Phenome-wide Mendelian randomization study of plasma triglycerides and 2,600 disease traits

Background Causality between plasma triglyceride (TG) levels and atherosclerotic cardiovascular disease (ASCVD) risk remains controversial despite more than four decades of study and two recent landmark trials, STRENGTH and REDUCE-IT. Further unclear is the association between TG levels and non-atherosclerotic diseases across organ systems. Methods Here, we conducted a phenome-wide, two-sample Mendelian randomization (MR) analysis using inverse-variance weighted (IVW) regression to systematically infer the causal effects of plasma TG levels on 2,600 disease traits in the European ancestry population of UK Biobank. For replication, we externally tested 221 nominally significant associations ( p < 0.05) in an independent cohort from FinnGen. To account for potential horizontal pleiotropy and the influence of invalid instrumental variables, we performed sensitivity analyses using MR-Egger regression, weighted median estimator, and MR-PRESSO. Finally, we used multivariable MR controlling for correlated lipid fractions to distinguish the independent effect of plasma TG levels. Results Our results identified 7 disease traits reaching Bonferroni-corrected significance in both the discovery ( p < 1.92 × 10-5) and replication analyses ( p < 2.26 × 10-4), supporting a causal relationship between plasma TG levels and ASCVDs, including coronary artery disease (OR 1.33, 95% CI 1.24-1.43, p = 2.47 × 10-13). We also identified 12 disease traits that were Bonferroni-significant in the discovery or replication analysis and at least nominally significant in the other analysis ( p < 0.05), identifying plasma TG levels as a novel risk factor for 9 non-ASCVD diseases, including uterine leiomyoma (OR 1.19, 95% CI 1.10-1.29, p = 1.17 × 10-5). Conclusions Taking a phenome-wide, two-sample MR approach, we identified causal associations between plasma TG levels and 19 disease traits across organ systems. Our findings suggest unrealized drug repurposing opportunities or adverse effects related to approved and emerging TG-lowering agents as well as mechanistic insights for future study. ### Competing Interest Statement RD reports receiving grants from AstraZeneca; grants and non-financial support from Goldfinch Bio; being a scientific co-founder, consultant, and equity holder (pending) for Pensieve Health; and a consultant for Variant Bio, all unrelated to this work. RSR reports receiving grants from Amgen, Arrowhead, Lilly, Novartis and Regeneron; consulting fees from Amgen, Arrowhead, Lilly, Novartis and Regeneron; honoraria for non-promotional lectures from Amgen, Kowa and Regeneron, royalties from Wolters Kluwer (UpToDate); and stock holdings in MediMergent, LLC. ### Funding Statement RD is supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) (R35-GM124836) and the National Heart, Lung, and Blood Institute of the NIH (R01-HL139865 and R01-HL155915). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UK Biobank has approval from the North West Multi Centre Research Ethics Committee (MREC) as a Research Tissue Bank (RTB) (11/NW/0382), and all participants of UKB provided written informed consent. More information is available at (https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/about-us/ethics). The work described in this study was approved by UKB under application number 16218. All participants of FinnGen provided written informed consent for biobank research, based on the Finnish Biobank Act. The Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa (HUS) approved the FinnGen study protocol Nr HUS/990/2017. More information is available at (https://www.finngen.fi/en/code\_of\_conduct). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Not Applicable All analyses used publicly available data (UKB, FinnGen), including previously published GWAS (GLGC) ([Willer et al., 2013][1]). Obtaining access to UKB (Pan-UKB\_Team, 2020) and FinnGen (FinnGen, 2020) GWAS summary statistics is detailed here (https://www.finngen.fi/en/access\_results) and here (https://pan.ukbb.broadinstitute.org/downloads). Please note the summary statistics for FinnGen and Pan-UKB are made publicly available. [1]: #ref-78