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Abstract Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

Objectives: Hip fractures are associated with a high burden of morbidity and mortality. Diet is essential for preventing fragility fractures, but the role of dietary fatty acids on the risk of hip fracture is uncertain. The aim was to investigate how intake of different dietary fatty acids relates to the risk of hip fracture. A relative validation of the long-term intake of dietary fatty acids estimated from food frequency questionnaires (FFQs) was also performed. Design, settings and participants: We used data collected in two population-based cohorts, the Swedish Mammography Cohort and the Cohort of Swedish men (n = 83,603, 54% men, aged 45–82 years). Data from the repeated investigations in the cohorts and cross-sectional data from their clinical sub-cohorts were used. Measurements: Diet data was collected in FFQs. Incident hip fractures were gathered by individual linkage to national registers. We performed Cox regression analysis to investigate associations between dietary fatty acids and hip fracture. Follow-up time was between January 1st, 1998 and December 31st, 2020. The validation was performed using correlation analyses, comparing fatty acids measured in adipose tissue with estimated fatty acid intakes from FFQs. Results: During up to 23 years of follow-up (mean 18 years) and 1,538,627 person-years at risk, 7345 participants (2840 men) experienced a hip fracture. A low linoleic acid (LA) and high intakes of long-chain n-3 fatty acids were associated with higher hip fracture risk in a non-linear way. In quartile 4 compared to quartile 1 of LA, the multivariable-adjusted hazard ratio of hip fracture was 0.89 (95% Confidence Interval: 0.81, 0.97). The study confirmed the validity of FFQs to capture the intake of the specific dietary long-chain n-3 fatty acids. The estimated intake of LA, α-linolenic acid, and myristic acid were also adequately captured by the FFQs. Validity was confirmed in both women and men. Conclusion: A low to moderate intake of linoleic acid and a higher intake of long-chain n-3 fatty acids were associated with a higher risk of hip fractures. The results indicate that attention should be paid to dietary fatty acid composition for the optimal prevention of fragility fractures.

Abstract Background Caffeine is one of the most utilized drugs in the world, yet its clinical effects are not fully understood. Circulating caffeine levels are influenced by the interplay between consumption behaviour and metabolism. This study aimed to investigate the effects of circulating caffeine levels by considering genetically predicted variation in caffeine metabolism. Methods Leveraging genetic variants related to caffeine metabolism that affect its circulating levels, we investigated the clinical effects of plasma caffeine in a phenome-wide association study (PheWAS). We validated novel findings using a two-sample Mendelian randomization framework and explored the potential mechanisms underlying these effects in proteome-wide and metabolome-wide Mendelian randomization. Results Higher levels of genetically predicted circulating caffeine among caffeine consumers were associated with a lower risk of obesity (odds ratio (OR) per standard deviation increase in caffeine = 0.97, 95% confidence interval (CI) CI: 0.95—0.98, p = 2.47 × 10−4), osteoarthrosis (OR = 0.97, 95% CI: 0.96—0.98, P=1.10 × 10−8) and osteoarthritis (OR: 0.97, 95% CI: 0.96 to 0.98, P = 1.09 × 10−6). Approximately one third of the protective effect of plasma caffeine on osteoarthritis risk was estimated to be mediated through lower bodyweight. Proteomic and metabolomic perturbations indicated lower chronic inflammation, improved lipid profiles, and altered protein and glycogen metabolism as potential biological mechanisms underlying these effects. Conclusions We report novel evidence suggesting that long-term increases in circulating caffeine may reduce bodyweight and the risk of osteoarthrosis and osteoarthritis. We confirm prior genetic evidence of a protective effect of plasma caffeine on risk of overweight and obesity. Further clinical study is warranted to understand the translational relevance of these findings before clinical practice or lifestyle interventions related to caffeine consumption are introduced.

Cardiovascular diseases (CVD), type 2 diabetes (T2D), and cancer are a significant public health burden in the Nordic and Baltic countries. High intake of eggs, mainly due to its high cholesterol content, has been suggested to have adverse health effects. The purpose of this scoping review is to describe the evidence related to the impact of egg intake on health. A literature search identified 38 systematic reviews and meta-analyses on egg consumption in relation to health outcomes published between 2011 and 30 April 2022. Overall, current evidence from systematic reviews of randomized clinical trials indicates that higher egg intake may increase serum total cholesterol concentration and the ratio of low-density lipoprotein to high-density lipoprotein cholesterol, but with substantial heterogeneity in the response. However, recent evidence from observational studies does not provide strong support for a detrimental role of moderate egg consumption (up to one egg/day) on the risk of CVD, especially in the European studies. The overall evidence from observational studies indicates that egg consumption is not associated with increased risk of mortality or T2D in European study populations. There is also little support for a role of egg consumption in cancer development, although a weak association with higher risk of certain cancers has been found in some studies, mainly case–control studies. Again, no associations with cancer risk have been observed in European studies. Systematic reviews and meta-analyses of egg consumption in relation to other health-related outcomes are scarce. There are also limited data available on the associations between the consumption of more than one egg/day and risk of diseases. Based on the available evidence, one egg/day is unlikely to adversely affect overall disease risk.

Abstract We aimed to estimate the absolute and age-standardized number of hip fractures in Sweden during the past two decades to produce time trends and future projections. We used nationwide register data from 1998 to 2019 and a validated algorithm to calculate the annual absolute and age-standardized number of incident hip fractures over time. The total hip fracture burden was 335,399 incident events over the 22 years, with a change from 16,180 in 1998 to 13,929 in 2019, a 14% decrease. One decade after the index hip fracture event, 80% of the patients had died, and 11% had a new hip fracture. After considering the steady growth of the older population, the decline in the age-standardized number of hip fractures from 1998 through 2019 was 29.2% (95% CI 28.1–30.2%) in women and 29.3% (95% CI 27.5–30.7%) in men. With a continued similar reduction in hip fracture incidence, we can predict that 14,800 hip fractures will occur in 2034 and 12,000 in 2050 despite doubling the oldest old (≥ 80 years). Without an algorithm, a naïve estimate of the total number of hip fractures over the study period was 539,947, with a second 10-year hip fracture risk of 35%. We note an ongoing decline in the absolute and age-standardized actual number of hip fractures in Sweden, with consequences for future projections.

Summary: Background: This study investigates the associations between air pollution and colorectal cancer (CRC) risk and survival from an epigenomic perspective. Methods: Using a newly developed Air Pollutants Exposure Score (APES), we utilized a prospective cohort study (UK Biobank) to investigate the associations of individual and combined air pollution exposures with CRC incidence and survival, followed by an up-to-date systematic review with meta-analysis to verify the associations. In epigenetic two-sample Mendelian randomization analyses, we examine the associations between genetically predicted DNA methylation related to air pollution and CRC risk. Further genetic colocalization and gene–environment interaction analyses provided different insights to disentangle pathogenic effects of air pollution via epigenetic modification. Findings: During a median 12.97-year follow-up, 5767 incident CRC cases among 428,632 participants free of baseline CRC and 533 deaths in 2401 patients with CRC were documented in the UK Biobank. A higher APES score was associated with an increased CRC risk (HR, 1.03, 95% CI = 1.01–1.06; P = 0.016) and poorer survival (HR, 1.13, 95% CI = 1.03–1.23; P = 0.010), particularly among participants with insufficient physical activity and ever smokers (Pinteraction > 0.05). A subsequent meta-analysis of seven observational studies, including UK Biobank data, corroborated the association between PM2.5 exposure (per 10 μg/m3 increment) and elevated CRC risk (RR,1.42, 95% CI = 1.12–1.79; P = 0.004; I2 = 90.8%). Genetically predicted methylation at PM2.5-related CpG site cg13835894 near TMBIM1/PNKD and cg16235962 near CXCR5, and NO2-related cg16947394 near TMEM110 were associated with an increased CRC risk. Gene-environment interaction analysis confirmed the epigenetic modification of aforementioned CpG sites with CRC risk and survival. Interpretation: Our study suggests the association between air pollution and CRC incidence and survival, underscoring the possible modifying roles of epigenomic factors. Methylation may partly mediate pathogenic effects of air pollution on CRC, with annotation to epigenetic alterations in protein-coding genes TMBIM1/PNKD, CXCR5 and TMEM110. Funding: Xue Li is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), the National Nature Science Foundation of China (No. 82204019) and Healthy Zhejiang One Million People Cohort (K-20230085). ET is supported by a Cancer Research UK Career Development Fellowship (C31250/A22804). MGD is supported by the MRC Human Genetics Unit Centre Grant (U127527198).

