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Cited by 483Genetic Associations and EpidemiologyGenetic Mapping and Diversity in Plants and AnimalsGenetic and phenotypic traits in livestock

Large Upward Bias in Estimation of Locus-Specific Effects from Genomewide Scans

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Göring, Harald H.H., Terwilliger, Joseph D., Blangero, John·2001·The American Journal of Human Genetics
DOI 10.1086/324471PMC PMC1235546
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Abstract

The primary goal of a genomewide scan is to estimate the genomic locations of genes influencing a trait of interest. It is sometimes said that a secondary goal is to estimate the phenotypic effects of each identified locus. Here, it is shown that these two objectives cannot be met reliably by use of a single data set of a currently realistic size. Simulation and analytical results, based on variance-components linkage analysis as an example, demonstrate that estimates of locus-specific effect size at genomewide LOD score peaks tend to be grossly inflated and can even be virtually independent of the true effect size, even for studies on large samples when the true effect size is small. However, the bias diminishes asymptotically. The explanation for the bias is that the LOD score is a function of the locus-specific effect-size estimate, such that there is a high correlation between the observed statistical significance and the effect-size estimate. When the LOD score is maximized over the many pointwise tests being conducted throughout the genome, the locus-specific effect-size estimate is therefore effectively maximized as well. We argue that attempts at bias correction give unsatisfactory results, and that pointwise estimation in an independent data set may be the only way of obtaining reliable estimates of locus-specific effect-and then only if one does not condition on statistical significance being obtained. We further show that the same factors causing this bias are responsible for frequent failures to replicate initial claims of linkage or association for complex traits, even when the initial localization is, in fact, correct. The findings of this study have wide-ranging implications, as they apply to all statistical methods of gene localization. It is hoped that, by keeping this bias in mind, we will more realistically interpret and extrapolate from the results of genomewide scans.

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  • The smaller odds ratios estimated from the replication data could be explained by the winner's curse and shrinkage to the mean.

    “Moreover, the winner's curse and shrinkage to the mean (22,25,26) could explain the smaller odds ratios that we estimated from the replication data (Table 2).”

    From A genome-wide scan for common alleles affecting risk for autism (2010) · cites this paper as [22]

  • The effect size at rs4141463 in the AGRE replication sample was much smaller than in the original AGP sample.

    “When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold.”

    From A genome-wide scan for common alleles affecting risk for autism (2010) · cites this paper as [22]

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Authors
Göring, H. H. H., Terwilliger, J. D., & Blangero, J.
Affiliations
  • Texas Biomedical Research Institute (US)
  • New York State Psychiatric Institute (US)
Corresponding author
Göring, Harald H.H.
ORCID
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2001-12
Volume
69
Issue
6
Pages
1357-1369
ISSN
0002-9297 (ISSN-L)
DOI
10.1086/324471
PMC
PMC1235546
OpenAlex
W1990250261
Cited by
483
References
52
Citations by year
2026: 7 · 2025: 11 · 2024: 4 · 2023: 10 · 2022: 6 · 2021: 11 · 2020: 9 · 2019: 5 · 2018: 7 · 2017: 16 · 2016: 12 · 2015: 9 · 2014: 7 · 2013: 19 · 2012: 19
FWCI
17.70
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Heart, Lung, and Blood Institute (HL-28972, P01HL045522, HL45522, P01HL028972)
  • National Institute of Mental Health (MH63749, R37MH059490, R01MH063749, MH59490, R01MH059490)
  • National Institute of General Medical Sciences (GM-31575, R01GM031575)
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
upward bias, lod score, gene localization, replication failure, complex traits, bias correction, statistical significance
MeSH terms
Chromosome Mapping, Computer Simulation, Humans, Lod Score, Pedigree, Research Design, Bias, Likelihood Functions, Sample Size

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