Alanine, commonly found in meaty foods and popular as a sports supplement, has interactions with neurotransmitters and brain energy supply, but its impact on mental health remains uncertain. This two-sample Mendelian randomisation (MR) study aimed to investigate causal associations of plasma alanine with major mental disorders-depression, bipolar disorder, schizophrenia, anxiety, and attention-deficit hyperactivity disorder (ADHD) and to further explore sex-specific associations using available data, considering potential sex disparity. We utilised genetic variants from the UK Biobank to predict plasma alanine (N = 115,074) and obtained their genetic associations with depression (Ncases = 194,180 and Ncontrols = 521,663), bipolar disorder (Ncases = 46,418 and Ncontrols = 563,769), schizophrenia (Ncases = 52,017 and Ncontrols = 75,889), anxiety (Ncases = 19,529 and Ncontrols = 212,855), and ADHD (Ncases = 46,418 and Ncontrols = 402,606) from genome-wide association studies (GWASs) in the Psychiatric Genomics Consortium (PGC) and FinnGen Biobank. MR estimates were primarily derived using the inverse variance weighted (IVW) method, with weighted median, MR-Egger, and MR-RAPS applied as sensitivity analyses. MR-PRESSO was used to detect pleiotropy and outliers. Genetically predicted alanine was nominally associated with a lower risk of schizophrenia overall (OR 0.88, 95% CI: 0.79–0.99) and in males (OR 0.88, 95% CI: 0.77–0.99), which were not significant after multiple testing. No association was detected in females (OR 0.92, 95% CI: 0.80–1.05). There was no evidence linking plasma alanine to depression, bipolar disorder, anxiety, or ADHD. These findings suggest that alanine might have an inverse association with schizophrenia, which may be more evident in males, but has no psychiatric side effects on other mental disorders. Replication in larger studies is warranted.

The interaction between 25-hydroxyvitamin D [25(OH)D] and physical activity (PA) in influencing hypertension remains underexplored. This study aimed to examine their independent and joint associations with hypertension risk among 5327 participants aged ≥ 50 years from the English Longitudinal Study of Ageing. Participants were categorised by 25(OH)D status (sufficient, ≥ 50 nmol/l; insufficient, ≥ 30 to < 50 nmol/l; deficient, < 30 nmol/l) and self-reported PA levels. Multivariable logistic regression, adjusting for the season of measurement and sociodemographic confounders, showed that sufficient 25(OH)D (OR = 0·66, 95 % CI 0·56, 0·78) and higher PA (OR = 0·82, 95 % CI 0·71, 0·94) were independently associated with reduced hypertension prevalence. In joint analyses, the group combining higher PA and sufficient 25(OH)D exhibited the lowest odds of hypertension (OR = 0·55, 95 % CI 0·43, 0·70) compared with the lower PA and deficient group. A significant synergistic interaction was identified, indicating that the combined protective effect of these factors was greater than the sum of their individual associations. These results were corroborated by Mendelian randomisation analysis, which identified inverse causal associations between genetically predicted 25(OH)D, vigorous PA and hypertension risk across independent datasets. These findings emphasise that vitamin D sufficiency acts in synergy with an active lifestyle to enhance cardiovascular protection. This relationship underscores the critical importance in nutritional science of integrating micronutrient status with PA to develop more effective, multifaceted lifestyle-based strategies for hypertension management in middle-aged and older populations.

Dysregulation of fatty acids metabolism has been associated with the risk of osteoarthritis (OA), yet current evidence from epidemiological or genetic studies remains inconclusive. We aimed to investigate the phenotypic association and genetic architecture between total fatty acids, saturated fatty acids (SFA), MUFA, PUFA and OA. Leveraging individual-level data from the UK Biobank, combined with the hitherto largest genome-wide association studies of fatty acids (n 136 016) and OA (n 826 690) in European individuals, we implemented a comprehensive analytical framework. This included observational and genetic analyses, incorporating phenotypic associations, genetic correlations, cross-trait meta-analysis, enrichment analysis and Mendelian randomisation (MR). Observational analysis identified SFA as a risk factor, while MUFA and PUFA as protective factors for OA. Despite a lack of genome-wide genetic correlation, statistically significant local signals were detected within three specific genomic regions. Cross-trait meta-analysis identified sixty-eight pleiotropic loci shared between fatty acids and OA, of which nine were novel. Enrichment analysis revealed the shared genes were enriched in lipoprotein metabolism, immune response and inflammation regulation pathways. Two-sample MR provided evidence for a causal relationship of MUFA and PUFA on OA that survived false discovery rate correction. This study supports associations between circulating fatty acids and OA, with MUFA and PUFA exerting a protective role. Our findings provide new perspectives into OA prevention especially regarding the potential dietary interventions.

