Quality control and conduct of genome-wide association meta-analyses (original) (raw)

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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

1. Iris M Heid and Ruth J F Loos: These authors jointly supervised this work.

Authors and 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

Authors

1. Thomas W Winkler
2. Felix R Day
3. Damien C Croteau-Chonka
4. Andrew R Wood
5. Adam E Locke
6. Reedik Mägi
7. Teresa Ferreira
8. Tove Fall
9. Mariaelisa Graff
10. Anne E Justice
11. Jian'an Luan
12. Stefan Gustafsson
13. Joshua C Randall
14. Sailaja Vedantam
15. Tsegaselassie Workalemahu
16. Tuomas O Kilpeläinen
17. André Scherag
18. Tonu Esko
19. Zoltán Kutalik
20. Iris M Heid
21. Ruth J F Loos

Consortia

The Genetic Investigation of Anthropometric Traits (GIANT) Consortium

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.

Corresponding authors

Correspondence toIris M Heid or Ruth J F Loos.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

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

Integrated supplementary information

Supplementary Figure 1 Ftp-site directory structure.

The DATA_UPLOAD directory is used for the collection of raw study-specific results, i.e. used by the collaborators to upload their results. Once all or at least files from >80% of studies have been collected, the DATA_UPLOAD folder should be frozen. The folder should be protected from further changes, be renamed to DATA_UPLOAD_FREEZE and a new DATA_UPLOAD folder should be created to collect any additional results. The CLEANED_FILES directory should be used for collection of cleaned files that passed the file-level QC routines. The META_ANALYSIS directory should be used to upload meta-analysis results and contains sub-folders, one for each meta-analyst (folders ANALYST_1 and ANALYST_2) and one to collect and freeze the final meta-analysis results (FINAL_RESULT).

Supplementary Figure 2 Effect of the trait transformation issue.

On the example of the phenotype hip circumference with and without adjustment for BMI (HIP, HIPadjBMI) in the GIANT Metabochip studies (81,000 subjects), it can be seen that (a) the trait transformation issue only affected the trait adjusted for BMI (SE-N plots; magenta: uncleaned studies affected by the issue; green: cleaned studies) ,(b) the uncleaned data had deteriorated power for the BMI-adjusted trait (QQ plot of association P-values from the Meta-analysis for all SNPs; red: meta-analysis on uncleaned data; green: meta-analysis on cleaned data) and (c) the uncleaned data yielded estimates biased towards the null for the BMI-adjusted trait (estimates from the Meta-analysis on uncleaned data on Y-axis and from cleaned data on X-axis).

Supplementary Figure 3 EasyQC panel of P-Z plots.

Example EasyQC panel of plots to check whether reported P-Values (X-axis, on -log10 scale) match P-Values calculated from the Z-statistic using the reported beta estimates and standard errors (Y-axis, on –log10 scale) with one plot per file. Clearly, several files show deviations, which were due to deviating software specifications used by these studies, which were resolved with study analysts.

Supplementary Figure 4 EasyQC panel of EAF-plots.

Example panel of plots to check issues with allele frequencies. Each plot contrasts the allele frequency of the input file (y-axis) with the allele frequency of the reference (x-axis). In this case the meta-analyzed GIANT height results have been used as reference to compare it to study-specific GWA results for height. Several issues can immediately be detected, which should be solved with the study analysts.

Supplementary information

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Winkler, T., Day, F., Croteau-Chonka, D. et al. Quality control and conduct of genome-wide association meta-analyses.Nat Protoc 9, 1192–1212 (2014). https://doi.org/10.1038/nprot.2014.071

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• Published: 24 April 2014
• Issue date: May 2014
• DOI: https://doi.org/10.1038/nprot.2014.071