mostly European adults from large consortia (Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) featuring up to 108,557 participants; Diabetes Genetics Replication And Meta-analysis (DIAGRAM) featuring up to 435,387 participants; Global Lipids Genetics Consortium (GLGC) featuring up to 173,082 participants; Genetic Investigation of Anthropometric Traits (GIANT) featuring up to 339,224 participants; Psychiatric Genomics Consortium (PGC) featuring up to 105,318 participants; and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium featuring up to 204,402 participants). We conducted two-sample uni- and multivariable mendelian randomization (MR) analysis to test whether (i) 10 cardiometabolic traits (fasting insulin, high-density lipoprotein and triglycerides representing an insulin resistance phenotype, and 7 related cardiometabolic traits: low-density lipoprotein, fasting plasma glucose, glycated haemoglobin, leptin, body mass index, glucose tolerance, and type 2 diabetes) could be causally associated with schizophrenia; and (ii) inflammation could be a shared mechanism for these phenotypes. We conducted a detailed set of sensitivity analyses to test the assumptions for a valid MR analysis. We did not find statistically significant evidence in support of a causal relationship between cardiometabolic traits and schizophrenia, or vice versa. However, we report that a genetically predicted inflammation-related insulin resistance phenotype (raised fasting insulin (raised fasting insulin (Wald ratio OR = 2.95, 95% C.I, 1.38–6.34, Holm-Bonferroni corrected p-value (p) = 0.035) and lower high-density lipoprotein (Wald ratio OR = 0.55, 95% C.I., 0.36–0.84; p = 0.035)) was associated with schizophrenia. Evidence for these associations attenuated to the null in multivariable MR analyses after adjusting for C-reactive protein, an archetypal inflammatory marker: (fasting insulin Wald ratio OR = 1.02, 95% C.I, 0.37–2.78, p = 0.975), high-density lipoprotein (Wald ratio OR = 1.00, 95% C.I., 0.85–1.16; p = 0.849), suggesting that the associations could be fully explained by inflammation. One potential limitation of the study is that the full range of gene products from the genetic variants we used as proxies for the exposures is unknown, and so we are unable to comment on potential biological mechanisms of association other than inflammation, which may also be relevant. Conclusions Our findings support a role for inflammation as a common cause for insulin resistance and schizophrenia, which may at least partly explain why the traits commonly co-occur in clinical practice. Inflammation and immune pathways may represent novel therapeutic targets for the prevention or treatment of schizophrenia and comorbid insulin resistance. Future work is needed to understand how inflammation may contribute to the risk of schizophrenia and insulin resistance., In a Mendelian randomization study, Benjamin Perry and colleagues investigate the genetic evidence supporting relationships between inflammation, insulin resistance, and schizophrenia., Author summary Why was this study done? Cardiometabolic disorders such as diabetes are up to 30% more common in people with schizophrenia than in the general population, and are among the predominant causes of a 10- to 15-year shortened life expectancy in people with schizophrenia. Insulin resistance, a precursor to diabetes, is sometimes detectable in young adults suffering their first episode of psychosis, which suggests that chronic lifestyle and clinical factors, such as smoking, physical inactivity, and medication side effects may not fully explain the comorbidity. Inflammation has been consistently associated with schizophrenia and cardiometabolic disorders, and so could be a common mechanism for schizophrenia and cardiometabolic disorders. This could help to at least in part explain why people who have schizophrenia also have higher rates of cardiometabolic disorders, over and above the commonly attributed lifestyle/clinical factors. What did the researchers do and find? To examine whether insulin resistance and 7 related cardiometabolic traits causally influence schizophrenia risk or vice versa, we conducted bidirectional, two-sample, uni- and multivariable mendelian randomizsation (MR) analyses. The MR approach uses genetic variants as proxies for modifiable exposures to untangle the problems of reverse causation and unmeasured confounding. To test a hypothesis that inflammation may be a common mechanism for schizophrenia and cardiometabolic disorders, we also examined a subset of genetic variants which were associated with inflammation as well as the cardiometabolic trait. We also used multivariable MR (MVMR) as a sensitivity analysis to adjust for C-reactive protein (CRP), an archetypal inflammatory marker, as a general downstream marker of systemic inflammation. After correction for multiple testing, overall, there was no significant evidence in support of a causal relationship between cardiometabolic traits and schizophrenia, or vice versa. However, we found evidence that supports a causal relationship of an inflammation-related insulin resistance phenotype with schizophrenia. Evidence for the association of an inflammation-related insulin resistance phenotype with schizophrenia attenuated fully in MVMR analysis after adjusting for CRP, suggesting that these associations may be underpinned by inflammation. What do these findings mean? These results suggest that cardiometabolic traits are unlikely to have a causal role in the pathogenesis of schizophrenia or vice versa. However, our results suggest that inflammation is related to the risk of both schizophrenia and insulin resistance, which may at least partly explain why they commonly occur in clinical practice. Treating or preventing inflammation may be a putative therapeutic option for prevention and/or treatment of both schizophrenia and comorbid insulin resistance. In the future, more research is needed to understand the biological mechanisms underpinning how inflammation may increase the risk of schizophrenia and insulin resistance.

