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Fatty acids are important dietary factors that have been extensively studied for their implication in health and disease. Evidence from epidemiological studies and randomised controlled trials on their role in cardiovascular, inflammatory, and other diseases remains inconsistent. The objective of this study was to assess whether genetically predicted fatty acid concentrations affect the risk of disease across a wide variety of clinical health outcomes. The UK Biobank (UKB) is a large study involving over 500,000 participants aged 40 to 69 years at recruitment from 2006 to 2010. We used summary-level data for 117,143 UKB samples (base dataset), to extract genetic associations of fatty acids, and individual-level data for 322,232 UKB participants (target dataset) to conduct our discovery analysis. We studied potentially causal relationships of circulating fatty acids with 845 clinical diagnoses, using mendelian randomisation (MR) approach, within a phenome-wide association study (PheWAS) framework. Regression models in PheWAS were adjusted for sex, age, and the first 10 genetic principal components. External summary statistics were used for replication. When several fatty acids were associated with a health outcome, multivariable MR and MR-Bayesian method averaging (MR-BMA) was applied to disentangle their causal role. Genetic predisposition to higher docosahexaenoic acid (DHA) was associated with cholelithiasis and cholecystitis (odds ratio per mmol/L: 0.76, 95% confidence interval: 0.66 to 0.87). This was supported in replication analysis (FinnGen study) and by the genetically predicted omega-3 fatty acids analyses. Genetically predicted linoleic acid (LA), omega-6, polyunsaturated fatty acids (PUFAs), and total fatty acids (total FAs) showed positive associations with cardiovascular outcomes with support from replication analysis. Finally, higher genetically predicted levels of DHA (0.83, 0.73 to 0.95) and omega-3 (0.83, 0.75 to 0.92) were found to have a protective effect on obesity, which was supported using body mass index (BMI) in the GIANT consortium as replication analysis. Multivariable MR analysis suggested a direct detrimental effect of LA (1.64, 1.07 to 2.50) and omega-6 fatty acids (1.81, 1.06 to 3.09) on coronary heart disease (CHD). MR-BMA prioritised LA and omega-6 fatty acids as the top risk factors for CHD. Although we present a range of sensitivity analyses to the address MR assumptions, horizontal pleiotropy may still bias the reported associations and further evaluation in clinical trials is needed. Our study suggests potentially protective effects of circulating DHA and omega-3 concentrations on cholelithiasis and cholecystitis and on obesity, highlighting the need to further assess them as prevention treatments in clinical trials. Moreover, our findings do not support the supplementation of unsaturated fatty acids for cardiovascular disease prevention.

Educational attainment (EA) has been linked to the risk of several types of cancer, despite having no expected direct biological connection. In this paper, we investigate the mediating role of alcohol consumption, smoking, vegetable consumption, fruit consumption and body mass index (BMI) in explaining the effect of EA on 7 cancer groupings. Large-scale genome wide association study (GWAS) results were used to construct the genetic instrument for EA and the lifestyle factors. We conducted GWAS in the UK Biobank sample in up to 335,024 individuals to obtain genetic association data for the cancer outcomes. Univariable and multivariable two-sample Mendelian randomization (MR) analyses and mediation analyses were then conducted to explore the causal effect and mediating proportions of these relations. MR mediation analysis revealed that reduced lifetime smoking index accounted for 81.7% (49.1% to 100%) of the protective effect of higher EA on lower respiratory cancer. Moreover, the effect of higher EA on lower respiratory cancer was mediated through vegetable consumption by 10.2% (4.4% to 15.9%). We found genetic evidence that the effect of EA on groups of cancer is due to behavioural changes in avoiding well established risk factors such as smoking and vegetable consuming.

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.

