Lipoprotein profile and metabolic fine-mapping of genetic lipid risk loci

Dysregulated blood lipid levels sit at the nexus of cardiometabolic disorders and are major predictors of human cardiovascular health. Using five major lipid traits (HDL-C, LDL-C, non- HDL-C, TC, and TG), a recent genome-wide association study (GWAS) in 1.65 million individuals identified and fine-mapped over 1,000 genetic loci that may be implicated in the etiology of dyslipidemia and related cardiovascular disease. However, a deeper functional understanding of these associations is needed to assess their therapeutic potential as druggable targets. Here we leveraged data from over 98,000 participants of UK Biobank for deep molecular phenotypic refinement and identified 225 lipid risk variants that associated with 168 distinct NMR-derived lipoprotein and metabolic traits, doubling the number of loci that are discoverable when using the five “classical” lipid traits alone. Hypothesis-free testing of >14,000 ratios between metabolite pairs significantly increased statistical power (p-gain) at 72% of the loci, revealing distinct groups of variants with functionally matching NMR-ratios that affect lipoprotein metabolism, transport, and remodeling (LPmtr). We demonstrate how these NMR- trait and -ratio associations can be used in the functional interpretation of the respective lipid risk loci and their evaluation as potential drug targets. Our study reveals a comprehensive picture of the biological roles that the different genetic variants play in LPmtr and supports the emerging view that lipoprotein size and core composition are essential for the understanding, prevention and treatment of lipid-related disorders, beyond the “classical” five major lipid traits currently used in clinical practice. ### Competing Interest Statement E.B.F. is an employee and stockholder of Pfizer. ### Funding Statement K.S. and S.H.N-Sh. are supported by the Biomedical Research Program at Weill Cornell Medicine in Qatar, a program funded by the Qatar Foundation. K.S. is also supported by Qatar National Research Fund (QNRF) grant NPRP11C-0115-180010. The statements made herein are solely the responsibility of the authors. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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. Yes 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). Yes 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. Yes All data produced in the present work are contained in the manuscript or available on FigShare at