Article | Published:

The impact of low-frequency and rare variants on lipid levels

Nature Genetics volume 47, pages 589597 (2015) | Download Citation

Abstract

Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing.

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Acknowledgements

We acknowledge CSC (IT Center for Science) and the Technology Centre of the Institute for Molecular Medicine for computational services. The High-Throughput Biomedicine Unit of the Institute for Molecular Medicine Finland, R. Kovanen and A. Uro are acknowledged for technical expertise. M. Jauhiainen is acknowledged for sharing his expertise in the manuscript writing process. This research was supported through funds from the European Union's Seventh Framework Programme (FP7/2007–2013), ENGAGE Consortium, grant agreement HEALTH-F4-2007-201413. I.S. was partly funded by the Helsinki University Doctoral Programme in Biomedicine (DPBM). M.H. was funded by a Manpei Suzuki Diabetes Foundation Grant-in-Aid for young scientists working abroad. A.P.M. and A. Mahajan acknowledge funding from the Wellcome Trust under awards WT098017, WT090532 and WT064890. V. Lagou, L.M., S.H. and I.P. were funded in part through the European Union's Seventh Framework Programme (FP7/2007–2013), ENGAGE project, grant agreement HEALTH-F4-2007- 201413. L.M. was in part sponsored by '5 per mille' contribution assigned to the University of Ferrara, income tax return year 2009, and in part by the ENGAGE Exchange and Mobility Program for ENGAGE training funds. M.D.T. holds a UK Medical Research Council Senior Clinical Fellowship (G0902313). S.T. is supported by the Sigrid Juselius Foundation. J.S.R. and C.G. have received funding from a grant from the RFBR (Russian Foundation for Basic Research)–Helmholtz Joint Research Group (12-04-91322). C.G. received funding from the European Union's Seventh Framework Programme (FP7-Health-F5-2012) under grant agreement 305280 (MIMOmics). M. Perola has been supported by the European Union's Seventh Framework Programme (grant agreements 313010; BBMRI-LPC, 305280; MIMOmics, and 261433; BioSHaRE-EU), Finnish Academy grant 269517, the Yrjö Jahnsson Foundation and the Juho Vainio Foundation. N.J.S. holds a chair funded by the British Heart Foundation (BHF) and is an NIHR Senior Investigator. C.P.N. is funded by the BHF and was preciously funded by the NIHR Leicester Cardiovascular Biomedical Research Unit. V. Salomaa was supported by the Finnish Foundation for Cardiovascular Research and the Finnish Academy (grant 139635). E. Ikonen was supported by the Academy of Finland Centre of Excellence in Biomembrane Research (272130), the Academy of Finland (263841) and the Sigrid Juselius Foundation. V.P. was supported by a University of Helsinki Postdoctoral Researcher grant, the Magnus Ehrnrooth Foundation and the Kymenlaakso Cultural Foundation. O.K., J.-P.M. and V.P. have received funding from the European Union's Seventh Framework Programme (FP7/2007–2013) under grant agreement 258068; EU-FP7-Systems Microscopy Network of Excellence. S.R. was supported by the Academy of Finland (251217 and 255847), the Center of Excellence in Complex Disease Genetics, the European Union's Seventh Framework Programme projects ENGAGE (201413) and BioSHaRE (261433), the Finnish Foundation for Cardiovascular Research, Biocentrum Helsinki and the Sigrid Juselius Foundation. Cohort-specific acknowledgments are provided in the Supplementary Note.

Author information

Affiliations

  1. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

    • Ida Surakka
    • , Antti-Pekka Sarin
    • , Benjamin Miraglio
    • , Sanna Timonen
    • , Johannes Kettunen
    • , Matti Pirinen
    • , John-Patrick Mpindi
    • , Markus Perola
    • , Jaakko Kaprio
    • , Leif Groop
    • , Olli Kallioniemi
    • , Vilja Pietiäinen
    • , Aarno Palotie
    •  & Samuli Ripatti
  2. National Institute for Health and Welfare, Helsinki, Finland.

    • Ida Surakka
    • , Antti-Pekka Sarin
    • , Johannes Kettunen
    • , Aki S Havulinna
    • , Markus Perola
    • , Jaakko Kaprio
    • , Johan G Eriksson
    • , Antti Jula
    • , Veikko Salomaa
    •  & Marjo-Riitta Järvelin
  3. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Momoko Horikoshi
    • , Anubha Mahajan
    • , Vasiliki Lagou
    • , Teresa Ferreira
    • , Erik Ingelsson
    • , Cecilia M Lindgren
    • , Mark I McCarthy
    •  & Andrew P Morris
  4. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

    • Momoko Horikoshi
    • , Vasiliki Lagou
    •  & Mark I McCarthy
  5. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Reedik Mägi
    • , Tõnu Esko
    • , Evelin Mihailov
    • , Markus Perola
    • , Natalia Tsernikova
    • , Andres Metspalu
    •  & Andrew P Morris
  6. Department of Life Sciences and Biotechnology, Genetic Section, University of Ferrara, Ferrara, Italy.

