Abstract

Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders1,2,3,4,5,6,7 and who may consequently have increased disease risk. Previous studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates8,9,10,11,12. We sequenced seven genes for maturity-onset diabetes of the young (MODY)13 in well-phenotyped population samples14,15 (n = 4,003). We filtered rare variants according to two prediction criteria for disease-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, conserved and protein damaging). Approximately 1.5% and 0.5% of randomly selected individuals from the Framingham and Jackson Heart Studies, respectively, carry variants from these two classes. However, the vast majority of carriers remain euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a substantial fraction of individuals as being at risk for MODY or other Mendelian diseases.

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Acknowledgements

We acknowledge the contribution of the participants of the Framingham and Jackson Heart Study, as well as the participants from the Malmö Preventive Project, the Scania Diabetes Registry and the Botnia Study. This work was supported by grants from the National Human Genome Research Institute of the US National Institutes of Health (NIH) (Medical Sequencing Program grant U54 HG003067 to the Broad Institute principal investigator, E. Lander) and the Howard Hughes Medical Institute, as well as funding from Pfizer Inc. J.F. was supported in part by NIH training grant 5-T32-GM007748-33. N.L.B. was supported by a Fulbright Diabetes UK Fellowship (BDA 11/0004348). D.A. was supported by funding from the Doris Duke Charitable Foundation (2006087). J.M. acknowledges support from National Institute of Diabetes and Digestive and Kidney Diseases grant K24 DK080140. J.B.M. and J.C.F. acknowledge support from NIH grant R01 DK078616. A.G.B. and V.A. were supported by NIH Medical Scientist Training Program fellowship T32GM007753. J.G.S. and C.E.S. were supported by NIH RO1 2R01HL080494, the National Heart, Lung, and Blood Institute (NHLBI) and the LeDucq Foundation. The Jackson Heart Study is supported by contracts N01-HC-95170, N01-HC-95171 and N01-HC-95172 from the NHLBI, the National Institute for Minority Health and Health Disparities and additional support from the National Institute of Biomedical Imaging and Bioengineering. The Framingham Heart Study was supported by contracts N01-HC-25195 and 6R01-NS 17950 from the NHLBI and genotyping services from Affymetrix, Inc. (contract N02-HL-6-4278 for the SNP Health Association Resource, SHARe, project). The Malmö Preventive Project and the Scania Diabetes Registry were supported by a Swedish Research Council grant (Linné) to the Lund University Diabetes Centre. The Botnia study was supported by funding from the Sigrid Juselius Foundation and the Folkhälsan Research Foundation, as well as a European Research Council advanced research grant to L.G. (GA 269045). The MODY study was supported by grants from the KG Jebsen Foundation, the Norwegian Research Council, the University of Bergen, Helse Vest, Innovest and the European Research Council (AdG).

Author information

Author notes

    • David R Cox

    Deceased.

    • Jason Flannick
    •  & Nicola L Beer

    These authors contributed equally to this work.

Affiliations

  1. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.

    • Jason Flannick
    • , Nicola L Beer
    • , Alexander G Bick
    • , Vineeta Agarwala
    • , Namrata Gupta
    • , Noël P Burtt
    • , Jose C Florez
    • , Christopher Newton-Cheh
    • , Sekar Kathiresan
    • , Joel N Hirschhorn
    • , Pål R Njølstad
    • , Stacey Gabriel
    •  & David Altshuler
  2. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Jason Flannick
    •  & David Altshuler
  3. Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Jason Flannick
  4. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Alexander G Bick
    • , Joel N Hirschhorn
    • , J G Seidman
    • , Christine E Seidman
    •  & David Altshuler
  5. Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, Massachusetts, USA.

    • Vineeta Agarwala
  6. Program in Biophysics, Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts, USA.

    • Vineeta Agarwala
  7. KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.

    • Janne Molnes
    • , Henrik Irgens
    • , Stefan Johansson
    • , Anders Molven
    •  & Pål R Njølstad
  8. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Jose C Florez
    • , Christopher Newton-Cheh
    •  & Sekar Kathiresan
  9. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Jose C Florez
    • , James B Meigs
    •  & David Altshuler
  10. General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • James B Meigs
  11. Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.

