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Estimation of significance thresholds for genomewide association scans

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Dudbridge, Frank, Gusnanto, Arief·2008·Genetic Epidemiology

DOI 10.1002/gepi.20297PMC PMC2573032

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Abstract

The question of what significance threshold is appropriate for genomewide association studies is somewhat unresolved. Previous theoretical suggestions have yet to be validated in practice, whereas permutation testing does not resolve a discrepancy between the genomewide multiplicity of the experiment and the subset of markers actually tested. We used genotypes from the Wellcome Trust Case‐Control Consortium to estimate a genomewide significance threshold for the UK Caucasian population. We subsampled the genotypes at increasing densities, using permutation to estimate the nominal P‐value for 5% family‐wise error. By extrapolating to infinite density, we estimated the genomewide significance threshold to be about 7.2 × 10−8. To reduce the computation time, we considered Patterson's eigenvalue estimator of the effective number of tests, but found it to be an order of magnitude too low for multiplicity correction. However, by fitting a Beta distribution to the minimum P‐value from permutation replicates, we showed that the effective number is a useful heuristic and suggest that its estimation in this context is an open problem. We conclude that permutation is still needed to obtain genomewide significance thresholds, but with subsampling, extrapolation and estimation of an effective number of tests, the threshold can be standardized for all studies of the same population. Genet. Epidemiol. 2008. © 2008 Wiley‐Liss, Inc.

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Authors: Dudbridge, F., & Gusnanto, A.
Affiliations: MRC Biostatistics Unit (GB)
Corresponding author: Dudbridge, Frank
ORCID: Dudbridge, Frank
Gusnanto, Arief
Venue: Genetic Epidemiology
Publisher: Wiley
Published: 2008-02-25
Volume: 32
Issue: 3
Pages: 227-234
ISSN: 0741-0395 (ISSN-L)
1098-2272
DOI: 10.1002/gepi.20297
PMC: PMC2573032
OpenAlex: W2105239414
Cited by: 703
References: 26
Citations by year: 2026: 18 · 2025: 24 · 2024: 26 · 2023: 30 · 2022: 26 · 2021: 36 · 2020: 45 · 2019: 32 · 2018: 49 · 2017: 32 · 2016: 30 · 2015: 36 · 2014: 47 · 2013: 47 · 2012: 46
FWCI: 33.84
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Genetic Epidemiology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
Funders: Sixth Framework Programme (LSHM-CT-2004-503485)
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 diversity and population structure
Keywords: genome-wide association study, permutation tests, family-wise error rate, multiple testing correction, subsampling, beta distribution, Wellcome Trust Case Control Consortium
MeSH terms: Genetic Markers, Genotype, United Kingdom, Humans, Genome, Human, Case-Control Studies, Genetic Predisposition to Disease, White People

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Estimation of significance thresholds for genomewide association scans

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