Summary: Background: The causal associations of physical activity and sedentary behavior with the risk of gastrointestinal disease are unclear. We performed a Mendelian randomization analysis to examine these associations. Methods: Genetic instruments associated with leisure screen time (LST, an indicator of a sedentary lifestyle) and moderate-to-vigorous intensity physical activity (MVPA) at the genome-wide significance (P

Abstract Background We aimed to investigate the protein pathways linking obesity and lifestyle factors to coronary artery disease (CAD). Methods Summary-level genome-wide association statistics of CAD were obtained from the CARDIoGRAMplusC4D consortium (60,801 cases and 123,504 controls) and the FinnGen study (R8, 39,036 cases and 303,463 controls). Proteome-wide Mendelian randomization (MR) analysis was conducted to identify CAD-associated blood proteins, supplemented by colocalization analysis to minimize potential bias caused by linkage disequilibrium. Two-sample MR analyses were performed to assess the associations of genetically predicted four obesity measures and 13 lifestyle factors with CAD risk and CAD-associated proteins’ levels. A two-step network MR analysis was conducted to explore the mediating effects of proteins in the associations between these modifiable factors and CAD. Results Genetically predicted levels of 41 circulating proteins were associated with CAD, and 17 of them were supported by medium to high colocalization evidence. PTK7 (protein tyrosine kinase-7), RGMB (repulsive guidance molecule BMP co-receptor B), TAGLN2 (transgelin-2), TIMP3 (tissue inhibitor of metalloproteinases 3), and VIM (vimentin) were identified as promising therapeutic targets. Several proteins were found to mediate the associations between some modifiable factors and CAD, with PCSK9, C1S, AGER (advanced glycosylation end product-specific receptor), and MST1 (mammalian Ste20-like kinase 1) exhibiting highest frequency among the mediating networks. Conclusions This study suggests pathways explaining the associations of obesity and lifestyle factors with CAD from alterations in blood protein levels. These insights may be used to prioritize therapeutic intervention for further study.

Summary: Background: Coeliac disease (CeD) has been associated with a broad range of diseases in observational data; however, whether these associations are causal remains undetermined. We conducted a phenome-wide Mendelian randomization analysis (MR-PheWAS) to investigate the comorbidities of CeD. Methods: Single nucleotide polymorphisms (SNPs) associated with CeD at the genome-wide significance threshold and without linkage disequilibrium (R2

Abstract Background The proteome is a major source of therapeutic targets. We conducted a proteome-wide Mendelian randomization (MR) study to identify candidate protein markers and therapeutic targets for colorectal cancer (CRC). Methods Protein quantitative trait loci (pQTLs) were derived from seven published genome-wide association studies (GWASs) on plasma proteome, and summary-level data were extracted for 4853 circulating protein markers. Genetic associations with CRC were obtained from a large-scale GWAS meta-analysis (16,871 cases and 26,328 controls), the FinnGen cohort (4957 cases and 304,197 controls), and the UK Biobank (9276 cases and 477,069 controls). Colocalization and summary-data-based MR (SMR) analyses were performed sequentially to verify the causal role of candidate proteins. Single cell-type expression analysis, protein-protein interaction (PPI), and druggability evaluation were further conducted to detect the specific cell type with enrichment expression and prioritize potential therapeutic targets. Results Collectively, genetically predicted levels of 13 proteins were associated with CRC risk. Elevated levels of two proteins (GREM1, CHRDL2) and decreased levels of 11 proteins were associated with an increased risk of CRC, among which four (GREM1, CLSTN3, CSF2RA, CD86) were prioritized with the most convincing evidence. These protein-coding genes are mainly expressed in tissue stem cells, epithelial cells, and monocytes in colon tumor tissue. Two interactive pairs of proteins (GREM1 and CHRDL2; MMP2 and TIMP2) were identified to be involved in osteoclast differentiation and tumorigenesis pathways; four proteins (POLR2F, CSF2RA, CD86, MMP2) have been targeted for drug development on autoimmune diseases and other cancers, with the potentials of being repurposed as therapeutic targets for CRC. Conclusions This study identified several protein biomarkers to be associated with CRC risk and provided new insights into the etiology and promising targets for the development of screening biomarkers and therapeutic drugs for CRC.

Abstract Background Caffeine exposure modifies the turnover of monoamine neurotransmitters, which play a role in several neuropsychiatric disorders. We conducted a Mendelian randomization study to investigate whether higher plasma caffeine levels are causally associated with the risk of anorexia nervosa, bipolar disorder, major depressive disorder (MDD), and schizophrenia. Methods Summary-level data on the neuropsychiatric disorders were obtained from large-scale genome-wide association studies (GWASs) of European ancestry participants (n = 72,517 to 807,553) and meta-analyzed with the corresponding data from the FinnGen study (n = 356,077). Summary-level data on plasma caffeine were extracted from a GWAS meta-analysis of 9876 European ancestry individuals. The Mendelian randomization analyses estimated the Wald ratio for each genetic variant and meta-analyzed the variant-specific estimates using multiplicative random effects meta-analysis. Results After correcting for multiple testing, genetically predicted higher plasma caffeine levels were associated with higher odds of anorexia nervosa (odds ratio [OR] = 1.124; 95% confidence interval [CI] = 1.024–1.238, p FDR = 0.039) and a lower odds of bipolar disorder (OR = 0.905, 95% CI = 0.827–0.929, p FDR = 0.041) and MDD (OR = 0.965, 95% CI = 0.937–0.995, p FDR = 0.039). Instrumented plasma caffeine levels were not associated with schizophrenia (OR = 0.986, 95% CI = 0.929–1.047, p FDR = 0.646). Conclusions These Mendelian randomization findings indicate that long-term higher plasma caffeine levels may lower the risk of bipolar disorder and MDD but increase the risk of anorexia nervosa. These results warrant further research to explore whether caffeine consumption, supplementation, or abstinence could render clinically relevant therapeutic or preventative psychiatric effects.

Abstract The causality of the association between depression and gastrointestinal diseases is undetermined. We conducted Mendelian randomization (MR) analyses to systematically explore the associations of depression with 24 gastrointestinal diseases. Independent genetic variants associated with depression at the genome-wide significance level were selected as instrumental variables. Genetic associations with 24 gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analysis was conducted to explore the mediation effects of body mass index, cigarette smoking, and type 2 diabetes. After multiple-testing corrections, genetic liability to depression was associated with an increased risk of irritable bowel syndrome, non-alcohol fatty liver disease, alcoholic liver disease, gastroesophageal reflux, chronic pancreatitis, duodenal ulcer, chronic gastritis, gastric ulcer, diverticular disease, cholelithiasis, acute pancreatitis, and ulcerative colitis. For the causal effect of genetic liability to depression on non-alcoholic fatty liver disease, a substantial proportion was mediated by body mass index. Genetic predisposition to smoking initiation mediated half of effect of depression on acute pancreatitis. This MR study suggests that depression may play a causal role in many gastrointestinal diseases.