Sepsis-related deaths remain prevalent in intensive care settings, with metabolic dysregulation as a key contributor. Although amino acid supplementation has shown promise, its clinical effectiveness in sepsis is unclear. This study evaluated the impact of intravenous amino acid administration on 28-d mortality in intensive care unit (ICU) sepsis patients using retrospective cohort analysis and Mendelian randomisation (MR). We analysed data from the Medical Information Mart for Intensive Care-IV database, matching 726 patients (363 per group) using propensity scores. The association between amino acid supplementation and mortality was assessed using logistic regression, Cox regression and targeted maximum likelihood estimation (TMLE). Two-sample MR was used to explore causal links between twenty common amino acids and sepsis mortality. In the cohort analysis, amino acid supplementation was consistently associated with significantly reduced 28-d mortality across all analytical methods (logistic regression: OR = 0·48, P < 0·01; Cox regression: HR = 0·48, P < 0·01; TMLE: average treatment effect = −0·102, P < 0·01). In contrast, the MR analysis did not find a significant causal association for any single amino acid after correction for multiple comparisons; although glycine showed a nominal protective signal, it did not remain significant after false discovery rate correction. This dual-method study demonstrates a strong association between compound amino acid infusions and reduced mortality in sepsis but did not identify any single amino acid as a robust causal mediator. These findings suggest the benefit may arise from a synergistic effect, highlighting the need for randomised controlled trials to validate these observational results and optimise nutritional strategies.

Traditional studies examining caffeine intake and age-related eye diseases (ARED) have shown inconsistent results, potentially related to variations in caffeine assessment methods. This two-sample Mendelian randomisation study investigated associations between plasma caffeine and four ARED: senile cataract, diabetic retinopathy (DR) and glaucoma and age-related macular degeneration (AMD). Summary data on genetically predicted plasma caffeine came from a genome-wide association study of 9876 European-ancestry participants across six population-based studies. ARED data were extracted from FinnGen Consortium clinical records. We further examined causal effects on glaucoma subtypes: primary open-angle glaucoma (POAG) and primary angle closure glaucoma (PACG) and assessed intraocular pressure (IOP) as a potential mediator. Higher genetically predicted plasma caffeine levels were associated with reduced risk of senile cataract (OR 0·84, 95 % CI 0·78, 0·90, P < 0·001), DR (OR 0·81, 95 % CI 0·74, 0·88, P < 0·001), glaucoma (OR 0·83, 95 % CI 0·73, 0·95, P = 0·008) and PACG (OR 0·74, 95 % CI 0·54, 0·99, P = 0·046). No associations were observed with AMD or POAG. Mediation analysis suggested that 41 % (95 % CI −0·14, −0·01) of caffeine’s effect on glaucoma was mediated by IOP. Our findings indicate that elevated plasma caffeine may protect against senile cataract, DR and glaucoma, but not AMD. Effects differed by glaucoma subtype, with IOP partially explaining the overall association. This study provides genetic evidence supporting caffeine’s role in mitigating ARED risk, highlighting its potential therapeutic implications.

Coffee is a widely consumed beverage, which has been extensively studied for its potential effects on health. We aimed to map genetic evidence for the effect of habitual coffee consumption on health. We searched PubMed, Embase, Cochrane Database of Systematic Reviews, Cumulative Index to Nursing and Allied Health Literature and two preprint repositories from inception to 30 September 2022, and included fifty-nine studies, spanning 160 disease or biomarker associations. We evaluated the articles for certainty of evidence using a modified GRADE tool and robustness of the associations by comparing Mendelian randomisation (MR) sensitivity analyses. Coffee consumption was associated with smaller grey matter brain volume in one study, and there was probable evidence for an increased risk of Alzheimer’s disease and younger age of onset of Huntington’s disease. MR studies provided probable evidence for an association with increased risk of oesophageal and digestive cancers, but protective effects for hepatocellular carcinomas and ovarian cancer. We found probable evidence for increased risk of type 2 diabetes mellitus, osteoarthritis, rheumatoid arthritis, menopausal disorders, glaucoma, higher total cholesterol, LDL-cholesterol and ApoB, and lowered risk of migraines, kidney disease and gallstone disease. Future studies should aim to understand underlying mechanisms of disease, expand knowledge in non-European cohorts and develop quality assessment tools for systematic reviews of MR studies.

