Letter | Published:

Population structure, differential bias and genomic control in a large-scale, case-control association study

Nature Genetics 37, 1243–1246 (2005) | Download Citation

Subjects

Abstract

The main problems in drawing causal inferences from epidemiological case-control studies are confounding by unmeasured extraneous factors, selection bias and differential misclassification of exposure1. In genetics the first of these, in the form of population structure, has dominated recent debate2,3,4. Population structure explained part of the significant +11.2% inflation of test statistics we observed in an analysis of 6,322 nonsynonymous SNPs in 816 cases of type 1 diabetes and 877 population-based controls from Great Britain. The remainder of the inflation resulted from differential bias in genotype scoring between case and control DNA samples, which originated from two laboratories, causing false-positive associations. To avoid excluding SNPs and losing valuable information, we extended the genomic control method2,3,4,5 by applying a variable downweighting to each SNP.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

Rent or Buy

All prices are NET prices.

References

  1. 1.

    & Statistical Methods in Cancer Research Vol. I. The Analysis of Case-Control Studies (International Agency for Research on Cancer, Lyon, 1980).

  2. 2.

    , & Genomic control to the extreme. Nat. Genet. 36, 1129–1130; author reply 1131 (2004).

  3. 3.

    et al. Assessing the impact of population stratification on genetic association studies. Nat. Genet. 36, 388–393 (2004).

  4. 4.

    , , & The effects of human population structure on large genetic association studies. Nat. Genet. 36, 512–517 (2004).

  5. 5.

    & Genomic control for association studies. Biometrics 55, 997–1004 (1999).

  6. 6.

    et al. Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am. J. Hum. Genet. 76, 773–779 (2005).

  7. 7.

    et al. Cost-effective analysis of candidate genes using htSNPs: a staged approach. Genes Immun. 5, 301–305 (2004).

  8. 8.

    , , & Genome-wide association studies: theoretical and practical concerns. Nat. Rev. Genet. 6, 109–118 (2005).

  9. 9.

    et al. Multiplexed genotyping with sequence-tagged molecular inversion probes. Nat. Biotechnol. 21, 673–678 (2003).

  10. 10.

    et al. Highly multiplexed molecular inversion probe genotyping: over 10,000 targeted SNPs genotyped in a single tube assay. Genome Res. 15, 269–275 (2005).

  11. 11.

    et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506–511 (2003).

  12. 12.

    The International HapMap Consortium. The International HapMap Project. Nature 426, 789–796 (2003).

  13. 13.

    Test for linear trend in proportions and frequencies. Biometrics II, 375–386 (1955).

  14. 14.

    Chi-square tests with one degree of freedom: extensions of the Mantel-Haenszel procedure. J. Am. Stat. Assoc. 58, 690–700 (1963).

  15. 15.

    & Generalised linear models. J. R. Statist. Soc. A 135, 370–384 (1972).

  16. 16.

    et al. Optimal genotype determination in highly multiplexed SNP data. Eur. J. Hum. Genet. (in the press).

Download references

Acknowledgements

We thank the individuals with T1D and control individuals for their participation; G. Coleman, S. Field, T. Mistry, K. Bourget, S. Clayton, M. Hardy, P. Lauder, M. Maisuria, W. Meadows and S. Wood for preparing DNA samples; D. Strachan, R. Jones, S. Ring and W. McArdle for providing DNA from the 1958 British Birth Cohort collection; and A. Long, N. Naclerio, T. Cormier, K. Tran, C. Bruckner and S. Picton for genotyping and technical assistance. We acknowledge use of DNA from the 1958 British Birth Cohort collection, funded by the Medical Research Council and the Wellcome Trust. We thank the Juvenile Diabetes Research Foundation, the Wellcome Trust, Diabetes UK and the Medical Research Council for financial support. D.G.C. is a Juvenile Diabetes Research Foundation and Wellcome Trust Principal Research Fellow.

Author information

Affiliations

  1. Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge, CB2 2XY, UK.