Subarachnoid haemorrhage (SAH) poses a life-threatening risk, contributing to half of all haemorrhagic strokes, with aneurysmal SAH (aSAH) affecting approximately 6 individuals per 100,000 annually. Following aSAH, the influx of plasma haptoglobin into the cerebrospinal fluid (CSF) is insufficient to sequester the released free haemoglobin in the subarachnoid space and avoid its neurotoxic effects. Exogenous administration of haptoglobin could be a therapeutic strategy for improving outcomes after aSAH. Using individual level data in the UK Biobank and genetic summary statistics from the largest relevant cohorts, Mendelian randomization analysis was conducted to explore the associations of genetically predicted CSF haptoglobin with the risk of catastrophic aSAH (i.e., fatal aSAH or non-fatal aSAH with at least one of: hemiparesis, aphasia, apraxia, or visual field defects within 7 days) and secondary traits, including stroke-related outcomes and imaging markers of brain swelling. Higher levels of genetically predicted CSF haptoglobin was associated with lower risk of catastrophic aSAH in multi-ancestry (OR: 0.79, 95% CI: 0.65 to 0.96, p = 0.019) and White British sample analyses (OR: 0.78, 95% CI: 0.63 to 0.95, p = 0.013), while the lack of association with related traits supported effects specific to outcomes after aSAH. A proof-of-concept analysis showing associations of genetically predicted haptoglobin with haemoglobin in plasma validated the proposed mechanism. Using human genetic data, we provide evidence to support a causal role of higher CSF haptoglobin in improving outcomes after aSAH. However, there was no evidence for an effect on the risk of aSAH or related cerebrovascular events. These findings support haptoglobin as a potential treatment in aSAH to mitigate the neurotoxic effects of free haemoglobin and improve outcomes.

Background Solute carrier family 13 member 5 (SLC13A5) is a Na + -coupled citrate co-transporter that mediates entry of extracellular citrate into the cytosol. SLC13A5 inhibition has been proposed as a target for reducing progression of kidney disease. The aim of this study was to leverage the Mendelian randomization paradigm to gain insight into the effects of SLC13A5 inhibition in humans, towards prioritizing and informing clinical development efforts. Methods The primary Mendelian randomization analyses investigated the effect of SLC13A5 inhibition on measures of kidney function, including creatinine and cystatin C-based measures of estimated glomerular filtration rate (creatinine-eGFR and cystatin C-eGFR), blood urea nitrogen (BUN), urine albumin-creatinine ratio (uACR), and risk of chronic kidney disease and microalbuminuria. Secondary analyses included a paired plasma and urine metabolome-wide association study, investigation of secondary traits related to SLC13A5 biology, a phenome-wide association study (PheWAS), and a proteome-wide association study. All analyses were compared to the effect of genetically predicted plasma citrate levels using variants selected from across the genome, and statistical sensitivity analyses robust to the inclusion of pleiotropic variants were also performed. Data were obtained from large-scale genetic consortia and biobanks, with sample sizes ranging from 5023 to 1,320,016 individuals. Results We found evidence of associations between genetically proxied SLC13A5 inhibition and higher creatinine-eGFR ( p  = 0.002), cystatin C-eGFR ( p  = 0.005), and lower BUN ( p  = 3 × 10 −4 ). Statistical sensitivity analyses robust to the inclusion of pleiotropic variants suggested that these effects may be a consequence of higher plasma citrate levels. There was no strong evidence of associations of genetically proxied SLC13A5 inhibition with uACR or risk of CKD or microalbuminuria. Secondary analyses identified evidence of associations with higher plasma calcium levels ( p  = 6 × 10 −13 ) and lower fasting glucose ( p  = 0.02). PheWAS did not identify any safety concerns. Conclusions This Mendelian randomization analysis provides human-centric insight to guide clinical development of an SLC13A5 inhibitor. We identify plasma calcium and citrate as biologically plausible biomarkers of target engagement, and plasma citrate as a potential biomarker of mechanism of action. Our human genetic evidence corroborates evidence from various animal models to support effects of SLC13A5 inhibition on improving kidney function.

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.

Two-sample MR is an increasingly popular method for strengthening causal inference in epidemiological studies. For the effect estimates to be meaningful, variant-exposure and variant-outcome associations must come from comparable populations. A recent systematic review of two-sample MR studies found that, if assessed at all, MR studies evaluated this assumption by checking that the genetic association studies had similar demographics. However, it is unclear if this is sufficient because less easily accessible factors may also be important. Here we propose an easy-to-implement falsification test. Since recent theoretical developments in causal inference suggest that a causal effect estimate can generalise from one study to another if there is exchangeability of effect modifiers, we suggest testing the homogeneity of variant-phenotype associations for a phenotype which has been measured in both genetic association studies as a method of exploring the ‘same-population’ test. This test could be used to facilitate designing MR studies with diverse populations. We developed a simple R package to facilitate the implementation of our proposed test. We hope that this research note will result in increased attention to the same-population assumption, and the development of better sensitivity analyses.