We conducted a two-sample Mendelian randomization study to explore the associations of iron status with overall cancer and 22 site-specific cancers. Single-nucleotide polymorphisms for iron status were obtained from a genome-wide association study of 48,972 European-descent individuals. Summary-level data for breast and other cancers were obtained from the Breast Cancer Association Consortium and UK Biobank. Genetically predicted iron status was positively associated with liver cancer and inversely associated with brain cancer but not associated with overall cancer or the other 20 studied cancer sites at p &lt, 0.05. The odds ratios of liver cancer were 2.45 (95% CI, 0.81, 7.45, p = 0.11), 2.11 (1.16, 3.83, p = 0.02), 10.89 (2.44, 48.59, p = 0.002) and 0.30 (0.17, 0.53, p = 2 &times, 10&minus, 5) for one standard deviation increment of serum iron, transferrin saturation, ferritin and transferrin levels, respectively. For brain cancer, the corresponding odds ratios were 0.69 (0.48, 1.00, p = 0.05), 0.75 (0.59, 0.97, p = 0.03), 0.41 (0.20, 0.88, p = 0.02) and 1.49 (1.04, 2.14, p = 0.03). Genetically high iron status was positively associated with liver cancer and inversely associated with brain cancer.

While comorbidity between coronary heart disease (CHD) and depression is evident, it is unclear whether the two diseases have shared underlying mechanisms. We performed a range of analyses in 367,703 unrelated middle-aged participants of European ancestry from UK Biobank, a population based cohort study, to assess whether comorbidity is primarily due to genetic or environmental factors, and to test whether cardiovascular risk factors and CHD are likely to be causally related to depression using Mendelian randomization. We showed family history of heart disease was associated with a 20% increase in depression risk (95% confidence interval [CI] 16% to 24%, p-5); per unit increase in genetically-predicted log-transformed I L-6 was 0.74 (95% CI 0.62 to 0.89; p=0.0012); and per unit increase in genetically-predicted log-transformed CRP was 1.18 (95% CI 1.07 to 1.29; p=0.0009). Our analyses suggest that comorbidity between depression and CHD arises largely from shared environmental factors. I L-6, CRP and triglycerides, are likely to be causally linked with depression, so could be targets for treatment and prevention of depression.