Systematic review registration: PROSPERO registration number CRD42021295323

Previous studies have reported co-morbidities of autoimmune thyroid disorders (AITD), including Hashimoto’s disease and Graves’ disease and celiac disease (CeD), as well as the possible beneficial effects of a gluten-free diet (GFD) on AITD. Nonetheless, it remains uncertain whether there is a genetic causal relationship between AITD and CeD, while the beneficial effects of a GFD are controversial. This study aims to explore the causal relationship between CeD and AITD, particularly with Hashimoto’s disease, and to determine whether a GFD is beneficial for AITD. We performed a two-sample Mendelian randomisation analysis on data from the largest meta-analysis summary statistics of AITD, CeD and GFD. Genetic instrumental variables were established by pinpointing SNP that relate to corresponding factors. In assessing sensitivity and heterogeneity, we conducted examinations of MR Egger, weighted median, simple mode, weighted mode and MR Egger intercept tests. Hashimoto’s disease was found to play a pathogenic role in increasing the risk of CeD (ORIVW = 1·544 (95 % CI 1·153, 2·068), P = 0·00355), and our Mendelian randomisation study does not support genetic liability related to CeD with Graves’ disease and GFD with AITD. This study supports the positive correlation between Hashimoto’s disease risk and CeD risk, while GFD has no protective effect on AITD and may exert its effect through other mechanisms. These findings provide valuable insights into potential targets for disease intervention and treatment at the genetic level.

Femoral neck bone mineral density (FNBMD) is a high risk factor for femoral head fractures, and coffee intake affects bone mineral density, but the effect on FNBMD remains to be explored. First, we conducted an observational study in the National Health and Nutrition Examination Survey and collected data on coffee intake, FNBMD, and sixteen covariates. Weight linear regression was used to explore the association of coffee intake with FNBMD. Then, Mendelian randomisation (MR) was used to explore the causal relationship between coffee intake and FNBMD, the exposure factor was coffee intake, and the outcome factor was FNBMD. The inverse variance weighting (IVW) method was used for the analysis, while heterogeneity tests, sensitivity, and pleiotropy analysis were performed. A total of 5 915 people were included in the cross-sectional study, including 3 178 men and 2 737 women. In the completely adjusted model, no coffee was used as a reference. The ORs for the overall population at ‘< 1’, ‘1–<2’, ‘2–<4’, and ‘4+’ (95% CI) were 0.02 (–0.01, 0.04), 0.00 (–0.01, 0.02), –0.01 (–0.02, 0.00), and 0.00 (–0.01, 0.02), respectively. The male and female population showed no statistically significant differences in both univariate and multivariate linear regressions. In the MR study, the IVW results showed an OR (95% CI) of 1.06 (0.88–1.27), a P-value of 0.55, and an overall F-value of 80.31. The heterogeneity, sensitivity analyses, and pleiotropy had no statistical significance. Our study used cross-sectional studies and MR to demonstrate that there is no correlation or causal relationship between coffee intake and FNBMD.

The composite dietary antioxidant index (CDAI) has been identified as a critical factor in the pathogenesis of certain inflammatory diseases. The study aimed to investigate the relationship between CDAI and Helicobacter pylori infection using cross-sectional design. In this study, participants from the 1999–2000 National Health and Nutrition Examination Survey were analysed using logistic and Cox regression analyses to assess the associations between H. pylori infection and CDAI, encompassing vitamin A, vitamin C, vitamin E, carotene, Zn, Se and Cu. The results demonstrated a negative correlation between CDAI scores and H. pylori infection, revealing a non-linear relationship between the odds of H. pylori infection and CDAI as a continuous variable. Subsequently, a two-sample Mendelian randomisation study was conducted utilising genome-wide association study summary statistics to explore the causal relationship between antioxidant levels and H. pylori infection. We found that the intake of Cu was a protective factor in the occurrence of H. pylori infection but did not support a causal association between circulating Cu levels and H. pylori infection. The prevalence of H. pylori infection was found to be elevated among individuals of older age, lower education levels, limited socio-economic status, smokers, diabetes and those with hypertension. The study suggests that higher CDAI is linked to decreased odds of H. pylori infection, and further prospective studies are needed to confirm the association. Our findings may have significant implications for the prevention and management of H. pylori-related diseases.

