Journal article
Quantifying the underestimation of relative risks from genome-wide association studies
- Abstract:
- Genome-wide association studies (GWAS) have identified hundreds of associated loci across many common diseases. Most risk variants identified by GWAS will merely be tags for as-yet-unknown causal variants. It is therefore possible that identification of the causal variant, by fine mapping, will identify alleles with larger effects on genetic risk than those currently estimated from GWAS replication studies. We show that under plausible assumptions, whilst the majority of the per-allele relative risks (RR) estimated from GWAS data will be close to the true risk at the causal variant, some could be considerable underestimates. For example, for an estimated RR in the range 1.2-1.3, there is approximately a 38% chance that it exceeds 1.4 and a 10% chance that it is over 2. We show how these probabilities can vary depending on the true efects associated with low-frequency variants and on the minor allele frequency (MAF) of the most associated SNP. We investigate the consequences of the underestimation of effect sizes for predictions of an individual's disease risk and interpret our results for the design of fine mapping experiments. Although these effects mean that the amount of heritability explained by known GWAS loci is expected to be larger than current projections, this increase is likely to explain a relatively small amout of the so-called "missing" heritability.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Version of record, bin, 721.4KB, Terms of use)
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- Publisher copy:
- 10.1371/journal.pgen.1001337
Authors
+ "Wellcome Trust", "Commonwealth Scholarship"
More from this funder
- Funding agency for:
- Vukcevic, D
- Publisher:
- Public Library of Science
- Journal:
- PLoS Genetics More from this journal
- Volume:
- 7
- Issue:
- 3
- Article number:
- e1001337
- Publication date:
- 2011-03-01
- Edition:
- Publisher's version
- DOI:
- EISSN:
-
1553-7404
- ISSN:
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1553-7390
- Language:
-
English
- Keywords:
- Subjects:
- UUID:
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uuid:ed793007-7def-4de3-b8e4-90916fb21eb8
- Local pid:
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ora:5177
- Deposit date:
-
2011-03-25
- ARK identifier:
Terms of use
- Copyright holder:
- Spencer et al
- Copyright date:
- 2011
- Notes:
- Citation: Spencer, C. et al. (2011). 'Quantifying the underestimation of relative risks from genome-wide association studies', PLoS Genetics 7(3), e1001337. [Available at http://www.plosgenetics.org]. © 2011 Spencer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
- Licence:
- CC Attribution (CC BY)
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