    • David G Clayton
    • , Neil M Walker
    • , Deborah J Smyth
    • , Rebecca Pask
    • , Jason D Cooper
    • , Lisa M Maier
    • , Luc J Smink
    • , Alex C Lam
    • , Nigel R Ovington
    • , Helen E Stevens
    • , Sarah Nutland
    • , Joanna M M Howson
    •  & John A Todd

  2. ParAllele BioScience, 7300 Shoreline Court, South San Francisco, California 94080, USA.

    • Malek Faham
    • , Martin Moorhead
    • , Hywel B Jones
    • , Matthew Falkowski
    • , Paul Hardenbol
    •  & Thomas D Willis

Authors

  1. Search for David G Clayton in:

  2. Search for Neil M Walker in:

  3. Search for Deborah J Smyth in:

  4. Search for Rebecca Pask in:

  5. Search for Jason D Cooper in:

  6. Search for Lisa M Maier in:

  7. Search for Luc J Smink in:

  8. Search for Alex C Lam in:

  9. Search for Nigel R Ovington in:

  10. Search for Helen E Stevens in:

  11. Search for Sarah Nutland in:

  12. Search for Joanna M M Howson in:

  13. Search for Malek Faham in:

  14. Search for Martin Moorhead in:

  15. Search for Hywel B Jones in:

  16. Search for Matthew Falkowski in:

  17. Search for Paul Hardenbol in:

  18. Search for Thomas D Willis in:

  19. Search for John A Todd in:

Competing interests

M. Faham, M.M., H.B.J., M. Falkowski, P.H. and T.D.W. are currently employed by ParAllele Bioscience.

Corresponding authors

Correspondence to David G Clayton or John A Todd.

Supplementary information

PDF files

  1. 1.

    Supplementary Note

To obtain permission to re-use content from this article visit RightsLink.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng1653

Further reading Further reading

  • 1.

    Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia

    • Jayaram Vijayakrishnan
    • , James Studd
    • , Peter Broderick
    • , Ben Kinnersley
    • , Amy Holroyd
    • , Philip J. Law
    • , Rajiv Kumar
    • , James M. Allan
    • , Christine J. Harrison
    • , Anthony V. Moorman
    • , Ajay Vora
    • , Eve Roman
    • , Sivaramakrishna Rachakonda
    • , Sally E. Kinsey
    • , Eamonn Sheridan
    • , Pamela D. Thompson
    • , Julie A. Irving
    • , Rolf Koehler
    • , Per Hoffmann
    • , Markus M. Nöthen
    • , Stefanie Heilmann-Heimbach
    • , Karl-Heinz Jöckel
    • , Douglas F. Easton
    • , Paul D. P. Pharaoh
    • , Alison M. Dunning
    • , Julian Peto
    • , Frederico Canzian
    • , Anthony Swerdlow
    • , Rosalind A. Eeles
    • , ZSofia Kote-Jarai
    • , Kenneth Muir
    • , Nora Pashayan
    • , Mel Greaves
    • , Martin Zimmerman
    • , Claus R. Bartram
    • , Martin Schrappe
    • , Martin Stanulla
    • , Kari Hemminki
    •  & Richard S. Houlston

    Nature Communications (2018)

  • 2.

    Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma

    • Molly Went
    • , Amit Sud
    • , Asta Försti
    • , Britt-Marie Halvarsson
    • , Niels Weinhold
    • , Scott Kimber
    • , Mark van Duin
    • , Gudmar Thorleifsson
    • , Amy Holroyd
    • , David C. Johnson
    • , Ni Li
    • , Giulia Orlando
    • , Philip J. Law
    • , Mina Ali
    • , Bowang Chen
    • , Jonathan S. Mitchell
    • , Daniel F. Gudbjartsson
    • , Rowan Kuiper
    • , Owen W. Stephens
    • , Uta Bertsch
    • , Peter Broderick
    • , Chiara Campo
    • , Obul R Bandapalli
    • , Hermann Einsele
    • , Walter A. Gregory
    • , Urban Gullberg
    • , Jens Hillengass
    • , Per Hoffmann
    • , Graham H. Jackson
    • , Karl-Heinz Jöckel
    • , Ellinor Johnsson
    • , Sigurður Y. Kristinsson
    • , Ulf-Henrik Mellqvist
    • , Hareth Nahi
    • , Douglas Easton
    • , Paul Pharoah
    • , Alison Dunning
    • , Julian Peto
    • , Federico Canzian
    • , Anthony Swerdlow
    • , Rosalind A. Eeles
    • , ZSofia Kote-Jarai
    • , Kenneth Muir
    • , Nora Pashayan
    • , Jolanta Nickel
    • , Markus M. Nöthen
    • , Thorunn Rafnar
    • , Fiona M. Ross
    • , Miguel Inacio da Silva Filho
    • , Hauke Thomsen
    • , Ingemar Turesson
    • , Annette Vangsted
    • , Niels Frost Andersen
    • , Anders Waage
    • , Brian A. Walker
    • , Anna-Karin Wihlborg
    • , Annemiek Broyl
    • , Faith E. Davies
    • , Unnur Thorsteinsdottir
    • , Christian Langer
    • , Markus Hansson
    • , Hartmut Goldschmidt
    • , Martin Kaiser
    • , Pieter Sonneveld
    • , Kari Stefansson
    • , Gareth J. Morgan
    • , Kari Hemminki
    • , Björn Nilsson
    •  & Richard S. Houlston

    Nature Communications (2018)

  • 3.

    Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility

    • Amit Sud
    • , Hauke Thomsen
    • , Philip J. Law
    • , Asta Försti
    • , Miguel Inacio da Silva Filho
    • , Amy Holroyd
    • , Peter Broderick
    • , Giulia Orlando
    • , Oleg Lenive
    • , Lauren Wright
    • , Rosie Cooke
    • , Douglas Easton
    • , Paul Pharoah
    • , Alison Dunning
    • , Julian Peto
    • , Federico Canzian
    • , Rosalind Eeles
    • , ZSofia Kote-Jarai
    • , Kenneth Muir
    • , Nora Pashayan
    • , Per Hoffmann
    • , Markus M. Nöthen
    • , Karl-Heinz Jöckel
    • , Elke Pogge von Strandmann
    • , Tracy Lightfoot
    • , Eleanor Kane
    • , Eve Roman
    • , Annette Lake
    • , Dorothy Montgomery
    • , Ruth F. Jarrett
    • , Anthony J. Swerdlow
    • , Andreas Engert
    • , Nick Orr
    • , Kari Hemminki
    •  & Richard S. Houlston

    Nature Communications (2017)

  • 4.

    Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor

    • Kevin Litchfield
    • , Max Levy
    • , Giulia Orlando
    • , Chey Loveday
    • , Philip J Law
    • , Gabriele Migliorini
    • , Amy Holroyd
    • , Peter Broderick
    • , Robert Karlsson
    • , Trine B Haugen
    • , Wenche Kristiansen
    • , Jérémie Nsengimana
    • , Kerry Fenwick
    • , Ioannis Assiotis
    • , ZSofia Kote-Jarai
    • , Alison M Dunning
    • , Kenneth Muir
    • , Julian Peto
    • , Rosalind Eeles
    • , Douglas F Easton
    • , Darshna Dudakia
    • , Nick Orr
    • , Nora Pashayan
    • , D Timothy Bishop
    • , Alison Reid
    • , Robert A Huddart
    • , Janet Shipley
    • , Tom Grotmol
    • , Fredrik Wiklund
    • , Richard S Houlston
    •  & Clare Turnbull

    Nature Genetics (2017)

  • 5.

    Fast diffusion of domesticated maize to temperate zones

    • Xiaolong Li
    • , Yinqiao Jian
    • , Chuanxiao Xie
    • , Jun Wu
    • , Yunbi Xu
    •  & Cheng Zou

    Scientific Reports (2017)