This study aimed to investigate the relationship between serum folate levels and the risk of psoriasis by integrating observational study with Mendelian Randomisation (MR) analysis. We firstly conducted an observational study using data from the National Health and Nutrition Examination Survey (NHANES). Subsequently, genetic instruments were selected for two-sample MR analyses to investigate the causal relationship between serum folate levels and the risk of psoriasis. The observational study showed no significant association between serum folate levels and psoriasis. In the fully adjusted model, neither serum folate level as a continuous variable (OR = 0·99, 95 % CI: 0·98, 1·00, P = 0·071) nor serum folate quartiles Q4 compared to Q1 (OR = 0·83, 95 % CI: 0·58, 1·19, P = 0·309) showed statistical significance. The MR analysis revealed that higher genetically predicted serum folate levels from Icelandic and Danish populations were significantly associated with a reduced risk of psoriasis (OR = 0·63, 95 % CI: 0·45, 0·88, P = 0·005). Similarly, higher genetically predicted serum folate levels from South Asian populations were significantly associated with a lower risk of psoriasis (OR = 0·84, 95 % CI: 0·72, 0·98, P = 0·025). Integrating observational study with MR analysis suggests that serum folate levels are protective factors against psoriasis, indicating that higher serum folate levels may help prevent the onset of the disease.

Despite previous observational studies suggesting that malnutrition could be involved in venous thromboembolism (VTE), definitive causality still lacks high-quality research evidence. This study aims to explore the genetic causal association between malnutrition and VTE. The study was performed using summary statistics from genome-wide association studies for VTE (cases = 23 367; controls = 430 366). SNP associated with exposure was selected based on quality control steps. The primary analysis employed the inverse variance weighted (IVW) method, with additional support from Mendelian randomisation (MR)-Egger, weighted median and weighted mode approaches. MR-Egger, leave-one-SNP-out analysis and MR pleiotropy residual sum and outlier (MR-PRESSO) were used for sensitivity analysis. Cochran’s Q test was used to assess heterogeneity between instrumental variables (IV). IVW suggested that overweight has a positive genetic causal effect on VTE (OR = 1·1344, 95 % CI = 1·056, 1·2186, P < 0·001). No genetic causal effect of malnutrition (IVW: OR = 0·9983, 95 % CI = 0·9593, 1·0388, P = 0·9333) was found on VTE. Cochran’s Q test suggests no possible heterogeneity in both related exposures. The results of the MR-Egger regression suggest that the analysis is not affected by horizontal pleiotropy. The results of the MR-PRESSO suggest that there are no outliers. The results revealed a statistical genetic association where overweight correlates with an increased risk of VTE. Meanwhile, no genetic causal link was observed between malnutrition and VTE. Further research is warranted to deepen our understanding of these associations.

Oxidative stress is present in chronic obstructive pulmonary disease (COPD); however, the effect of increased dietary antioxidants on reducing COPD risk remains unclear. The aim of this study was to investigate the association of the composite dietary antioxidant index (CDAI) with COPD in adults. This study conducted a cross-sectional investigation using data from the National Health and Nutrition Examination Survey (NHANES) spanning from 2015 to March 2020 to explore the association between CDAI and COPD in adults. This study included 9295 participants. Three logistic regression models (crude model, partially adjusted model and fully adjusted model) and restricted cubic spline (RCS) curves were utilised to assess the association between CDAI levels and COPD risk. Subsequently, a two-sample Mendelian randomisation (MR) was employed to analyse the causal impact of antioxidant levels within CDAI on the occurrence of COPD. CDAI levels were inversely associated with COPD after adjusting for confounders (OR = 0·97, 95 % CI 0·95, 1·00), and the association was linear (P < 0·001), and the results of the RCS showed that CDAI was linearly correlated with COPD occurrence (P < 0·001). MR analysis revealed a causal relationship between vitamin C and COPD occurrence (OR = 0·99, 95 % CI 0·98, 1·00, P < 0·05). Our study indicates that dietary sources of antioxidants may reduce the risk of COPD occurrence, and the results of the MR analysis further show that vitamin C is causally associated with a reduced risk of COPD occurrence. However, further exploration is needed to understand how antioxidants prevent COPD.

