Abstract

Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) QC at the study file level, the meta-level across studies and the meta-analysis output level. Real-world examples highlight issues experienced and solutions developed by the GIANT Consortium that has conducted meta-analyses including data from 125 studies comprising more than 330,000 individuals. We provide a general protocol for conducting GWAMAs and carrying out QC to minimize errors and to guarantee maximum use of the data. We also include details for the use of a powerful and flexible software package called EasyQC. Precise timings will be greatly influenced by consortium size. For consortia of comparable size to the GIANT Consortium, this protocol takes a minimum of about 10 months to complete.

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Acknowledgements

This work was supported by grants from the German Federal Ministry of Education and Research (BMBF) (01ER1206 for I.M.H.); the Leenaards Foundation and the Swiss National Science Foundation (31003A-143914 for Z.K.); the US National Institutes of Health (DK078150, T32 HL007427 for D.C.C.-C.; R01DK075787 for T.E.); the UK Medical Research Council (MRC; U106179471, U106179472 for F.R.D.); the European Research Council (SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC for A.R.W.); the Targeted Financing from the Estonian Ministry of Science and Education (SF0180142s08 for T.E.); the Development Fund of the University of Tartu (SP1GVARENG for T.E.); the European Regional Development Fund to the Centre of Excellence in Genomics (EXCEGEN, 3.2.0304.11-0312 for T.E.); and FP7 (313010 for T.E.). We are also thankful for the GIANT Consortium and the many participating research groups that have allowed us to develop this protocol.

Author information

Author notes

    • Iris M Heid
    •  & Ruth J F Loos

    These authors jointly supervised this work.

Affiliations

  1. Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany.

    • Thomas W Winkler
    •  & Iris M Heid
  2. Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • Felix R Day
    •  & Jian'an Luan
  3. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Damien C Croteau-Chonka
  4. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Damien C Croteau-Chonka
  5. Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.

    • Andrew R Wood
  6. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.

    • Adam E Locke
  7. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Reedik Mägi
    •  & Tonu Esko
  8. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Teresa Ferreira
  9. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

    • Tove Fall
    •  & Stefan Gustafsson
  10. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Tove Fall
  11. Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Mariaelisa Graff
    •  & Anne E Justice
  12. Wellcome Trust Sanger Institute, Cambridge, UK.

    • Joshua C Randall
  13. Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Sailaja Vedantam
    •  & Tonu Esko
  14. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

    • Sailaja Vedantam
    •  & Tonu Esko
  15. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Sailaja Vedantam
    •  & Tonu Esko
  16. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Tsegaselassie Workalemahu
  17. The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Tuomas O Kilpeläinen
  18. Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.

    • André Scherag
  19. Clinical Epidemiology, Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.

    • André Scherag
  20. Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

    • Zoltán Kutalik
  21. Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.

    • Zoltán Kutalik
  22. Swiss Institute of Bioinformatics, Lausanne, Switzerland.

    • Zoltán Kutalik
  23. The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Ruth J F Loos
  24. The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Ruth J F Loos
  25. The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Ruth J F Loos

Consortia

  1. The Genetic Investigation of Anthropometric Traits (GIANT) Consortium

    A full list of members is available in the Supplementary Note.

Authors

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  2. Search for Felix R Day in:

  3. Search for Damien C Croteau-Chonka in:

  4. Search for Andrew R Wood in:

  5. Search for Adam E Locke in:

  6. Search for Reedik Mägi in:

  7. Search for Teresa Ferreira in:

  8. Search for Tove Fall in:

  9. Search for Mariaelisa Graff in:

  10. Search for Anne E Justice in:

  11. Search for Jian'an Luan in:

  12. Search for Stefan Gustafsson in:

  13. Search for Joshua C Randall in:

  14. Search for Sailaja Vedantam in:

  15. Search for Tsegaselassie Workalemahu in:

  16. Search for Tuomas O Kilpeläinen in:

  17. Search for André Scherag in:

  18. Search for Tonu Esko in:

  19. Search for Zoltán Kutalik in:

  20. Search for Iris M Heid in:

  21. Search for Ruth J F Loos in:

Contributions

T.W.W., F.R.D., D.C.C.-C., A.R.W., A.E.L., R.M., T. Ferreira, T.O.K., A.S., T.E., Z.K., I.M.H. and R.J.F.L. comprised the writing group. T.W.W., F.R.D., D.C.C.-C., A.R.W., A.E.L., R.M., T. Ferreira, T.O.K., A.S., T.E. and Z.K. were involved in the pipeline and procedure development. T.W.W., F.R.D., D.C.C.-C., A.R.W., A.E.L., R.M., T. Ferreira, T. Fall, M.G., A.E.J., J.L., S.G., J.C.R., S.V., T.W., T.O.K., A.S., T.E. and Z.K. were the analysts contributing to the QC of the recent GIANT papers.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Iris M Heid or Ruth J F Loos.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Figure 1

    Ftp-site directory structure.

  2. 2.

    Supplementary Figure 2

    Effect of the trait transformation issue.

  3. 3.

    Supplementary Figure 3

    EasyQC panel of P-Z plots.

  4. 4.

    Supplementary Figure 4

    EasyQC panel of EAF-plots.

  5. 5.

    Supplementary Table 1

    Description of EasyQC report variables (File-level QC).

  6. 6.

    Supplementary Table 2

    Description of EasyQC report variables (Meta-level QC).

  7. 7.

    Supplementary Table 3

    Description of EasyQC report variables (Meta-analysis QC).

  8. 8.

    Supplementary Methods

    Creation of the SNP identifier reference panel.

  9. 9.

    Supplementary Manual

    Exemplary GWA analysis plan.

  10. 10.

    Supplementary Note

    Membership list of the GIANT Consortium.

About this article

Publication history

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DOI

https://doi.org/10.1038/nprot.2014.071

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