BackgroundThe interleukin-1 pathway has been linked to pancreatic diseases. We applied the Mendelian randomization approach to explore whether higher interleukin-1 receptor antagonist (IL-1RA) levels reduce the risk of acute and chronic pancreatitis and pancreatic cancer.MethodsGenetic variants associated with blood IL-1RA levels at the genome-wide significance level and located 5MB downstream or upstream of the IL1RN gene were extracted from a genome-wide meta-analysis of 21,758 participants. After pruning, genetic variants without linkage disequilibrium were used as genetic instrument for IL-1RA. Summary-level data on acute and chronic pancreatitis and pancreatic cancer were obtained from the UK Biobank and FinnGen studies. The associations were meta-analyzed for one outcome from two sources.ResultsGenetically predicted higher levels of IL-1RA were associated with a lower risk of acute and chronic pancreatitis and pancreatic cancer. In the meta-analysis of UK Biobank and FinnGen, the combined odds ratio was 0.87 (95% confidence interval [CI] 0.77-0.97, P=0.003) for acute pancreatitis, 0.73 (95% CI 0.65-0.82, P=2.93×10-8) for chronic pancreatitis, and 0.86 (95% CI 0.77-0.96, P=0.009) for pancreatic cancer per one standard deviation increment in genetically predicted levels of IL-1RA.ConclusionThis study suggests a protective role of IL-1RA in three major pancreatic diseases, which hints the therapeutic potentials of IL-1RA in pancreatic diseases.

Abstract Background The associations of rheumatoid arthritis (RA) with risk of site-specific cancers beyond lymphohematopoietic cancer have been scarcely explored. We conducted a Mendelian randomization investigation of the associations of RA with site-specific cancers in European and East Asian populations. Methods Independent genetic variants strongly associated with RA in European and East Asian populations were selected as instrumental variables from genome-wide association studies of 58,284 European individuals (14,361 cases and 43,923 controls) and 22,515 East Asian individuals (4873 cases and 17,642 controls), respectively. The associations of genetic variants with overall and 22 site-specific cancers were extracted from the UK Biobank study (n = 367,561), the FinnGen study (n = 260,405), Biobank Japan (n = 212,453), and international consortia. The associations for one outcome from different data sources were combined by meta-analysis. Results In the European population, the combined odds ratios per 1-unit increase in log odds of genetic liability to RA were 1.06 (95% confidence interval [CI] 1.03–1.10) for head and neck cancer, 1.06 (95% CI 1.02–1.10) for cervical cancer, 0.92 (95% CI 0.87–0.96) for testicular cancer, and 0.94 (95% CI 0.90–0.98) for multiple myeloma. In the East Asian population, the corresponding odds ratios were 1.17 (95% CI 1.06–1.29) for pancreatic cancer, 0.91 (95% CI 0.88–0.94) for breast cancer, and 0.90 (95% CI 0.84–0.96) for ovarian cancer. There were suggestive associations for breast and ovarian cancer and overall cancer in the European population. No other associations were observed. Conclusion This study suggests that RA may play a role in the development of several site-specific cancers.

Abstract Background We performed phenome-wide Mendelian randomization analysis (MR-PheWAS), two-sample MR analysis, and systemic review to comprehensively explore the health effects of milk consumption in the European population. Methods Rs4988235 located upstream of the LCT gene was used as the instrumental variable for milk consumption. MR-PheWAS analysis was conducted to map the association of genetically predicted milk consumption with 1081 phenotypes in the UK Biobank study (n=339,197). The associations identified in MR-PheWAS were examined by two-sample MR analysis using data from the FinnGen study (n=260,405) and international consortia. A systematic review of MR studies on milk consumption was further performed. Results PheWAS and two-sample MR analyses found robust evidence in support of inverse associations of genetically predicted milk consumption with risk of cataract (odds ratio (OR) per 50 g/day increase in milk consumption, 0.89, 95% confidence interval (CI), 0.84–0.94; p=3.81×10−5), hypercholesterolemia (OR, 0.91, 95% CI 0.86–0.96; p=2.97×10−4), and anal and rectal polyps (OR, 0.85, 95% CI, 0.77–0.94; p=0.001). An inverse association for type 2 diabetes risk (OR, 0.92, 95% CI, 0.86–0.97; p=0.003) was observed in MR analysis based on genetic data with body mass index adjustment but not in the corresponding data without body mass index adjustment. The systematic review additionally found evidence that genetically predicted milk consumption was inversely associated with asthma, hay fever, multiple sclerosis, colorectal cancer, and Alzheimer’s disease, and positively associated with Parkinson’s disease, renal cell carcinoma, metabolic syndrome, overweight, and obesity. Conclusions This study suggests several health effects of milk consumption in the European population.

Abstract Autoimmune diseases and coronavirus disease 2019 (COVID-19) share many similarities. Concerns have arisen that autoimmune diseases may increase the susceptibility and severity of COVID-19. We used Mendelian randomization to investigate whether liability to autoimmune diseases is related to COVID-19 susceptibility and severity. Genetic instruments for 8 autoimmune diseases, including type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, multiple sclerosis, primary sclerosing cholangitis, primary biliary cirrhosis and juvenile idiopathic arthritis, were obtained from published genome-wide association studies. Two-sample Mendelian randomization analyses of the associations of liability to each autoimmune disease with COVID-19 infection, hospitalized COVID-19, and very severe COVID-19 were performed using the latest publicly available genome-wide association study for COVID-19. Genetic liability to each of the autoimmune diseases was largely not associated with COVID-19 infection, hospitalized COVID-19, or very severe COVID-19 after accounting for multiple comparison. Sensitivity analysis excluding genetic variants in the human leukocyte antigen gene, which has an important role in the immune response, showed similar results. The autoimmune diseases examined were largely not genetically associated with the susceptibility or severity of COVID-19. Further investigations are warranted.

Abstract Tobacco smoking is an important risk factor for peripheral artery disease (PAD), but it remains unknown whether smokeless tobacco, such as Swedish snuff (snus), is also associated with this disease. We used data from the Cohort of Swedish Men including 24,085 men. Individuals were grouped into never, past, and current snus dippers as well as never, past quitting ≥ 10 years, past, quitting

BackgroundA bidirectional association between atopic dermatitis and chronic kidney disease (CKD) has been revealed in observational studies, whereas the causality of this association was unclear. We conducted a Mendelian randomization study to determine the bidirectional causal association between atopic dermatitis and CKD.MethodsIndependent genetic instruments associated with atopic dermatitis and CKD at the genome-wide significance level were chosen from corresponding meta-analyses of genome-wide association studies. Summary-level data for atopic dermatitis were obtained from the EAGLE Eczema consortium (30,047 cases and 40,835 controls) and FinnGen consortium (7,024 cases and 198,740 controls). Summary-level data for CKD were derived from CKDGen consortium (64,164 cases and 625,219 controls) and FinnGen consortium (3,902 cases and 212,841 controls). The inverse-variance weighted method was used in the main analysis and supplemented with three sensitivity analyses.ResultsGenetic predisposition to atopic dermatitis was associated with an increased risk of CKD. For a one-unit increase in the prevalence of atopic dermatitis, the odds ratio of CKD was 1.07 (95% confidence interval: 1.01–1.12). In the reverse Mendelian randomization analysis, the odds ratio of atopic dermatitis was 1.14 (95% confidence interval: 1.03–1.26) for a one-unit increase in the prevalence of CKD. The associations persisted in sensitivity analyses and no pleiotropy was detected.ConclusionThis Mendelian randomization study suggests a bidirectional positive association between atopic dermatitis and CKD.

