Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk

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Blood lipid levels are heritable, treatable risk factors for cardiovascular disease. We systematically assessed genome-wide coding variation to identify new genes influencing lipid traits, fine map known lipid loci and evaluate whether low-frequency variants with large effects exist for these traits. Using an exome array, we genotyped 80,137 coding variants in 5,643 Norwegians. We followed up 18 variants in 4,666 Norwegians and identified ten loci with coding variants associated with a lipid trait (P < 5 × 10−8). One variant in TM6SF2 (encoding p.Glu167Lys), residing in a known genome-wide association study locus for lipid traits, influences total cholesterol levels and is associated with myocardial infarction. Transient TM6SF2 overexpression or knockdown of Tm6sf2 in mice alters serum lipid profiles, consistent with the association observed in humans, identifying TM6SF2 as a functional gene within a locus previously known as NCAN-CILP2-PBX4 or 19p13. This study demonstrates that systematic assessment of coding variation can quickly point to a candidate causal gene.

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The Nord-Trøndelag Health Study (The HUNT Study) is a collaboration between the HUNT Research Centre (Faculty of Medicine, Norwegian University of Science and Technology NTNU), the Nord-Trøndelag County Council, the Central Norway Health Authority and the Norwegian Institute of Public Health. C.J.W. is supported by HL094535 and HL109946 from the National Heart, Lung and Blood Institute. M.B. is supported by DK062370 from the National Institute of Diabetes and Digestive and Kidney Diseases. Y.E.C. is supported by HL068878 and HL117491 from the National Heart, Lung and Blood Institute. G.R.A. is supported by HL117626 from the National Heart, Lung and Blood Institute and HG007022 from the National Human Genome Research Institute. For frequency look up for the RNF111 variant, we thank the following: R. Loos and K. Lu of the BioMe Clinical Care Cohort operated by The Charles Bronfman Institute for Personalized Medicine (IPM) at the Mount Sinai Medical Center (the Mount Sinai IPM Biobank Program is supported by The Andrea and Charles Bronfman Philanthropies); A. Metspalu of the Estonian Genome Center (the Estonian Biobank data were provided by E. Mihailov from the Estonian Genome Center of University of Tartu, Estonia); and A. Uitterlinden, F. Rivadeneira and K. Estrada of Erasmus University Rotterdam.

Author information

Author notes

    • Oddgeir L Holmen
    • , He Zhang
    •  & Yanbo Fan

    These authors contributed equally to this work.


  1. HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway.

    • Oddgeir L Holmen
    • , Arnulf Langhammer
    •  & Kristian Hveem
  2. St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.

    • Oddgeir L Holmen
  3. Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.

    • He Zhang
    • , Yanbo Fan
    • , Daniel H Hovelson
    • , Ellen M Schmidt
    • , Wei Zhou
    • , Yanhong Guo
    • , Ji Zhang
    • , Santhi K Ganesh
    • , Jifeng Zhang
    • , Jin Chen
    • , Y Eugene Chen
    •  & Cristen J Willer
  4. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.

    • Daniel H Hovelson
    • , Ellen M Schmidt
    •  & Cristen J Willer
  5. Epidemiology of Chronic Diseases Research Group, Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.

    • Maja-Lisa Løchen
    • , Tom Wilsgaard
    •  & Inger Njølstad
  6. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.

    • Santhi K Ganesh
    •  & Cristen J Willer
  7. Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway.

    • Lars Vatten
  8. Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.

    • Frank Skorpen
  9. Department of Medicine, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, Norway.

    • Håvard Dalen
    • , Carl Platou
    •  & Kristian Hveem
  10. Medical Imaging Laboratory for Innovative Future Healthcare, Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway.

    • Håvard Dalen
  11. Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA.

    • Subramaniam Pennathur
  12. Brain and Circulation Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.

    • Ellisiv B Mathiesen
  13. Brain and Circulation Research Group, University Hospital of North Norway, Tromsø, Norway.

    • Ellisiv B Mathiesen
  14. Department of Biostatistics, Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

    • Michael Boehnke
    •  & Gonçalo R Abecasis


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A.L., I.N., K.H., H.D., C.P., E.B.M., T.W., L.V., F.S., M.-L.L. and O.L.H. obtained, contributed and analyzed the phenotype data. O.L.H. and T.W. were responsible for sample selection. O.L.H. and H.Z. were responsible for genetic data analysis and interpretation. H.Z. and J.C. performed variant calling from sequence data. D.H.H., E.M.S. and W.Z. generated figures and performed secondary analyses. L.V., M.-L.L., S.K.G., A.L., E.B.M., I.N. and K.H. provided epidemiological expertise. H.D. and C.P. provided clinical expertise. G.R.A., F.S. and M.B. provided genotyping and genetic epidemiology expertise. Y.F., Y.G., Ji Zhang, S.P. and Jifeng Zhang conducted mouse experiments under the supervision of Y.E.C. with assistance from C.J.W. C.J.W., G.R.A. and O.L.H. drafted the manuscript with assistance from D.H.H., H.Z., M.B. and K.H. Y.F., E.M.S., W.Z., Y.G., Ji Zhang, Jifeng Zhang, A.L., M.-L.L., S.K.G., L.V., F.S., H.D., J.C., C.P., E.B.M., T.W., I.N. and Y.E.C. critically reviewed the manuscript and provided comments and feedback. C.J.W., O.L.H. and K.H. conceived the study. C.J.W., O.L.H., K.H., M.B. and G.R.A. designed the study. K.H. and C.J.W. provided overall leadership for the project.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Kristian Hveem or Cristen J Willer.

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