Abstract

To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.

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Acknowledgements

We are indebted to the many volunteers who generously participated in these studies. We thank our colleagues from the DGI for sharing prepublication data; M. Erdos, P. Chines, P. Deodhar, K. Kubalanza, A. Sprau and M. Tong of FUSION and E. Pugh, K. Doheny and Center for Inherited Disease Research (CIDR) investigators for expert technical work; N. Rosenberg for helpful discussions about population genetics; the SardiNIA Research Clinic staff; and the Amish Research Clinic staff. This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data are available from the WTCCC website. Funding for the WTCCC project was provided by the Wellcome Trust under award 076113. The Caerphilly study was funded by the Medical Research Council (UK). The Caerphilly study was undertaken by the former MRC Epidemiology Unit (South Wales) and was funded by the Medical Research Council of the United Kingdom. The data archive is maintained by the Department of Social Medicine, University of Bristol. This work was supported in part by the Intramural Research Program of the National Institute on Aging (NIA), by extramural grants from National Human Genome Research Institute (NHGRI), the National Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Heart Lung and Blood Institute (NHLBI), by the American Diabetes Association, the Department of Veterans Affairs, the British Heart Foundation, the Medical Research Council of the United Kingdom and the French Ministry of Higher Education and Research. FUSION genome-wide genotyping was carried out by the Johns Hopkins University Genetic Resources Core Facility (GRCF) SNP Center at CIDR with support from CIDR NIH (contract N01-HG-65403) and the GRCF SNP Center. Additional support for the SardiNIA study was provided by the mayors, administration and residents of Lanusei, Ilbono, Arzana and Elini and the head of Public Health Unit ASL4 in Sardinia. C.J.W. is the recipient of a postdoctoral fellowship from the American Diabetes Association. G.R.A. and K.L.M. are Pew Scholars for the Biomedical Sciences.

Author information

Author notes

    • Cristen J Willer
    •  & Serena Sanna

    These authors contributed equally to the work.

Affiliations

  1. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, 1420 Washington Heights, Ann Arbor, Michigan 48109, USA.

    • Cristen J Willer
    • , Serena Sanna
    • , Anne U Jackson
    • , Heather M Stringham
    • , William L Duren
    • , Wei-Min Chen
    • , Yun Li
    • , Laura J Scott
    • , Paul A Scheet
    • , Michael Boehnke
    •  & Gonçalo R Abecasis
  2. Istituto di Neurogenetica e Neurofarmacologia (INN), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy 09042.

    • Serena Sanna
    • , Andrea Maschio
    • , Fabio Busonero
    • , Antonella Mulas
    • , Giuseppe Albai
    • , Manuela Uda
    •  & Antonio Cao
  3. Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, Maryland 21224, USA.

    • Angelo Scuteri
    • , Samer S Najjar
    • , James Strait
    • , Ramaiah Nagaraja
    • , Edward Lakatta
    •  & David Schlessinger
  4. Unitá Operativa Geriatria, Istituto per la Patologia Endocrina e Metabolica, Rome, Italy.

    • Angelo Scuteri
  5. Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland 20892, USA.

    • Lori L Bonnycastle
    • , Amy J Swift
    • , Mario A Morken
    • , Narisu Narisu
    •  & Francis S Collins
  6. Clinical Trial Service Unit, University of Oxford, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK.

    • Robert Clarke
    • , Derrick Bennett
    • , Sarah Parish
    •  & Rory Collins
  7. Centre National de Génotypage, Institut Génomique, Commissariat à l'Énergie Atomique, 2 rue Gaston Crémieux, CP 5721, 91057 Evry Cedex, France.

    • Simon C Heath
    • , Diana Zelenika
    •  & G Mark Lathrop
  8. Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol BS8 2PR, UK.

    • Nicholas J Timpson
    • , Debbie A Lawlor
    • , Yoav Ben-Shlomo
    •  & George Davey-Smith
  9. Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

    • Haiqing Shen
    •  & Alan R Shuldiner
  10. U872 Institut National de la Santé et de la Recherche Médicale (INSERM) and Département de Santé Publique et d'Informatique Médicale, Faculté de Médecine René Descartes, 15 rue de l'Ecole de Médecine, 75270 Paris, France.

    • Pilar Galan
  11. U557 INSERM; U1125 Institut National de la Recherche Agronomique (INRA); Cnam; Paris 13 University; Centre de Recherche en Nutrition Humaine (CRNH) IdF, 74 rue Marcel Cachin, 93017 Bobigny Cedex, France.

    • Pierre Meneton
    •  & Serge Hercberg
  12. Laboratory of Analytical Biochemistry, Department of Health and Functional Capacity, National Public Health Institute, 00300 Helsinki, Finland.

    • Jouko Sundvall
  13. Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.

    • Richard M Watanabe
    •  & Richard N Bergman
  14. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA.

    • Richard M Watanabe
  15. Department of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, Keppel St. London WC1E 7HT, UK.

    • Shah Ebrahim
  16. Diabetes Unit, Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, 00300 Helsinki, Finland and Department of Public Health, University of Helsinki, 00014 Helsinki, Finland.

    • Jaakko Tuomilehto
  17. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

    • Karen L Mohlke

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DOI

https://doi.org/10.1038/ng.76

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