Caffeine is a psychoactive substance widely consumed worldwide, mainly via sources such as coffee and tea. The effects of caffeine on kidney function remain unclear. We leveraged the genetic variants in the CYP1A2 and AHR genes via the two-sample Mendelian randomization (MR) framework to estimate the association of genetically predicted plasma caffeine and caffeine intake on kidney traits. Genetic association summary statistics on plasma caffeine levels and caffeine intake were taken from genome-wide association study (GWAS) meta-analyses of 9876 and of >47,000 European ancestry individuals, respectively. Genetically predicted plasma caffeine levels were associated with a decrease in estimated glomerular filtration rate (eGFR) measured using either creatinine or cystatin C. In contrast, genetically predicted caffeine intake was associated with an increase in eGFR and a low risk of chronic kidney disease. The discrepancy is likely attributable to faster metabolizers of caffeine consuming more caffeine-containing beverages to achieve the same pharmacological effect. Further research is needed to distinguish whether the observed effects on kidney function are driven by the harmful effects of higher plasma caffeine levels or the protective effects of greater intake of caffeine-containing beverages, particularly given the widespread use of drinks containing caffeine and the increasing burden of kidney disease.

Abstract Background Previous studies have reported associations between attention-deficit/hyperactivity disorder (ADHD) and lower socioeconomic status and intelligence. We aimed to evaluate the causal directions and strengths for these associations by use of a bi-directional two-sample Mendelian randomization (MR) design. Methods We used summary-level data from the largest available genome-wide association studies (GWAS) to identify genetic instruments for ADHD, intelligence, and markers of socioeconomic status including the Townsend deprivation index, household income, and educational attainment. Effect estimates from individual genetic variants were combined using inverse-variance weighted regression. Results A genetically predicted one standard deviation (SD) increment in the Townsend deprivation index conferred an odds ratio (OR) of 5.29 (95% confidence interval (CI) 1.89–14.76) for an ADHD diagnosis (p

Summary: Background: Identifying new drug targets for inflammatory bowel disease (IBD) is urgently needed. The proteome is a major source of therapeutic targets. We conducted a proteome-wide Mendelian randomization (MR) and colocalization analyses to identify possible targets for IBD. Methods: Summary-level data of 4907 circulating protein levels were extracted from a large-scale protein quantitative trait loci study including 35,559 individuals. Genetic associations with IBD and its subtypes were obtained from the Inflammatory Bowel Disease Genetics Consortium (25,024 cases and 34,915 controls), the FinnGen study (7206 cases and 253,199 controls), and the UK Biobank study (7045 cases and 449,282 controls). MR analysis was conducted to estimate the associations between protein and IBD risk. The colocalization analysis was used to examine whether the identified proteins and IBD shared casual variants. Findings: Genetically predicted levels of 3, and 5 circulating proteins were associated with IBD and ulcerative colitis (UC), respectively. With high supporting evidence of colocalization, genetically predicted MST1 (macrophage stimulating 1) and HGFAC (hepatocyte growth factor activator) levels were inversely associated with IBD risks. The associations of STAT3 (signal transducer and activator of transcription 3), MST1, CXCL5 (C-X-C motif chemokine ligand 5), and ITPKA (inositol-trisphosphate 3-kinase A) with the risk of UC were supported by colocalization analysis. Interpretation: The proteome-wide MR investigation identified many proteins associated with the risk of IBD. MST1, HGFAC, STAT3, ITPKA, and CXCL5 deserve further investigation as potential therapeutic targets for IBD. Funding: SCL is supported by research grants from the Swedish Research Council for Health, Working Life and Welfare (Forte; grant no. 2018-00123) and the Swedish Research Council (Vetenskapsrådet; grant no. 2019-00977). XYW is supported by research grants from the National Natural Science Foundation of China (81970494) and Key Project of Research and Development Plan of Hunan Province (2019SK2041). XL is supported by research grants from the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001).

Abstract We conducted a Mendelian randomization study to determine the associations of body mass index (BMI), type 2 diabetes (T2D), systolic blood pressure (SBP), coffee and alcohol consumption and smoking initiation with senile cataract. Independent single nucleotide polymorphisms associated with the metabolic and lifestyle factors at the p

Abstract Background Obesity is a worldwide epidemic that has been associated with a plurality of diseases in observational studies. The aim of this study was to summarize the evidence from Mendelian randomization (MR) studies of the association between body mass index (BMI) and chronic diseases. Methods PubMed and Embase were searched for MR studies on adult BMI in relation to major chronic diseases, including diabetes mellitus; diseases of the circulatory, respiratory, digestive, musculoskeletal, and nervous systems; and neoplasms. A meta-analysis was performed for each disease by using results from published MR studies and corresponding de novo analyses based on summary-level genetic data from the FinnGen consortium (n = 218,792 individuals). Results In a meta-analysis of results from published MR studies and de novo analyses of the FinnGen consortium, genetically predicted higher BMI was associated with increased risk of type 2 diabetes mellitus, 14 circulatory disease outcomes, asthma, chronic obstructive pulmonary disease, five digestive system diseases, three musculoskeletal system diseases, and multiple sclerosis as well as cancers of the digestive system (six cancer sites), uterus, kidney, and bladder. In contrast, genetically predicted higher adult BMI was associated with a decreased risk of Dupuytren’s disease, osteoporosis, and breast, prostate, and non-melanoma cancer, and not associated with Alzheimer’s disease, amyotrophic lateral sclerosis, or Parkinson’s disease. Conclusions The totality of the evidence from MR studies supports a causal role of excess adiposity in a plurality of chronic diseases. Hence, continued efforts to reduce the prevalence of overweight and obesity are a major public health goal.

Abstract Associations of serum calcium (S-Ca) and 25-hydroxyvitamin D (S-25(OH)D) concentrations with longevity, cardiovascular disease, and cancer are not clear. We conducted a Mendelian randomization study to examine the associations of S-Ca and S-25(OH)D with longevity and risk of cardiovascular disease and cancer. The primary genetic instruments for S-Ca and S-25(OH)D were obtained from genome-wide association meta-analyses that included 61,054 individuals for S-Ca and up to 79,366 individuals for S-25(OH)D. Genetic variants associated with S-Ca and S-25(OH)D in the UK Biobank were used as confirmatory instruments. We obtained summary-level data for associations of these instruments with individual survival later than the 90th versus at most the 60th percentile of expected age at death from a genome-wide association meta-analysis including 11,262 cases and 25,483 controls, and with parental longevity (both parents in top 10% percentile) from the UK Biobank including 7,182 cases and 79,767 controls. Data for cardiovascular disease (111,108 cases and 107,684 controls) and cancer (38,036 cases and 180,756 controls) were obtained from the FinnGen consortium. A one standard deviation increase in genetically-predicted S-Ca concentration was associated with lower odds of longevity (odds ratio, 0.72; 95% CI, 0.55-0.95) and increased risk of cardiovascular disease (odds ratio, 1.11; 95% CI, 1.03-1.20). The associations were consistent in confirmatory analyses. There was no evidence supporting an association between genetically-predicted S-Ca and cancer, and no associations of genetically-predicted S-25(OH)D with the studied outcomes. Lifelong higher levels of S-Ca but not S-25(OH)D may shorten life expectancy and increase the risk of cardiovascular disease.

