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Case–control association mapping by proxy using family history of disease

Nature Genetics volume 49, pages 325331 (2017) | Download Citation

Abstract

Collecting cases for case–control genetic association studies can be time-consuming and expensive. In some situations (such as studies of late-onset or rapidly lethal diseases), it may be more practical to identify family members of cases. In randomly ascertained cohorts, replacing cases with their first-degree relatives enables studies of diseases that are absent (or nearly absent) in the cohort. We refer to this approach as genome-wide association study by proxy (GWAX) and apply it to 12 common diseases in 116,196 individuals from the UK Biobank. Meta-analysis with published genome-wide association study summary statistics replicated established risk loci and yielded four newly associated loci for Alzheimer's disease, eight for coronary artery disease and five for type 2 diabetes. In addition to informing disease biology, our results demonstrate the utility of association mapping without directly observing cases. We anticipate that GWAX will prove useful in future genetic studies of complex traits in large population cohorts.

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Acknowledgements

We thank T. Hayeck and J. Jakobsdottir for comments on a draft of this manuscript. J.Z.L. and J.K.P. are partially supported by the National Institute of Mental Health (NIH grant R01MH106842). This research has been conducted using the UK Biobank Resource.

Author information

Affiliations

  1. New York Genome Center, New York, New York, USA.

    • Jimmy Z Liu
    • , Yaniv Erlich
    •  & Joseph K Pickrell
  2. Department of Computer Science, Columbia University, New York, New York, USA.

    • Yaniv Erlich
  3. Department of Biological Sciences, Columbia University, New York, New York, USA.

    • Joseph K Pickrell

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Contributions

All authors contributed to the study design and writing, and all approved this manuscript. J.Z.L. performed the statistical analysis.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jimmy Z Liu.

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DOI

https://doi.org/10.1038/ng.3766

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