Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 × 10−8), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10−15 for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
The FHS authors thank the FHS participants for their long-term voluntary commitment to this study. The FHS is supported by a contract from the National Heart, Lung and Blood Institute (NHLBI; contract no. N01-HC-25195). The NHLBI's SNP Health Association Resource research program supported the FHS genotyping. J.M.O. is supported by NHLBI grant HL-54776 and by contracts 53-K06-5-10 and 58-1950-9-001 from the US Department of Agriculture Research Service.
The DGI and MDC-CC authors thank R. Saxena, V. Lyssenko, M. Daly, J. Hirschhorn, S. Gabriel, H. Chen, T. Hughes, the entire DGI study team and the Botnia Study team for their roles in sample collection, phenotyping, design and conduct of the DGI study; and M. Svenson and L. Rosberg for technical assistance in Malmö. S.K. is supported by a Doris Duke Charitable Foundation Clinical Scientist Development Award, a charitable gift from the Fannie E. Rippel Foundation, the Donovan Family Foundation, a career development award from the United States National Institutes of Health (NIH) and institutional support from the Department of Medicine and Cardiovascular Research Center at Massachusetts General Hospital. L.G. is supported by the Sigrid Juselius Foundation, the Finnish Diabetes Research Foundation, The Folkhalsan Research Foundation and Clinical Research Institute HUCH Ltd. His work in Malmö, Sweden, was also funded by a Linné grant from the Swedish Medical Research Council. M.O.-M. is supported by a European Foundation for the Study of Diabetes–Pfizer grant and the Novo Nordisk Foundation. M.O.-M. and O.M. are supported by the Swedish Medical Research Council, the Swedish Heart and Lung Foundation, the Medical Faculty of Lund University, Malmö University Hospital, the Albert Påhlsson Research Foundation and the Crafoord Foundation. O.M. is also supported by the Swedish Medical Society, the Ernhold Lundströms Research Foundation, the Mossfelt Foundation, the King Gustav V and Queen Victoria Foundation and the Region Skane.
The FUSION and METSIM authors thank the Finnish citizens who generously participated in these studies. Support for FUSION was provided by NIH grants DK062370 (to M.B.) and DK072193 (to K.L.M.), intramural project number 1Z01 HG000024 (to F.S.C.) and a postdoctoral fellowship award from the American Diabetes Association (to C.J.W.). K.L.M. is a Pew Scholar for the Biomedical Sciences. Genome-wide genotyping was conducted by the Johns Hopkins University Genetic Resources Core Facility SNP Center at the Center for Inherited Disease Research (CIDR), with support from CIDR NIH contract no. N01-HG-65403. Support for METSIM was provided by grant 124243 from the Academy of Finland (to M.L.).
The SardiNIA authors thank the many volunteers who generously participated in these studies. This work was supported in part by the Intramural Research Program of the National Institute on Aging and by extramural grants from the National Human Genome Research Institute (HG02651) and the NHLBI (HL084729). Additional support was provided by the mayors, administrations and residents of Lanusei, Ilbono, Arzana and Elini and the head of Public Health Unit ASL4 in Sardinia. G.R.A. is a Pew Scholar for the Biomedical Sciences.
FINRISK97 author L.P. is supported by the Center of Excellence in Complex Disease Genetics of the Academy of Finland and the Nordic Center of Excellence in Disease Genetics. V.S. was supported by the Sigrid Juselius Foundation and the Finnish Foundation for Cardiovascular Research.
The ISIS trials and epidemiological studies were supported by the manufacturers of the study drugs and by the British Heart Foundation, Medical Research Council, Cancer Research UK, Tobacco Products Research Trust of the UK Department of Health Independent Scientific Committee on Smoking and Health, and the Oxford Genetics Knowledge Park.
Supplementary Methods, Supplementary Figures 1–3 and Supplementary Tables 1–7
About this article
International Journal of Obesity (2019)