Abstract Background Circulating vitamin C concentrations have been associated with several cancers in observational studies, but little is known about the causal direction of the associations. This study aims to explore the potential causal relationship between circulating vitamin C and risk of five most common cancers in Europe. Methods We used summary-level data for genetic variants associated with plasma vitamin C in a large vitamin C genome-wide association study (GWAS) meta-analysis on 52,018 Europeans, and the corresponding associations with lung, breast, prostate, colon, and rectal cancer from GWAS consortia including up to 870,984 participants of European ancestry. We performed two-sample, bi-directional Mendelian randomization (MR) analyses using inverse-variance-weighted method as the primary approach, while using 6 additional methods (e.g., MR-Egger, weighted median-based, and mode-based methods) as sensitivity analysis to detect and adjust for pleiotropy. We also conducted a meta-analysis of prospective cohort studies and randomized controlled trials to examine the association of vitamin C intakes with cancer outcomes. Results The MR analysis showed no evidence of a causal association of circulating vitamin C concentration with any examined cancer. Although the odds ratio (OR) per one standard deviation increase in genetically predicted circulating vitamin C concentration was 1.34 (95% confidence interval 1.14 to 1.57) for breast cancer in the UK Biobank, this association could not be replicated in the Breast Cancer Association Consortium with an OR of 1.05 (0.94 to 1.17). Smoking initiation, as a positive control for our reverse MR analysis, showed a negative association with circulating vitamin C concentration. However, there was no strong evidence of a causal association of any examined cancer with circulating vitamin C. Sensitivity analysis using 6 different analytical approaches yielded similar results. Moreover, our MR results were consistent with the null findings from the meta-analysis exploring prospective associations of dietary or supplemental vitamin C intakes with cancer risk, except that higher dietary vitamin C intake, but not vitamin C supplement, was associated with a lower risk of lung cancer (risk ratio: 0.84, 95% confidence interval 0.71 to 0.99). Conclusions These findings provide no evidence to support that physiological-level circulating vitamin C has a large effect on risk of the five most common cancers in European populations, but we cannot rule out very small effect sizes.

Summary: Background: The causal association between cigarette smoking and several diseases remains equivocal. The purpose of this study was to appraise the causal role of smoking in a wide range of diseases by summarizing the evidence from Mendelian randomization (MR) studies. Methods: MR studies on genetic liability to smoking initiation or lifetime smoking (composite of smoking initiation, heaviness, duration, and cessation) in relation to circulatory system, digestive system, nervous system, musculoskeletal system, endocrine, metabolic, and eye diseases, and neoplasms published until February 15, 2022, were identified in PubMed. De novo MR analyses were performed using summary statistics data from genome-wide association studies. Meta-analysis was applied to combine study-specific estimates. Findings: Meta-analyses of findings of 29 published MR studies and 123 de novo MR analyses of 57 distinct primary outcomes showed that genetic liability to smoking (smoking initiation or lifetime smoking) was associated with increased risk of 13 circulatory system diseases, several digestive system diseases (including diverticular, gallstone, gastroesophageal reflux, and Crohn's disease, acute pancreatitis, and periodontitis), epilepsy, certain musculoskeletal system diseases (including fracture, osteoarthritis, and rheumatoid arthritis), endocrine (polycystic ovary syndrome), metabolic (type 2 diabetes) and eye diseases (including age-related macular degeneration and senile cataract) as well as cancers of the lung, head and neck, esophagus, pancreas, bladder, kidney, cervix, and ovaries, and myeloid leukemia. Smoking liability was associated with decreased risk of Parkinson's disease and prostate cancer. Interpretation: This study found robust evidence that cigarette smoking causes a wide range of diseases. Funding: This work was supported by research grants from the Swedish Cancer Society (Cancerfonden), the Swedish Heart Lung Foundation (Hjärt-Lungfonden, 20210351), the Swedish Research Council for Health, Working Life and Welfare (Forte, 2018-00123), and the Swedish Research Council (Vetenskapsrådet, 2019-00977). Stephen Burgess is supported by Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z) and the National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care.

Abstract Background Cigarette smoking is a well-known risk factor for cardiovascular disease (CVD), but whether smokeless tobacco such as snuff is associated with the risk of CVD is still unclear. We investigated the association of the use of Swedish oral moist snuff (snus) with a broad range of CVDs and CVD mortality. Methods We used data from a population-based cohort of 41,162 Swedish adults with a mean baseline age of 70 (56–94) years who completed questionnaires regarding snus use and other lifestyle habits and health characteristics. Participants were followed up for incident cardiovascular outcomes and death over 8 years through linkage to the Swedish National Patient and Death Registers. Hazard ratios (HR) were estimated by Cox proportional hazards regression. We conducted analyses among all subjects as well as among never smokers to reduce residual confounding from smoking. Results After adjustment for smoking and other confounders, snus use was not associated with myocardial infarction, heart failure, atrial fibrillation, aortic valve stenosis, abdominal aortic aneurysm, stroke, or CVD mortality. However, in never smokers, snus use was associated with a statistically significant increased risk of total and ischemic stroke (HRs [95% confidence intervals] = 1.52 [1.01–2.30] and 1.63 [1.05–2.54], respectively) and non-significantly positively associated with some other CVDs. Conclusions In this middle-aged and elderly Swedish population, current Swedish snus use was not associated with the risk of major heart and valvular diseases, abdominal aortic aneurysm, or CVD mortality in the entire study population, but was linked to an increased risk of stroke in never smokers.

Abstract Background Whether a modestly elevated homocysteine level is causally associated with an increased risk of cardiovascular disease remains unestablished. We conducted a Mendelian randomization study to assess the associations of circulating total homocysteine (tHcy) and B vitamin levels with cardiovascular diseases in the general population. Methods Independent single nucleotide polymorphisms associated with tHcy (n = 14), folate (n = 2), vitamin B6 (n = 1), and vitamin B12 (n = 14) at the genome-wide significance level were selected as instrumental variables. Summary-level data for 12 cardiovascular endpoints were obtained from genetic consortia, the UK Biobank study, and the FinnGen consortium. Results Higher genetically predicted circulating tHcy levels were associated with an increased risk of stroke. For each one standard deviation (SD) increase in genetically predicted tHcy levels, the odds ratio (OR) was 1.11 (95% confidence interval (CI), 1.03, 1.21; p = 0.008) for any stroke, 1.26 (95% CI, 1.05, 1.51; p = 0.013) for subarachnoid hemorrhage, and 1.11 (95% CI, 1.03, 1.21; p = 0.011) for ischemic stroke. Higher genetically predicted folate levels were associated with decreased risk of coronary artery disease (ORSD, 0.88; 95% CI, 0.78, 1.00, p = 0.049) and any stroke (ORSD, 0.86; 95% CI, 0.76, 0.97, p = 0.012). Genetically predicted increased vitamin B6 levels were associated with a reduced risk of ischemic stroke (ORSD, 0.88; 95% CI, 0.81, 0.97, p = 0.009). None of these associations persisted after multiple testing correction. There was no association between genetically predicted vitamin B12 and cardiovascular disease. Conclusions This study reveals suggestive evidence that B vitamin therapy and lowering of tHcy may reduce the risk of stroke, particularly subarachnoid hemorrhage and ischemic stroke.