Prior observational studies have reported the potential protective effect of n-3 fatty acids on the prognosis of acute pancreatitis (AP). However, the causal impact of n-3 fatty acids on AP is unclear. We aimed to investigate further the association of n-3 fatty acids with AP. We performed a meta-analysis and Mendelian randomisation (MR) to explore the association between n-3 fatty acids and the prognosis of AP from clinical observation and genetics perspectives, respectively. Nine randomised controlled trials were included in this study. The result meta-analysis showed that complementary therapy of n-3 fatty acids significantly decreased mortality (Relative Risk (RR): 0·30; 95 % CI 0·14, 0·65, P < 0·05) and infectious complications in AP (RR: 0·45; 95 % CI 0·27, 0·77, P < 0·05). Compared with the control groups, the hospital stays (MD: −1·02; 95 % CI −1·85, −0·20, P < 0·05) in AP patients with n-3 fatty acids treatment were statistically reduced. However, the ICU stay (MD: −0·49; 95 % CI −1·29, −0·31, P > 0·05) between control groups and AP patients with n-3 fatty acids treatment was insignificant. Utilising genetic susceptibility analysis in the MR approach, the MR showed n-3 fatty acids have a significant causal effect on the AP risk (OR, 0·887; 95 % CI 0·797, 0·986, P = 0·027, fixed-effect; OR, 0·887; 95 % CI 0·792, 0·993, P = 0·037, random-effect). n-3 fatty acids complementary therapy may improve the prognosis of AP. Furthermore, genetically predicted serum levels of n-3 fatty acids can significantly lower AP risk.

Rheumatoid arthritis (RA) is a prevalent autoimmune disease, and there is growing evidence suggesting a potential correlation between dietary factors and the pathogenesis of this condition. In order to investigate the causal relationship between diet and RA, we conducted a two-sample Mendelian randomisation (MR) analysis to examine the causal associations between twenty-two dietary factors and RA. Summary data from genome-wide association studies (GWAS) of RA were obtained from large GWAS meta-analyses. GWAS summary data for twenty-two dietary factors were obtained from UK Biobank. Random-effects inverse variance weighted was used as the primary method for assessing causality, and analyses of heterogeneity and horizontal pleiotropy were performed to ensure the accuracy of the results. Research indicates a negative genetic causal relationship between cereal intake (OR = 0·64, 95 % CI: 0·41, 0·99, P = 0·048) and oily fish intake (OR = 0·70, 95 % CI: 0·52, 0·95, P = 0·020) with the risk of RA. Other dietary factors were not causally related to RA. Sensitivity analysis shows that our results are reliable. This study provides genetic evidence suggesting that cereal intake and oily fish intake are protective factors for RA, indicating that RA patients and individuals at high risk should make appropriate dietary adjustments.

Emerging evidence has shown a strong correlation between serum TAG levels, the inflammatory response and Parkinson’s disease (PD) onset. However, the causal relationship between TAG levels and PD has not been well established. We aimed to investigate the relationship between serum TAG levels and risk of PD and explore the potential mediating role of circulating immune cells and inflammatory proteins. We utilised genotype data from the GeneRISK cohort, and summary data from genome-wide association studies investigating PD, circulating immune cells, inflammatory proteins and plasma lipidomes. Using Mendelian randomisation (MR) and multivariate MR (MVMR) analysis, we further adjusted for phosphatidylcholine (17:0_18:1) and TAG (58:7). Our results suggested a robust causal link between higher serum TAG (51:4) levels and a decreased risk of PD, with 1 sd genetically instrumented higher serum TAG (51:4) level leading to a 21 per cent (95 % CI 0·66, 0·96) reduction in the risk of PD (P= 0·015). Additionally, the results of the mediation analysis suggested a possible role for mediation through circulating immune cells (including IgD-CD38-B cells and resting CD4 regulatory T cells), but not circulating inflammatory proteins, in the causal relationship between the plasma lipidomes and PD. Our study confirms a causal relationship between higher serum TAG (51:4) levels and a lower risk of PD and clarifies a possible role for mediation through circulating immune cells, but not inflammatory proteins. These findings indicate that serum TAG (51:4) regulates immunity to effectively lower the risk of PD.

Tea is one of the most widely consumed beverages in the world. However, the association between tea and risk of pancreatic adenocarcinoma remains controversial. This study aimed to investigate the causal relationship between tea consumption and risk of pancreatic adenocarcinoma and to explore their mediating effects. The two-sample Mendelian randomisation (MR) analysis showed an inverse causal relationship between tea intake and pancreatic adenocarcinoma (OR: 0·111 (0·02, 0·85), P < 0·04). To examine the mediating effects, we explored the potential mechanisms by which tea intake reduces the risk of pancreatic adenocarcinoma. Based on the oral bioavailability and drug-like properties in Traditional Chinese Medicine Systems Pharmacology database, we selected the main active ingredients of tea. We screened out the fifteen representative targeted genes by Pharmmapper database, and the gene ontology enrichment analysis showed that these targeted genes were related to vascular endothelial growth factor (VEGF) pathway. The two-step MR analysis of results showed that only VEGF-D played a mediating role, with a mediation ratio of 0·230 (0·066, 0·394). In conclusion, the findings suggest that VEGF-D mediates the effect of tea intake on the risk of pancreatic adenocarcinoma.