    • Herman Taylor
    •  & Ervin Fox
  12. Jackson State University, Jackson, Mississippi, USA.

    • Herman Taylor
  13. Division of Natural Sciences, Tougaloo College, Tougaloo, Mississippi, USA.

    • Herman Taylor
  14. Department of Clinical Sciences, Diabetes and Endocrinology, Clinical Research Centre, Lund University, Malmö, Sweden.

    • Valeriya Lyssenko
    •  & Leif Groop
  15. Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.

    • Henrik Irgens
    •  & Pål R Njølstad
  16. Cardiovascular and Metabolic Diseases Practice, Prescient Life Sciences, London, UK.

    • Frank Burslem
  17. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.

    • Stefan Johansson
  18. Cardiovascular and Metabolic Diseases Research Unit, Pfizer Inc., Cambridge, Massachusetts, USA.

    • M Julia Brosnan
    • , Jeff K Trimmer
    •  & Tim Rolph
  19. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Christopher Newton-Cheh
    •  & Christopher J O'Donnell
  20. Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Christopher Newton-Cheh
    • , Christopher J O'Donnell
    •  & Sekar Kathiresan
  21. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.

    • Tiinamaija Tuomi
  22. Department of Medicine, Helsinki University Central Hospital and Research Program for Molecular Medicine, Helsinki, Finland.

    • Tiinamaija Tuomi
  23. Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.

    • Anders Molven
  24. Department of Pathology, Haukeland University Hospital, Bergen, Norway.

    • Anders Molven
  25. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.

    • James G Wilson
  26. Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.

    • Christopher J O'Donnell
  27. Divisions of Genetics and Endocrinology and Program in Genomics, Children's Hospital, Boston, Massachusetts, USA.

    • Joel N Hirschhorn
  28. Applied Quantitative Genotherapeutics, Pfizer Inc., South San Francisco, California, USA.

    • David R Cox
  29. Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Christine E Seidman
  30. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

    • Christine E Seidman
  31. Finnish Institute for Molecular Medicine (FIMM), Helsinki University, Helsinki, Finland.

    • Leif Groop

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Contributions

This manuscript describes an integrated analysis that draws together two studies that were initially independent: the Pfizer/Massachusetts General Hospital/Broad/Lund collaborative project 'Towards Therapeutic Targets for Type 2 Diabetes and Myocardial Infarction in the Background of Type 2 Diabetes' (PMBL), which was supervised by D.A., L.G., T.R., D.R.C., S.K., J.K.T. and M.J.B., and the National Human Genome Research Institute–funded project 'Analyses of the Allelic Spectrum of Cardiovascular Disease Genes in the Framingham Heart Study and Jackson Heart Study Cohorts' (FHS/JHS), which was led by C.E.S. and S.G. For the PMBL project, N.P.B. was the project manager, and L.G., T.T., V.L. and F.B. were responsible for clinical investigation and sample management. For the FHS/JHS project, N.G. was the project manager; H.T., E.F., J.G.W. and C.J.O. were responsible for clinical investigation and sample management; and J.G.W., C.J.O., C.N.-C., S.K., J.N.H., J.G.S., D.A., S.G. and C.E.S. supervised the project. All DNA sequencing and data processing for these two projects was performed at the Broad Institute. J.M., H.I., S.J., A.M. and P.R.N. were responsible for all clinical investigation, sample management, sequencing and data processing for the MODY study. J.F., N.L.B. and D.A. designed and conceived the joint analysis. J.F., N.L.B., J.C.F., J.B.M. and D.A. provided methodological expertise. N.L.B., A.G.B., J.F. and V.A. defined and interpreted the clinical information included. J.F. performed all analyses of the three population-based cohorts and performed annotation and comparative analysis of the patients from the MODY study. J.F., N.L.B. and D.A. wrote the manuscript. All authors reviewed, edited and approved the manuscript.

Competing interests

M.J.B., J.K.T. and T.R. are employees of Pfizer, Inc. F.B. and D.R.C. are former employees of Pfizer, Inc.; F.B. retains shares in the company.

Corresponding author

Correspondence to David Altshuler.

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https://doi.org/10.1038/ng.2794

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