Growth differentiation factor 15 (GDF-15) levels have been revealed as a robust biomarker for metformin use. We conducted Mendelian randomization (MR) analysis to explore the association between GDF-15 and gallstone disease to inform potential therapeutic effects targeting GDF-15. Four genetic variants associated with GDF-15 levels at p < 5 × 10–8 were selected as instrumental variables from a genome-wide association meta-analysis including 21,758 individuals. Two-sample MR analysis was conducted using summary-level data from UK Biobank (10,520 gallstone cases and 350,674 controls) and FinnGen consortium (19,023 gallstone cases and 195,144 controls). Polygenic risk score analysis using individual-level data in UK biobank was performed to complement the MR findings by examining the non-linearity of the association. Diabetic complications were taken as positive controls to validate the therapeutic effect of targeting GDF-15. Linear and nonlinear associations between genetically predicted GDF-15 levels and gallstones were estimated with stratification by the diabetic status. In the two-sample MR analysis, the odds ratio (OR) of gallstones was 1.09 (95% confidence interval (CI), 1.03–1.15; p = 0.001) for one standard deviation increase in genetically predicted GDF-15 levels in the meta-analysis of two datasets. Polygenic risk score analysis found this association to be U-shaped (p = 0.037). The observed association was predominantly seen in nondiabetic population (OR = 1.11, 95% CI: 1.01–1.21; p = 0.003). An inverse association between genetically predicted GDF-15 levels and diabetic complications (OR = 0.77, 95% CI: 0.62–0.96; p = 0.023) was observed, validating the potential therapeutic effects of targeting GDF-15 levels. This MR study indicates that the increased risk of gallstone disease should be taken into account when considering GDF-15 as a therapeutic target for diabetic complications.

Abstract We conducted a Mendelian randomization study to determine the potential causal associations of gallstone disease, diabetes, serum calcium, triglyceride levels, smoking and alcohol consumption with acute and chronic pancreatitis. Genetic variants associated with the exposures at p

Abstract A deeper understanding of the causal links from education level to health outcomes may shed a light for disease prevention. In the present Mendelian randomization study, we found that genetically higher education level was associated with lower risk of major mental disorders and most somatic diseases, independent of intelligence. Higher education level adjusted for intelligence was associated with lower risk of suicide attempts, insomnia, major depressive disorder, heart failure, stroke, coronary artery disease, lung cancer, breast cancer, type 2 diabetes and rheumatoid arthritis but with higher risk of obsessive–compulsive disorder, anorexia nervosa, anxiety, bipolar disorder and prostate cancer. Higher education level was associated with reduced obesity and smoking, which mediated quite an extent of the associations between education level and health outcomes. These findings emphasize the importance of education to reduce the burden of common diseases.

Abstract Background Observational studies have shown that milk consumption is inversely associated with colorectal, bladder, and breast cancer risk, but positively associated with prostate cancer. However, whether the associations reflect causality remains debatable. We investigated the potential causal associations of milk consumption with the risk of colorectal, bladder, breast, and prostate cancer using a genetic variant near the LCT gene as proxy for milk consumption. Methods We obtained genetic association estimates for cancer from the UK Biobank (n = 367,643 women and men), FinnGen consortium (n = 135,638 women and men), Breast Cancer Association Consortium (n = 228,951 women), and Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (n = 140,254 men). Milk consumption was proxied by a genetic variant (rs4988235 or rs182549) upstream of the gene encoding lactase, which catalyzes the breakdown of lactose. Results Genetically proxied milk consumption was associated with a reduced risk of colorectal cancer. The odds ratio (OR) for each additional milk intake increasing allele was 0.95 (95% confidence interval [CI] 0.91–0.99; P = 0.009). There was no overall association of genetically predicted milk consumption with bladder (OR 0.99; 95% CI 0.94–1.05; P = 0.836), breast (OR 1.01; 95% CI 1.00–1.02; P = 0.113), and prostate cancer (OR 1.01; 95% CI 0.99–1.02; P = 0.389), but a positive association with prostate cancer was observed in the FinnGen consortium (OR 1.07; 95% CI 1.01–1.13; P = 0.026). Conclusions Our findings strengthen the evidence for a protective role of milk consumption on colorectal cancer risk. There was no or limited evidence that milk consumption affects the risk of bladder, breast, and prostate cancer.

Summary: Background: Calcium plays a role in a wide range of biological functions. Here we conducted a phenome-wide Mendelian randomisation (MR-PheWAS) analysis and a systematic review for MR studies to comprehensively investigate the health effects of serum calcium. Methods: One-hundred and thirty genetic variants strongly associated with serum calcium levels were used as instrumental variables. A phenome-wide association analysis (PheWAS) was conducted to examine the associations of genetically predicted serum calcium with 1473 distinct phenotypes in the UK Biobank including 339,197 individuals. Observed associations in PheWAS were further tested for replication in two-sample MR replication analysis. A systematic review for MR studies on serum calcium was performed to synthesize the published evidence and compare with the current MR-PheWAS findings. Findings: Higher genetically predicted calcium levels were associated with decreased risk of 5 diseases in dermatologic and musculoskeletal systems and increased risk of 17 diseases in circulatory, digestive, endocrine, genitourinary and immune systems. Eight associations were replicated in two-sample MR analysis. These included decreased risk of osteoarthritis and increased risk of coronary artery disease, myocardial infarction, coronary atherosclerosis, hyperparathyroidism, disorder of parathyroid gland, gout, and calculus of kidney and ureter with increased serum calcium. Systematic review of 25 MR studies provided supporting evidence on five out of the eight disease outcomes, while the increased risk of gout, hyperparathyroidism and disorder of parathyroid gland were novel findings. Interpretation: This study found wide-ranged health effects of high serum calcium, which suggests that the benefits and adversities of strategies promoting calcium intake should be assessed. Funding: ET is supported by a CRUK Career Development Fellowship (C31250/A22804). XL is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province. SCL acknowledges research funding from the Swedish Heart Lung Foundation (Hjärt-Lungfonden, 20210351), the Swedish Research Council (Vetenskapsrådet, 2019-00977), and the Swedish Cancer Society (Cancerfonden).

Abstract Background Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex. Methods In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P

Abstract 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.

Background We conducted a 2‐sample Mendelian randomization study to assess the associations of cardiometabolic, lifestyle, and nutritional factors with varicose veins. Methods and Results Independent single‐nucleotide polymorphisms associated with height (positive control), body mass index, type 2 diabetes, diastolic and systolic blood pressure, smoking, alcohol and coffee consumption, 7 circulating vitamins (A, B6, B9, B12, C, 25‐hydroxyvitamin D, and E), and 5 circulating minerals (calcium, iron, magnesium, selenium, and zinc) at the genome‐wide significance level were used as instrumental variables. Summary‐level data for the genetic associations with varicose veins were obtained from the UK Biobank (8763 cases and 352 431 noncases) and the FinnGen consortium (13 928 cases and 153 951 noncases). Genetically predicted higher height, body mass index, smoking, and circulating iron levels were associated with an increased risk of varicose veins. The odds ratios (ORs) per 1‐SD increase in the exposure were 1.34 (95% CI, 1.25–1.43) for height, 1.39 (95% CI, 1.27–1.52) for body mass index, 1.12 (95% CI, 1.04–1.22) for the prevalence of smoking initiation, and 1.24 (95% CI, 1.16–1.33) for iron. Higher genetically predicted systolic blood pressure and circulating calcium and zinc levels were associated with a reduced risk of varicose veins, whereas the association for systolic blood pressure did not persist after adjustment for genetically predicted height. The OR was 0.75 (95% CI, 0.62–0.92) per 1‐SD increase in calcium levels and 0.97 (95% CI, 0.95–0.98) for zinc. Conclusions This study identified several modifiable risk factors for varicose veins.