Funder: Junior Research Fellowship from Homerton College, Cambridge, Funder: National Institute for Health Research [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust], Background: Smoking is a well-established cause of lung cancer and there is strong evidence that smoking also increases the risk of several other cancers. Alcohol consumption has been inconsistently associated with cancer risk in observational studies. This mendelian randomisation (MR) study sought to investigate associations in support of a causal relationship between smoking and alcohol consumption and 19 site-specific cancers. Methods and findings: We used summary-level data for genetic variants associated with smoking initiation (ever smoked regularly) and alcohol consumption, and the corresponding associations with lung, breast, ovarian, and prostate cancer from genome-wide association studies consortia, including participants of European ancestry. We additionally estimated genetic associations with 19 site-specific cancers among 367,643 individuals of European descent in UK Biobank who were 37 to 73 years of age when recruited from 2006 to 2010. Associations were considered statistically significant at a Bonferroni corrected p-value below 0.0013. Genetic predisposition to smoking initiation was associated with statistically significant higher odds of lung cancer in the International Lung Cancer Consortium (odds ratio [OR] 1.80; 95% confidence interval [CI] 1.59–2.03; p = 2.26 × 10−21) and UK Biobank (OR 2.26; 95% CI 1.92–2.65; p = 1.17 × 10−22). Additionally, genetic predisposition to smoking was associated with statistically significant higher odds of cancer of the oesophagus (OR 1.83; 95% CI 1.34–2.49; p = 1.31 × 10−4), cervix (OR 1.55; 95% CI 1.27–1.88; p = 1.24 × 10−5), and bladder (OR 1.40; 95% CI 1.92–2.65; p = 9.40 × 10−5) and with statistically nonsignificant higher odds of head and neck (OR 1.40; 95% CI 1.13–1.74; p = 0.002) and stomach cancer (OR 1.46; 95% CI 1.05–2.03; p = 0.024). In contrast, there was an inverse association between genetic predisposition to smoking and prostate cancer in the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (OR 0.90; 95% CI 0.83–0.98; p = 0.011) and in UK Biobank (OR 0.90; 95% CI 0.80–1.02; p = 0.104), but the associations did not reach statistical significance. We found no statistically significant association between genetically predicted alcohol consumption and overall cancer (n = 75,037 cases; OR 0.95; 95% CI 0.84–1.07; p = 0.376). Genetically predicted alcohol consumption was statistically significantly associated with lung cancer in the International Lung Cancer Consortium (OR 1.94; 95% CI 1.41–2.68; p = 4.68 × 10−5) but not in UK Biobank (OR 1.12; 95% CI 0.65–1.93; p = 0.686). There was no statistically significant association between alcohol consumption and any other site-specific cancer. The main limitation of this study is that precision was low in some analyses, particularly for analyses of alcohol consumption and site-specific cancers. Conclusions: Our findings support the well-established relationship between smoking and lung cancer and suggest that smoking may also be a risk factor for cancer of the head and neck, oesophagus, stomach, cervix, and bladder. We found no evidence supporting a relationship between alcohol consumption and overall or site-specific cancer risk.

Background: The large-scale quantitative evidence base to understand and improve health and healthcare outcomes for people who are trans and/or non-binary is still developing, although what research there is suggests that risk of poor health is high, and experiences of healthcare services are often poor. In 2021 the GP Patient Survey, which is carried out annually to measure patient experience in primary care in England, added inclusive questions about gender identity and trans status for the first time. Methods: This protocol paper pre-registers the methods that we will use for this work for a secondary analysis of these data, including both the statistical analysis protocol and early patient and public involvement work, to answer the following three research questions: (1) What are the (a) demographic characteristics, (b) health conditions, and (c) healthcare experiences of trans and/or non-binary adults in England? (2) Was there any difference in whether people who are trans and/or non-binary had been asked to shield during the COVID-19 pandemic or not compared with all other survey responders? (3) Does the relationship between being trans and/or non-binary, and self-reported long-term mental health problems, autism and autistic spectrum disorder and learning disability vary by age, gender, ethnicity, deprivation, sexual orientation or region?

Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte–endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations.

