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Cited by 88Genetic Associations and EpidemiologyGenetic diversity and population structureGenetic Mapping and Diversity in Plants and Animals

Effects of Differential Genotyping Error Rate on the Type I Error Probability of Case-Control Studies

Moskvina, Valentina, Craddock, Nick, Holmans, Peter, Owen, Michael J., O’Donovan, Michael C.·2006·Human Heredity
DOI 10.1159/000092553
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Abstract

Objectives: It is well known that genotyping error adversely affects the power of genetic case-control association studies but there is little research on its effects on type I error, and none that has addressed possible differences in genotype error rates between cases and controls. Methods: We used simulations to examine the influence of genotyping error on the type I error probability given by case-control studies. The effect of genotyping error on the magnitude of type I error was explored for a single marker of varying minor allele frequency (MAF), and for haplotypic tests based on two markers with varying MAF and linkage disequilibrium (LD) measure r2. Results: We show that even with low genotyping error rates (<0.01), systematic differences in the error rate between samples can result in type I error rates substantially above 0.05. The effect was maximal for markers with small MAF, markers in strong LD, and where a common allele is more frequently misclassified as a rare allele than vice versa. The problem was also exacerbated by the use of large samples. Conclusions: Our results show that small differential genotyping error rates between cases and controls pose significant problems for association analyses. Differential genotyping error rates are particularly likely to arise where genotype data are combined from multiple sites, or where case genotypes are examined against archived reference population cohort genotypes that are being generated in several countries. Although these strategies may be necessary to obtain adequately powered samples, our data show the importance of stringent quality control. Furthermore, associations based on rare haplotypes should be treated with caution.

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  • Stringent QC filters were applied separately to each of the 8 groups to remove poorly performing samples.

    “As we used genotype data from multiple sources, it was important to apply stringent QC filters, as differential genotyping error rates between groups could result in spurious associations when the data are combined 50, 51.These filters were applied separately to each of these 8 groups to remove poorly performing samples using tools implemented in PLINK v1.0552.”

    From Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease (2009) · cites this paper as [52]

  • Differential genotyping error rate can have a substantial impact on common-variant based genome-wide association studies.

    “It has been shown that differential genotyping error rate can have substantial impact on common-variant based GWA studies.89”

    From Statistical analysis strategies for association studies involving rare variants (2010) · cites this paper as [89]

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Authors
Moskvina, V., Craddock, N., Holmans, P., Owen, M. J., & O’Donovan, M. C.
Affiliations
Cardiff University (GB)
ORCID
Venue
Human Heredity
Publisher
S. Karger AG
Published
2006
Volume
61
Issue
1
Pages
55-64
ISSN
  • 0001-5652 (ISSN-L)
  • 1423-0062
DOI
10.1159/000092553
OpenAlex
W2069420421
Cited by
88
References
21
Citations by year
2026: 1 · 2025: 2 · 2023: 2 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 1 · 2017: 1 · 2016: 3 · 2015: 1 · 2014: 3 · 2013: 8 · 2012: 4
FWCI
6.63
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Human Heredity (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic diversity and population structure
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords
genotyping errors, type I error, case-control association, linkage disequilibrium, minor allele frequency, rare haplotypes, quality control
MeSH terms
Alleles, Computer Simulation, Data Interpretation, Statistical, Gene Frequency, Genotype, Haplotypes, Humans, Models, Genetic, Probability, Reproducibility of Results, Models, Statistical, Linkage Disequilibrium, Case-Control Studies

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