BackgroundFatty acids are important dietary factors that have been extensively studied for their implication in health and disease. Evidence from epidemiological studies and randomised controlled trials on their role in cardiovascular, inflammatory, and other diseases remains inconsistent. The objective of this study was to assess whether genetically predicted fatty acid concentrations affect the risk of disease across a wide variety of clinical health outcomes.Methods and findingsThe UK Biobank (UKB) is a large study involving over 500,000 participants aged 40 to 69 years at recruitment from 2006 to 2010. We used summary-level data for 117,143 UKB samples (base dataset), to extract genetic associations of fatty acids, and individual-level data for 322,232 UKB participants (target dataset) to conduct our discovery analysis. We studied potentially causal relationships of circulating fatty acids with 845 clinical diagnoses, using mendelian randomisation (MR) approach, within a phenome-wide association study (PheWAS) framework. Regression models in PheWAS were adjusted for sex, age, and the first 10 genetic principal components. External summary statistics were used for replication. When several fatty acids were associated with a health outcome, multivariable MR and MR-Bayesian method averaging (MR-BMA) was applied to disentangle their causal role. Genetic predisposition to higher docosahexaenoic acid (DHA) was associated with cholelithiasis and cholecystitis (odds ratio per mmol/L: 0.76, 95% confidence interval: 0.66 to 0.87). This was supported in replication analysis (FinnGen study) and by the genetically predicted omega-3 fatty acids analyses. Genetically predicted linoleic acid (LA), omega-6, polyunsaturated fatty acids (PUFAs), and total fatty acids (total FAs) showed positive associations with cardiovascular outcomes with support from replication analysis. Finally, higher genetically predicted levels of DHA (0.83, 0.73 to 0.95) and omega-3 (0.83, 0.75 to 0.92) were found to have a protective effect on obesity, which was supported using body mass index (BMI) in the GIANT consortium as replication analysis. Multivariable MR analysis suggested a direct detrimental effect of LA (1.64, 1.07 to 2.50) and omega-6 fatty acids (1.81, 1.06 to 3.09) on coronary heart disease (CHD). MR-BMA prioritised LA and omega-6 fatty acids as the top risk factors for CHD. Although we present a range of sensitivity analyses to the address MR assumptions, horizontal pleiotropy may still bias the reported associations and further evaluation in clinical trials is needed.ConclusionsOur study suggests potentially protective effects of circulating DHA and omega-3 concentrations on cholelithiasis and cholecystitis and on obesity, highlighting the need to further assess them as prevention treatments in clinical trials. Moreover, our findings do not support the supplementation of unsaturated fatty acids for cardiovascular disease prevention.

Neuropsychiatric disorders present a global health challenge, necessitating an understanding of their molecular mechanisms for therapeutic development. Using Mendelian randomization (MR) analysis, this study explored associations between genetically predicted levels of 173 proteins in cerebrospinal fluid (CSF) and 25 in the brain with 14 neuropsychiatric disorders and risk factors. Follow-up analyses assessed consistency across plasma protein levels and gene expression in various brain regions. Proteins were instrumented using tissue-specific genetic variants, and colocalization analysis confirmed unbiased gene variants. Consistent MR and colocalization evidence revealed that lower cortical expression of low-density lipoprotein receptor-related protein 8, coupled higher abundance in the CSF and plasma, associated with lower fluid intelligence scores and decreased bipolar disorder risk. Additionally, elevated apolipoprotein-E2 and hepatocyte growth factor-like protein in the CSF and brain were related to reduced leisure screen time and lower odds of physical activity, respectively. Furthermore, elevated CSF soluble tyrosine-protein kinase receptor 1 level increased liability to attention deficit hyperactivity disorder and schizophrenia alongside lower fluid intelligence scores. This research provides genetic evidence supporting novel tissue-specific proteomic targets for neuropsychiatric disorders and their risk factors. Further exploration is necessary to understand the underlying biological mechanisms and assess their potential for therapeutic intervention.

Mendelian randomisation (MR) is an increasingly popular method for strengthening causal inference in epidemiological studies. cis-MR in particular uses genetic variants in the gene region of a drug target protein as an instrumental variable to provide quasi-experimental evidence for on-target drug effects. A limitation of this framework is when the genetic variant is correlated to another variant that also effects the outcome of interest (confounding through linkage disequilibrium). Methods for correcting this bias, such as multivariable MR, struggle in a cis setting because of the high correlation among genetic variants. Here, through simulation experiments and an applied example considering the effect of interleukin 6 receptor signaling on coronary artery disease risk, we present an alternative method for attenuating bias that does not suffer from this problem. As our method uses both MR and the product and difference method for mediation analysis, our proposal inherits all assumptions of these methods. We have additionally developed an R package, TwoStepCisMR, to facilitate the implementation of the method.