    • Letizia Marullo
  7. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Juha Karjalainen
    • , Harm-Jan Westra
    •  & Lude Franke
  8. deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.

    • Gudmar Thorleifsson
    • , Valgerdur Steinthorsdottir
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  9. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Sara Hägg
    • , Stefan Gustafsson
    • , Patrik K E Magnusson
    •  & Nancy L Pedersen
  10. Molecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

    • Sara Hägg
    • , Stefan Gustafsson
    •  & Erik Ingelsson
  11. Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

    • Sara Hägg
    • , Stefan Gustafsson
    •  & Erik Ingelsson
  12. Department of Biological Psychology, EMGO Institute for Health and Care Research, VU University and VU University Medical Center, Amsterdam, the Netherlands.

    • Jouke-Jan Hottenga
    • , Eco J de Geus
    • , Gonneke Willemsen
    •  & Dorret I Boomsma
  13. Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • Aaron Isaacs
    • , Lennart C Karssen
    • , Elisabeth M van Leeuwen
    • , Sara M Willems
    •  & Cornelia M van Duijn
  14. Centre for Medical Systems Biology, Leiden, the Netherlands.

    • Aaron Isaacs
    •  & Cornelia M van Duijn
  15. Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden.

    • Claes Ladenvall
    • , Valeriya Lyssenko
    •  & Leif Groop
  16. Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

    • Marian Beekman
    • , Anton J M de Craen
    • , Joris Deelen
    •  & P Eline Slagboom
  17. Netherlands Consortium for Healthy Ageing, Leiden, the Netherlands.

    • Marian Beekman
    • , Joris Deelen
    •  & P Eline Slagboom
  18. Division of Endocrinology, Children's Hospital, Boston, Massachusetts, USA.

    • Tõnu Esko
    •  & Tune H Pers
  19. Center for Basic and Translational Obesity Research, Children's Hospital, Boston, Massachusetts, USA.

    • Tõnu Esko
    •  & Tune H Pers
  20. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Tõnu Esko
    • , Tune H Pers
    • , Cecilia M Lindgren
    •  & Aarno Palotie
  21. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Tõnu Esko
  22. Institute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Janina S Ried
    • , Martina Müller-Nurasyid
    •  & Christian Gieger
  23. Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

    • Christopher P Nelson
    •  & Nilesh J Samani
  24. National Institute for Health Research (NIHR) Leicester Cardiovascular Disease Biomedical Research Unit, Glenfield Hospital, Leicester, UK.

    • Christopher P Nelson
    •  & Nilesh J Samani
  25. Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany.

    • Christina Willenborg
    •  & Jeanette Erdmann
  26. Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner site Hamburg, Lübeck and Kiel, Germany.

    • Christina Willenborg
    •  & Jeanette Erdmann
  27. Bioinformatics and Biostatistics Analysis Support Hub (BBASH), University of Leicester, Leicester, UK.

  28. Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.

    • Anton J M de Craen
  29. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Harald Grallert
    • , Annette Peters
    •  & Christian Gieger
  30. German Center for Diabetes Research (DZD), Neuherberg, Germany.

    • Harald Grallert
  31. Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Harald Grallert
    • , Annette Peters
    •  & Christian Gieger
  32. Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

    • Anders Hamsten
  33. Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.

    • Christian Hengstenberg
    • , Annette Peters
    •  & Heribert Schunkert
  34. Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner site Munich Heart Alliance, Munich, Germany.

    • Christian Hengstenberg
    • , Martina Müller-Nurasyid
    •  & Heribert Schunkert
  35. Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.

    • Jeanine J Houwing-Duistermaat
  36. Population, Policy and Practice, University College London Institute of Child Health, London, UK.

    • Elina Hyppönen
    •  & Christine Power
  37. South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.

    • Elina Hyppönen
  38. School of Population Health, University of South Australia, Adelaide, South Australia, Australia.

    • Elina Hyppönen
  39. Sansom Institute, University of South Australia, Adelaide, South Australia, Australia.

    • Elina Hyppönen
  40. Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland.

    • Terho Lehtimäki
  41. Steno Diabetes Center, Gentofte, Denmark.

