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Replication of past candidate loci for common diseases and phenotypes in 100 genome-wide association studies

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Siontis, Konstantinos C M, Patsopoulos, Nikolaos A, Ioannidis, John P A·2010·European Journal of Human Genetics
DOI 10.1038/ejhg.2010.26PMC PMC2987361
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Abstract

Genome-wide association studies (GWASs) have created a paradigm shift in discovering genetic associations for common diseases and phenotypes, but it is unclear whether the thousands of candidate genetic association studies performed in the pre-GWAS era had found any reliable associations for common diseases and phenotypes. We aimed to systematically evaluate whether loci proposed to harbor candidate associations before the advent of GWASs are replicated in GWASs. The GWAS data published through August, 2008 and included in the NHGRI catalog were screened and variants in candidate loci were selected on the basis of statistical significance (P<0.05) to create a list of independent, non-redundant associations. Altogether, 159 articles on GWASs were evaluated, 100 of which addressed past proposed candidate loci. A total of 291 independent, nominally significant (P<0.05) candidate gene associations were assembled after keeping only the SNP with lowest P-value for each locus and each phenotype; 108 of those had P<10(-3) for association and 41 had P<10(-7). A total of 22 of these 41 candidate gene associations pertained to binary phenotypes with a median odds ratio=2.91 (IQR: 1.82-4.6) and median minor allele frequency=0.17 (IQR: 0.12-0.29) in Caucasians; for comparison, 60 new associations of binary outcomes with P<10(-7) discovered in the same GWASs had much smaller effects (median odds ratio 1.30, IQR: 1.18-1.58) and modestly larger minor allele frequencies (median 0.27, IQR: 0.15-0.43). Overall, few of the numerous genetic associations proposed in the candidate gene era have been replicated in GWASs, but those that have been conclusively replicated have large genetic effects that should not be discarded.

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  • Previously almost all of the proposed candidate gene associations from small studies were false, with some exceptions, but collaborative consortia have substantially improved power, and the replicated results can be considered highly reliable.

    “Although previously almost all of the proposed candidate gene associations from small studies were false 99 (with some exceptions 100 ), collaborative consortia have substantially improved power, and the replicated results can be considered highly reliable.”

    From Power failure: why small sample size undermines the reliability of neuroscience (2013) · cites this paper as [100]

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  • The 'replication crisis' reached headlines and catalyzed the uptake of open science as a means to improve the trustworthiness of scientific findings.

    “Meanwhile, the “replication crisis” reached headlines and catalyzed the uptake of open science as a means to improve the trustworthiness of scientific findings [6–9] (see Box 1 for a first-hand account).”

    From Open Science 2.0: Towards a truly collaborative research ecosystem (2023) · cites this paper as [9]

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Authors
Siontis, K. C. M., Patsopoulos, N. A., & Ioannidis, J. P. A.
Affiliations
  • University of Ioannina (GR)
  • Tufts University (US)
Corresponding author
Ioannidis, John P A
ORCID
Venue
European Journal of Human Genetics
Publisher
Springer Science and Business Media LLC
Published
2010-03-17
Volume
18
Issue
7
Pages
832-837
ISSN
  • 1018-4813 (ISSN-L)
  • 1476-5438
DOI
10.1038/ejhg.2010.26
PMC
PMC2987361
OpenAlex
W2052880407
Cited by
117
References
5
Citations by year
2026: 3 · 2025: 2 · 2023: 6 · 2021: 6 · 2020: 8 · 2019: 4 · 2018: 10 · 2017: 13 · 2016: 5 · 2015: 5 · 2014: 16 · 2013: 11 · 2012: 11
FWCI
7.02
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • European Journal of Human Genetics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
Funders
  • European Commission
  • General Secretariat for Research and Technology
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
Keywords
candidate gene association, replication of genetic associations, common diseases, phenotypes, single nucleotide polymorphisms, genetic effect size, odds ratio, minor allele frequency
MeSH terms
Bayes Theorem, Disease, Humans, Phenotype, Reproducibility of Results, Genome, Human, Odds Ratio, Polymorphism, Single Nucleotide, Databases, Genetic, Genome-Wide Association Study, Genetic Loci

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