Background The aim of this study was to assess the associations of modifiable lifestyle factors (smoking, coffee consumption, sleep, and physical activity) and cardiometabolic factors (body mass index, glycemic traits, type 2 diabetes, systolic and diastolic blood pressure, lipids, and inflammation and kidney function markers) with risks of any (ruptured or unruptured) intracranial aneurysm and aneurysmal subarachnoid hemorrhage using Mendelian randomization. Methods and Results Summary statistical data for the genetic associations with the modifiable risk factors and the outcomes were obtained from meta‐analyses of genome‐wide association studies. The inverse‐variance weighted method was used as the main Mendelian randomization analysis, with additional sensitivity analyses conducted using methods more robust to horizontal pleiotropy. Genetic predisposition to smoking, insomnia, and higher blood pressure was associated with an increased risk of both intracranial aneurysm and aneurysmal subarachnoid hemorrhage. For intracranial aneurysm, the odds ratios were 3.20 (95% CI, 1.93–5.29) per SD increase in smoking index, 1.24 (95% CI, 1.10–1.40) per unit increase in log‐odds of insomnia, and 2.92 (95% CI, 2.49–3.43) per 10 mm Hg increase in diastolic blood pressure. In addition, there was weak evidence for associations of genetically predicted decreased physical activity, higher triglyceride levels, higher body mass index, and lower low‐density lipoprotein cholesterol levels with higher risk of intracranial aneurysm and aneurysmal subarachnoid hemorrhage, with 95% CI overlapping the null for at least 1 of the outcomes. All results were consistent in sensitivity analyses. Conclusions This Mendelian randomization study suggests that smoking, insomnia, and high blood pressure are major risk factors for intracranial aneurysm and aneurysmal subarachnoid hemorrhage.

Background: Observational research has found a bidirectional relationship between major depressive disorder and gastroesophageal reflux disease; however, the causal association of this relationship is undetermined. Aims: A bidirectional Mendelian randomization study was performed to explore the causal relationships between major depressive disorder and gastroesophageal reflux disease. Methods: For the instrumental variables of major depressive disorder and gastroesophageal reflux disease, 31 and 24 single-nucleotide polymorphisms without linkage disequilibrium (r2 ≤ 0.001) were selected from relevant genome-wide association studies, respectively, at the genome-wide significance level (p ≤ 5 × 10−8). We sorted summary-level genetic data for major depressive disorder, gastroesophageal reflux disease, gastroesophageal reflux disease without esophagitis, and reflux esophagitis from meta-analysis study of genome-wide association studies involving 173,005 individuals (59,851 cases and 113,154 non-cases), 385,276 individuals (80,265 cases and 305,011 non-cases), 463,010 individuals (4360 cases and 458,650 non-cases), and 383,916 individuals (12,567 cases and 371,349 non-cases), respectively. Results: Genetic liability to major depressive disorder was positively associated with gastroesophageal reflux disease and its subtypes. Per one-unit increase in log-transformed odds ratio of major depressive disorder, the odds ratio was 1.31 (95% confidence interval [CI], 1.19–1.43; p = 1.64 × 10−8) for gastroesophageal reflux disease, 1.51 (95% CI, 1.15–1.98; p = 0.003) for gastroesophageal reflux disease without esophagitis, and 1.21 (95% CI, 1.05–1.40; p = 0.010) for reflux esophagitis. Reverse-direction analysis suggested that genetic liability to gastroesophageal reflux disease was causally related to increasing risk of major depressive disorder. Per one-unit increase in log-transformed odds ratio of gastroesophageal reflux disease, the odds ratio of major depressive disorder was 1.28 (95% confidence interval, 1.11–1.47; p = 1.0 × 10−3). Conclusions: This Mendelian randomization study suggests a bidirectional causal relationship between major depressive disorder and gastroesophageal reflux disease.

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

Circulating fatty acids may affect thrombosis but epidemiological data on the associations between fatty acids and risk of venous thromboembolism (VTE) are limited and conflicting. We conducted a Mendelian randomization study to examine the causal associations of 10 circulating fatty acids with VTE risk. Genetic variants strongly associated with ten fatty acids and without linkage disequilibrium were selected as instrumental variables from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Genetic associations for VTE and its subtypes were obtained from the International Network Against Venous Thrombosis Consortium (30,234 cases and 172,122 controls) and the FinnGen study (11,288 VTE cases and 254,771 controls). Estimates from the two data sources were combined. Per standard deviation increase in genetically predicted fatty acid levels, the combined odds ratio (OR) of VTE was 0.88 (95% confidence interval [CI] 0.84–0.92) for α-linolenic acid, 0.92 (95% CI 0.90–0.95) for linoleic acid, 0.85 (95% CI 0.78–0.92) for palmitoleic acid, 0.77 (95% CI 0.77–0.84) for oleic acid, 1.16 (95% CI 1.10–1.23) for eicosapentaenoic acid, 1.10 (95% CI 1.06–1.14) for docosapentaenoic acid, 1.06 (95% CI 1.04–1.08) for arachidonic acid, and 1.19 (95% CI 1.11–1.28) for stearic acid. Genetically predicted levels of docosahexaenoic acid or palmitoleic acid were not associated with VTE risk. Four and eight out of ten genetically predicted fatty acid levels were associated with risk of pulmonary embolism and deep vein thrombosis, respectively. This study suggests that strategies targeting at fatty acids may act as prevention approaches for VTE.

Poor diet is a leading cause of morbidity and mortality [...]

Abstract Introduction We conducted a two‐sample Mendelian randomization study to determine the associations of modifiable risk factors with epilepsy. Methods Fourteen potential risk factors for epilepsy were selected based on a systematic review of risk factors for epilepsy. Single‐nucleotide polymorphisms associated with each exposure at the genome‐wide significance threshold (p

Background We conducted Mendelian randomization analyses investigating the linear associations of genetically proxied inhibition of different coagulation factors with risk of common cardiovascular diseases. Methods and Results Genetic instruments proxying coagulation factor inhibition were identified from genome‐wide association studies for activated partial thromboplastin time and prothrombin time in BioBank Japan (up to 58 110 participants). Instruments were identified for 9 coagulation factors (fibrinogen alpha, beta, and gamma chain; and factors II, V, VII, X, XI, and XII). Age‐ and sex‐adjusted estimates for associations of the instruments with the outcomes were derived from UK Biobank and the FinnGen, CARDIoGRAMplusC4D (Coronary Artery Disease Genome‐wide Replication and Meta‐analysis), and MEGASTROKE consortia with numbers of incident and prevalent cases of 820 to 60 810. Genetically proxied inhibition of fibrinogen alpha, beta, and gamma chain, factor II, and factor XI were associated with reduced risk of venous thromboembolism (P

We leveraged genetic variants associated with caffeine metabolism in the two-sample Mendelian randomization framework to investigate the effect of plasma caffeine levels on the risk of Alzheimer’s disease and Parkinson’s disease. Genetic association estimates for the outcomes were obtained from the International Genomics of Alzheimer’s Project, the International Parkinson’s Disease Genomics consortium, the FinnGen consortium, and the UK Biobank. Genetically predicted higher plasma caffeine levels were associated with a non-significant lower risk of Alzheimer’s disease (odds ratio 0.87; 95% confidence interval 0.76, 1.00; p = 0.056). A suggestive association was observed for genetically predicted higher plasma caffeine levels and lower risk of Parkinson’s disease in the FinnGen consortium. but not in the International Parkinson’s Disease Genomics consortium; no overall association was found (odds ratio 0.92; 95% confidence interval 0.77, 1.10; p = 0.347). This study found possible suggestive evidence of a protective role of caffeine in Alzheimer’s disease. The association between caffeine and Parkinson’s disease requires further study.

Angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 have been implicated in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). The expression of ACE2 and TMPRSS2 in the lung epithelium might have implications for the risk of SARS-CoV-2 infection and severity of COVID-19. We use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to investigate whether these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels. We observed no consistent evidence of an association of genetically predicted serum ACE levels with any of our outcomes. There was weak evidence for an association of genetically predicted serum ACE levels with ACE2 gene expression in the Lung eQTL Consortium (p = 0.014), but this finding did not replicate. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in the Gene-Tissue Expression (GTEx) study (p = 4 × 10−4) and with circulating plasma ACE2 levels in the INTERVAL study (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68). There were no associations of genetically proxied liability to the other cardiometabolic traits with any outcome. This study does not provide consistent evidence to support an effect of serum ACE levels (as a proxy for ACE inhibitors) or cardiometabolic risk factors on lung ACE2 and TMPRSS2 expression or plasma ACE2 levels.

The role of milk and fermented milk consumption in stroke risk is unclear. We investigated associations of time-updated information on milk and fermented milk consumption (1997 and 2009) with total stroke, cerebral infarction, and hemorrhagic stroke risk among 79,618 Swedish women and men (mean age 61.3 years). During a mean follow-up of 17.7 years, we identified 9735 incident cases of total stroke, of which 7573 were cerebral infarctions, 1470 hemorrhagic strokes, and 692 unspecified strokes. Compared with an intake of 100 g/day of milk, the multivariable-adjusted hazard ratios (95% confidence interval) of cerebral infarction were 1.05 (1.02–1.08) for 0 g/day, 0.97 (0.95–0.99) for 200 g/day, 0.96 (0.92–1.00) for 400 g/day, 0.98 (0.94–1.03) for 600 g/day, and 1.01 (0.94–1.07) for 800 g/day. Corresponding estimates for hemorrhagic stroke were 0.98 (0.91–1.05) for 0 g/day, 1.02 (0.97–1.07) for 200 g/day, 1.07 (0.98–1.17) for 400 g/day, 1.13 (1.02–1.25) for 600 g/day, and 1.19 (1.03–1.36) for 800 g/day. No associations were observed between milk consumption and total stroke or for fermented milk consumption and any of the stroke outcomes. Higher long-term milk consumption based on repeated measures of intake was weakly and non-linearly associated with cerebral infarction, and was directly associated with hemorrhagic stroke.

Elevated circulating copper levels have been associated with chronic kidney disease (CKD), kidney damage, and decline in kidney function. Using a two sample Mendelian randomization approach where copper-associated genetic variants were used as instrumental variables, genetically predicted higher circulating copper levels were associated with higher CKD prevalence (odds ratio 1.17; 95% confidence interval 1.04, 1.32; p-value = 0.009). There was suggestive evidence that genetically predicted higher copper was associated with a lower estimated glomerular filtration rate and a more rapid kidney damage decline. In conclusion, we observed that elevated circulating copper levels may be a causal risk factor for CKD.

Background: Tumour necrosis factor (TNF) inhibitors are used in the treatment of certain autoimmune diseases but given the role of TNF in tumour biology and atherosclerosis, such therapies may influence the risk of cancer and cardiovascular disease. We conducted a Mendelian randomization study to explore whether TNF levels are causally related to cardiovascular disease and cancer. Methods: Single-nucleotide polymorphisms associated with TNF levels at genome-wide significance were identified from a genome-wide association study of 30 912 European-ancestry individuals. Three TNF-associated single-nucleotide polymorphisms associated with higher risk of autoimmune diseases were used as instrumental variables. Summary-level data for 14 cardiovascular diseases, overall cancer and 14 site-specific cancers were obtained from UK Biobank and consortia. Findings: Genetically-predicted TNF levels were positively associated with coronary artery disease (odds ratio (OR) 2.25; 95% confidence interval (CI) 1.50, 3.37) and ischaemic stroke (OR 2.27; 95% CI 1.50, 3.43), and inversely associated with overall cancer (OR 0.54; 95% CI 0.42, 0.69), breast cancer (OR 0.51; 95% CI 0.39, 0.67), and colorectal cancer (OR 0.20; 95% CI 0.09, 0.45). There were suggestive associations of TNF with venous thromboembolism (OR 2.18; 95% CI 1.32, 3.59), endometrial cancer (OR 0.25; 95% CI 0.07, 0.94), and lung cancer (OR 0.45; 95% CI 0.21, 0.94). Interpretation: This study found evidence of causal associations of increased TNF levels with higher risk of common cardiovascular diseases and lower risk of overall and certain cancers.

Evidence from observational studies suggests that increased exposure to calcium may increase the risk of coronary heart disease and stroke whereas magnesium might have a protective effect on disease risk. However, studies of the associations of these minerals with heart failure are scarce and limited by potential biases introduced by confounding and reverse causality. We applied a two-sample Mendelian randomization design using summary estimates to assess whether serum calcium and magnesium concentrations are causally associated with heart failure. Summary statistics data were collected for seven and six single-nucleotide polymorphisms associated with calcium and magnesium, respectively, from the hitherto largest genome-wide association studies on these minerals. Corresponding summary statistics for genetic associations with heart failure were available from publicly available data based on the UK Biobank study and based on participants of European ancestry. The findings showed that neither serum calcium nor magnesium concentrations were associated with heart failure. In the standard inverse-variance weighted analysis, the odds ratios of heart failure per genetically predicted one standard deviation increase in mineral concentrations were 0.89 (95% confidence interval 0.67–1.17; p = 0.41) for serum calcium and 0.89 (95% confidence interval 0.72–1.10; p = 0.28) for serum magnesium. Results were robust in sensitivity analyses, including the weighted median and Mendelian randomization Egger analyses. In conclusion, these findings do not support previous findings suggesting a link between serum calcium and magnesium and heart failure, but this study was underpowered to detect weak associations.

Abstract Background Observational studies have shown that serum magnesium levels are inversely associated with risk of cardiovascular disease, but whether this association is causal is unknown. We conducted a Mendelian randomisation study to investigate whether serum magnesium levels may be causally associated with coronary artery disease (CAD). Methods This Mendelian randomisation analysis is based on summary-level data from the CARDIoGRAMplusC4D consortium’s 1000 Genomes-based genome-wide association meta-analysis of 48 studies with a total of 60,801 CAD cases and 123,504 non-cases. Six single-nucleotide polymorphisms associated with serum magnesium levels at genome-wide significance were used as instrumental variables. Results A genetic predisposition to higher serum magnesium levels was inversely associated with CAD. In conventional Mendelian randomisation analysis, the odds ratio of CAD was 0.88 (95% confidence interval [CI] 0.78 to 0.99; P = 0.03) per 0.1-mmol/L (about 1 standard deviation) increase in genetically predicted serum magnesium levels. Results were consistent in sensitivity analyses using the weighted median and heterogeneity-penalised model averaging methods, with odds ratios of 0.84 (95% CI 0.72 to 0.98; P = 0.03) and 0.83 (95% CI 0.71 to 0.96; P = 0.02), respectively. Conclusions This study based on genetics provides evidence that serum magnesium levels are inversely associated with risk of CAD. Randomised controlled trials elucidating whether magnesium supplementation lowers the risk of CAD, preferably in a setting at higher risk of hypomagnesaemia, are warranted.