Comprehensive genetic analysis of the human lipidome identifies novel loci controlling lipid homeostasis with links to coronary artery disease

Gemma Cadby, Corey Giles, Phillip E Melton, Kevin Huynh, Natalie A Mellett, Thy Duong, Anh Nguyen, Michelle Cinel, Alex Smith, Gavriel Olshansky, Tingting Wang, Marta Brozynska, Mike Inouye, Nina S McCarthy, Amir Ariff, Joseph Hung, Jennie Hui, John Beilby, Marie-Pierre Dubé, Gerald F WattsSonia Shah, Naomi R Wray, Wei Ling Florence Lim, Pratishtha Chatterjee, Ian Martins, Simon M Laws, Tenielle Porter, Michael Vacher, Ashley I Bush, Christopher C Rowe, Victor L Villemagne, David Ames, Colin L Masters, Kevin Taddei, Matthias Arnold, Gabi Kastenmüller, Kwangsik Nho, Andrew J Saykin, Xianlin Han, Rima Kaddurah-Daouk, Ralph N Martins, John Blangero, Peter J Meikle, Eric K Moses

Research output: Working paperPreprint


We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species that are putatively in the mechanistic pathway to coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 phenotyped individuals from the Busselton Health Study. In our discovery GWAS we identified 667 independent loci associations with these lipid species (479 novel), followed by meta-analysis and validation in two independent cohorts. Lipid endophenotypes (134) identified for CAD were associated with variation at 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P<1×10−3), 43 loci were associated with at least one of the 134 lipid endophenotypes. The findings of this study illustrate the value of integrative biology to investigate the genetics and lipid metabolism in the aetiology of atherosclerosis and CAD, with implications for other complex diseases.Competing Interest StatementThe authors have declared no competing interest.Funding StatementSupport was provided by the National Health and Medical Research Council of Australia (#1101320 and 1157607). K.H. was supported by a Dementia Australia Research Foundation Scholarship. This work was also supported in part by the Victorian Government's Operational Infrastructure Support Program, and the Royal Perth Hospital Research Foundation. The BHS acknowledges the generous support for the 1994/95 Busselton follow-up studies from HealthWay, the Department of Health, PathWest Laboratory Medicine of WA, and The Great Wine Estates of the Margaret River region of Western Australia. Statistical analyses performed in this work were supported by resources provided by The Pawsey Supercomputing Centre with funding from the Australian Government and the Government of Western Australia. Funding for the AIBL study was provided in part by the study partners [Commonwealth. Scientific Industrial and research Organization (CSIRO), Edith Cowan University (ECU), Mental Health Research institute (MHRI), National Ageing Research Institute (NARI), Austin Health, CogState Ltd]. The AIBL study has also received support from the National Health and Medical Research Council (NHMRC) and the Dementia Collaborative Research Centres program (DCRC2), as well as funding from the Science and Industry Endowment Fund (SIEF) and the Cooperative Research Centre (CRC) for Mental Health-funded through the CRC Program (Grant ID:20100104), an Australian Government Initiative. Support for AIBL genetic data acquisition and analysis was provided by a grant from the NHMRC (APP1161706) awarded to S.M.L and through the CRC for Mental Health (Grant ID:20100104). T.P. is supported by ECU strategic research funding. Support for the metabolomics sample processing, assays and analytics reported here was provided by grants from the National Institute on Aging (NIA); NIA supported the Alzheimer's Disease Metabolomics Consortium which is a part of NIA's national initiatives AMP-AD and M2OVE-AD (R01 AG046171, RF1 AG051550, RF1 AG057452 and 3U01 AG024904-09S4). Additional NIH support from the NIA, NLM and NCI for analysis includes P30 AG10133, R01 AG19771, R01 LM012535, R03 AG054936, R01 AG061788, K01 AG049050 and R01 CA129769. M.A. is supported by National Institute on Aging grants RF1 AG057452, RF1 AG058942, RF1 AG059093, 1U19AG063744 and U01 AG061359. K.N. is supported by NLM R01 LM012535 and NIA R03AG054936. Data collection and sharing for the ADNI was supported by National Institutes of Health Grant U01 AG024904. ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Informed consent was obtained from all participants and the 1994/95 Busselton Health Study was approved by the University of Western Australia Human Research Ethics Committee (UWA HREC). The lipidomics and genetic analysis was approved by UWA HREC (RA/4/1/7894) and the Western Australian Department of Health HREC (RGS03656). For the lipidomics analysis, the AIBL study was deemed low risk (The Alfred Ethics Committee; Project 183/19), and the ADNI study was deemed RESEARCH NOT INVOLVING HUMAN SUBJECTS (Duke Institute review board; ID:Pro00053208). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as 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).YesI 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.YesComplete summary statistics of all lipid species and classes will be available via the NHGRI-EBI GWAS catalog (, GCP ID: GCP000197; study accession nos. GCST90023981-GCST90025848. In addition, summary-level statistics are available at our data portal ( Individual-level data for the BHS are accessible through applications to the Busselton Population Medical Research Institute ( Individual-level data for the ADNI and AIBL studies are available through applications to the LONI Image and Data Archive ( Individual-level data for AIBL are also available through applications to the AIBL management committee ( Publically available datasets used within the study are available via UK Biobank (, HRC (, 1000 Genomes (, SNiPA (, GTEx (, and eQTLGen (
Original languageEnglish
Publication statusPublished - 20 Aug 2021


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