    • Valeriya Lyssenko
  42. Department of Medicine I, University Hospital Großhadern, Ludwig Maximilians Universität, Munich, Germany.

    • Martina Müller-Nurasyid
  43. Chair of Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians Universität, Munich, Germany.

    • Martina Müller-Nurasyid
  44. Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands.

    • Brenda W J H Penninx
    •  & Johannes H Smit
  45. Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland.

    • Markus Perola
  46. European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Johan Rung
  47. Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK.

    • Martin D Tobin
  48. Department of Medicine, University of Turku, Turku, Finland.

    • Jorma S Viikari
  49. Division of Medicine, Turku University Hospital, Turku, Finland.

    • Jorma S Viikari
  50. Department of Public Health, University of Helsinki, Helsinki, Finland.

    • Jaakko Kaprio
    •  & Samuli Ripatti
  51. Department of Medical Sciences, Uppsala University, Akademiska Sjukhuset, Uppsala, Sweden.

    • Lars Lind
  52. Institute of Molecular and Cell Biology of the University of Tartu, Tartu, Estonia.

    • Andres Metspalu
  53. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.

    • Johan G Eriksson
  54. Folkhälsan Research Centre, Helsinki, Finland.

    • Johan G Eriksson
  55. Unit of Primary Health Care, Helsinki University Hospital, Helsinki, Finland.

    • Johan G Eriksson
  56. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.

    • Olli T Raitakari
  57. Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland.

    • Olli T Raitakari
  58. Department of Epidemiology and Biostatistics, Medical Research Council (MRC) Health Protection Agency (HPA), Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

    • Matthew Blades
  59. Institute of Health Sciences, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Järvelin
  60. Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Järvelin
  61. Unit of Primary Care, Oulu University Hospital, Oulu, Finland.

    • Marjo-Riitta Järvelin
  62. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Unnur Thorsteinsdottir
    •  & Kari Stefansson
  63. Anatomy, Institute of Biomedicine, University of Helsinki, Helsinki, Finland.

    • Elina Ikonen
  64. Minerva Foundation Institute for Medical Research, Helsinki, Finland.

    • Elina Ikonen
  65. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Aarno Palotie
  66. Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Aarno Palotie
  67. Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Aarno Palotie
  68. Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.

    • Mark I McCarthy
  69. Department of Biostatistics, University of Liverpool, Liverpool, UK.

    • Andrew P Morris
  70. Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, UK.

    • Inga Prokopenko
  71. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Samuli Ripatti

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I.S., M.H., R.M., A.-P.S., A. Mahajan, V. Lagou, L.M., T.F., E. Ikonen, O.K., V.P., C.M.L., U.T., A. Palotie, M.I.M., A.P.M., I.P. and S.R. designed and performed experiments, analyzed data and wrote the manuscript. B.M., S.T., J. Kettunen, M. Pirinen, J. Karjalainen, H.-J.W., J.-P.M., T.H.P. and L.F. performed follow-up experiments and analyzed the data. G.T., S.H., J.-J.H., A.I., C.L., M. Beekman, T.E., J.S.R., C.P.N., C.W. and S.G. analyzed cohort-specific data. H.S., J.E., N.J.S., J. Kaprio, L.L., C.G., A. Metspalu, P.E.S., L.G., C.M.v.D., J.G.E., A.J., V. Salomaa, D.I.B., C.P., O.T.R., E. Ingelsson, M.-R.J. and K.S. designed cohort-specific experiments. M. Blades, A.J.M.d.C., E.J.d.G., J.D., H.G., A.H., A.S.H., C.H., J.J.H.-D., E.H., L.C.K., T.L., V. Lyssenko, P.K.E.M., E.M., M.M.-N., N.L.P., B.W.J.H.P., M. Perola, A. Peters, J.R., J.H.S., V. Steinthorsdottir, M.D.T., N.T., E.M.v.L., J.S.V., S.M.W. and G.W. performed cohort-specific experiments and analyzed cohort-specific data. All authors contributed to the research and reviewed the manuscript.

Competing interests

U.T., G.T., V. Steinthorsdottir and K.S. are employed by deCODE Genetics/Amgen, Inc.

Corresponding author

Correspondence to Samuli Ripatti.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–8, Supplementary Tables 1–8 and 10–15, and Supplementary Note.

Excel files

  1. 1.

    Supplementary Table 9

    Lists of genes with higher MGI-based predictions in the GeneNetwork database for the knockout phenotypes listed in Supplementary Table 8a,b.

About this article

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DOI

https://doi.org/10.1038/ng.3300

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