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values 105 mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Background & aims: Vitamin C is an antioxidant with a potential role in the prevention of digestive system cancers, but there is yet no consensus whether vitamin C has a causal role in these cancers. The aim of this study was to utilize Mendelian randomization to decipher the potential causal associations of vitamin C with risk of digestive system cancers.Methods: Ten genetic variants previously found to be significantly associated with circulating vitamin C were used as instrumental variables. Effect size estimates for the genetic associations of the vitamin Cassociated genetic variants with six major malignancies of digestive system were obtained from the FinnGen (N = 309 154) and UK Biobank (N = 367 542) studies. Results from the two studies were combined using meta-analysis.Results: Genetically predicted higher circulating vitamin C showed a suggestive association with lower risk of small intestine and colorectal cancer after accounting for multiple testing. The odds ratio per 1 standard deviation increment in circulating vitamin C was 0.55 (95% confidence interval 0.32-0.94; P = 0.029) for small intestine cancer and 0.84 (95% confidence interval 0.73-0.96; P = 0.013) for colorectal cancer. There was a suggestive association between genetically predicted higher circulating vitamin C with lower risk of liver cancer in FinnGen but no association in the meta-analysis (odds ratio 0.69; 95% CI 0.36-1.32; P = 0.265). Genetically predicted circulating vitamin C was not associated with cancers of the esophagus, stomach, or pancreas.Conclusion: This Mendelian randomization study indicates that vitamin C might play a role in the prevention of small intestine and colorectal cancer. (c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Funder: Wellcome Trust, Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte-endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations.

Coffee consumption has been linked to a lower risk of cardiovascular disease in observational studies, but whether the associations are causal is not known. We conducted a Mendelian randomization investigation to assess the potential causal role of coffee consumption in cardiovascular disease. Twelve independent genetic variants were used to proxy coffee consumption. Summary-level data for the relations between the 12 genetic variants and cardiovascular diseases were taken from the UK Biobank with up to 35,979 cases and the FinnGen consortium with up to 17,325 cases. Genetic predisposition to higher coffee consumption was not associated with any of the 15 studied cardiovascular outcomes in univariable MR analysis. The odds ratio per 50% increase in genetically predicted coffee consumption ranged from 0.97 (95% confidence interval (CI), 0.63, 1.50) for intracerebral hemorrhage to 1.26 (95% CI, 1.00, 1.58) for deep vein thrombosis in the UK Biobank and from 0.86 (95% CI, 0.50, 1.49) for subarachnoid hemorrhage to 1.34 (95% CI, 0.81, 2.22) for intracerebral hemorrhage in FinnGen. The null findings remained in multivariable Mendelian randomization analyses adjusted for genetically predicted body mass index and smoking initiation, except for a suggestive positive association for intracerebral hemorrhage (odds ratio 1.91, 95% CI, 1.03, 3.54) in FinnGen. This Mendelian randomization study showed limited evidence that coffee consumption affects the risk of developing cardiovascular disease, suggesting that previous observational studies may have been confounded.

Aims/hypothesis Our aim was to investigate the relationship between average blood glucose levels and incident CHD in individuals without diabetes mellitus. Methods To investigate average blood glucose levels, we studied HbA1c as predicted by 40 variants previously shown to be associated with both type 2 diabetes and HbA1c. Linear and non-linear Mendelian randomisation analyses were performed to investigate associations with incident CHD risk in 324,830 European ancestry individuals from the UK Biobank without diabetes mellitus. Results Every one mmol/mol increase in genetically proxied HbA1c was associated with an 11% higher CHD risk (HR 1.11, 95% CI 1.05, 1.18). The dose–response curve increased at all levels of HbA1c, and there was no evidence favouring a non-linear relationship over a linear one. Conclusions/interpretations In individuals without diabetes mellitus, lowering average blood glucose levels may reduce CHD risk in a dose-dependent way. Graphical abstract

Background The causal relevance of elevated blood pressure for several cardiovascular diseases (CVDs) is uncertain, as is the population impact of blood pressure lowering. This study systematically assesses evidence of causality for various CVDs in a 2‐sample Mendelian randomization framework, and estimates the potential reduction in the prevalence of these diseases attributable to long‐term population shifts in the distribution of systolic blood pressure (SBP). Methods and Results We investigated associations of genetically predicted SBP as predicted by 256 genetic variants with 21 CVDs in UK Biobank, a population‐based cohort of UK residents. The sample consisted of 376 703 participants of European ancestry, aged 40 to 69 years at recruitment. Genetically predicted SBP was positively associated with 14 of the outcomes ( P Conclusions Risk of many CVDs is influenced by long‐term differences in SBP. The burden of a broad range of CVDs could be substantially reduced by long‐term population‐wide reductions in the distribution of blood pressure.

