Associations of genetically predicted fatty acid levels across the phenome: A mendelian randomisation study

Background 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. Methods and findings 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. Conclusions 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. Author summary Why was this study done? Epidemiological studies have investigated the influence of dietary fatty acids on several chronic diseases including cardiovascular disease (CVD), inflammatory diseases, cancers, and neurodegenerative conditions. The evidence is conflicting and inconclusive and is not supported by randomised controlled trials (RCTs) on fatty acids supplementation. The fact that the human fatty acid metabolome partly reflects the fatty acid intake was leveraged in this work. What did the researchers do and find? Mendelian randomisation analysis was conducted to investigate potential causal associations of circulating fatty acids and 845 disease outcomes in UK Biobank. We found that 1 mmol/L increase in genetically predicted docosahexaenoic acid (DHA) was associated with 24% reduced odds of cholelithiasis and cholecystitis, as well as 17% reduced odds of obesity. One mmol/L higher genetically predicted linoleic acid (LA) was associated with 27% increased odds of ischemic heart disease. When assessed with other fatty acid classes simultaneously, 1 mmol/L higher genetically predicted LA and omega-6 fatty acids were associated with higher odds of coronary heart disease (64% and 81% increase, respectively). What do these findings mean? Our results support the prioritisation of RCTs examining the role of primary and secondary prevention of cholelithiasis via dietary modification or supplementation of DHA and other omega-3 fatty acids. Our principal findings also provide evidence against the supplemental use of fatty acids for CVD prevention. Triangulation of evidence for causal inference of fatty acid levels through experimental studies susceptible to different assumptions is needed to strengthen the evidence.