The MendelianRandomization package is a software package written for the R software environment that implements methods for Mendelian randomization based on summarized data. In this manuscript, we describe functions that have been added to the package or updated in recent years. These features can be divided into four categories: robust methods for Mendelian randomization, methods for multivariable Mendelian randomization, functions for data visualization, and the ability to load data into the package seamlessly from the PhenoScanner web-resource. We provide examples of the graphical output produced by the data visualization commands, as well as syntax for obtaining suitable data and performing a Mendelian randomization analysis in a single line of code.

Insulin-like growth factor-1 (IGF-1) is involved in several processes relevant to carcinogenesis. We used 416 single-nucleotide polymorphisms robustly associated with serum IGF-1 levels to assess the potential causal associations between this hormone and site-specific cancers through Mendelian randomization. Summary-level genetic association estimates for prostate, breast, ovarian, and lung cancer were obtained from large-scale consortia including individuals of European-descent. Furthermore, we estimated genetic associations with 14 site-specific cancers in European-descent individuals in UK Biobank. Supplementary analyses were conducted for six site-specific cancers using summary-level data from the BioBank Japan Project. Genetically predicted serum IGF-1 levels were associated with colorectal cancer. The odds ratio (OR) per standard deviation increase of IGF-1 levels was 1.11 (95% confidence interval [CI] 1.01-1.22; P = .03) in UK Biobank and 1.22 (95% CI 1.09-1.36; P = 3.9 × 10-4 ) in the BioBank Japan Project. For prostate cancer, the corresponding OR was 1.10 (95% CI 1.01-1.21; P = .04) in UK Biobank, 1.03 (95% CI 0.97-1.09; P = .41) in the prostate cancer consortium, and 1.08 (95% CI 0.95-1.22; P = .24) in the BioBank Japan Project. For breast cancer, the corresponding OR was 0.99 (95% CI 0.92-1.07; P = .85) in UK Biobank and 1.08 (95% CI 1.02-1.13; P = 4.4 × 10-3 ) in the Breast Cancer Association Consortium. There was no statistically significant association between genetically predicted IGF-1 levels and 14 other cancers. This study found some support for a causal association between elevated serum IGF-1 levels and increased risk of colorectal cancer. There was inconclusive or no evidence of a causal association of IGF-1 levels with prostate, breast, and other cancers.

Whether circulating fatty acids (FAs) play a causal role in the development of cardiovascular disease (CVD) remains unclear. We conducted a Mendelian randomisation study to explore the associations between plasma phospholipid FA levels and 15 CVDs. Summary-level data from the CARDIoGRAMplusC4D, MEGASTROKE, and Atrial Fibrillation consortia and UK Biobank were used. Sixteen single-nucleotide polymorphisms (SNPs) associated with ten plasma FAs were used as instrumental variables. SNPs in or close to the FADS1 gene were associated with most FAs. We performed a secondary analysis of the association between a functional variant (rs174547) in FADS1, which encodes ?5-desaturase (a key enzyme in the endogenous FA synthesis), and CVD. Genetic predisposition to higher plasma &alpha, linolenic, linoleic, and oleic acid levels was associated with lower odds of large-artery stroke and venous thromboembolism, whereas higher arachidonic and stearic acid levels were associated with higher odds of these two CVDs. The associations were driven by SNPs in or close to FADS1. In the secondary analysis, the minor allele of rs174547 in FADS1 was associated with significantly lower odds of any ischemic stroke, large-artery stroke, and venous thromboembolism and showed suggestive evidence of inverse association with coronary artery disease, abdominal aortic aneurysm and aortic valve stenosis. Genetically higher plasma &alpha, linolenic, linoleic, and oleic acid levels are inversely associated with large-artery stroke and venous thromboembolism, whereas arachidonic and stearic acid levels are positively associated with these CVDs. The associations were driven by FADS1, which was also associated with other CVDs.