Evaluation of an approximation method for assessment of overall significance of multiple‐dependent tests in a genomewide association study
Open accessAbstract
We describe implementation of a set‐based method to assess the significance of findings from genomewide association study data. Our method, implemented in PLINK, is based on theoretical approximation of Fisher's statistics such that the combination of P‐vales at a gene or across a pathway is carried out in a manner that accounts for the correlation structure, or linkage disequilibrium, between single nucleotide polymorphisms. We compare our method to a permutation‐based product of P‐values approach and show a typical correlation in excess of 0.98 for a number of comparisons. The method gives Type I error rates that are less than or equal to the corresponding nominal significance levels, making it robust to the effects of false positives. We show that in broadly similar populations, reference data sets of markers are an appropriate substrate for deriving marker‐marker linkage disequilibrium (LD), negating the need to access individual level genotypes, greatly facilitating its generic applicability. We show that the method is thus robust to LD‐associated bias and has equivalent performance to permutation‐based methods, with a significantly shorter runtime. This is particularly relevant at a time of increasing public availability of significantly larger genetic data sets and should go a long way to assist in the rapid analysis of these data sets. Genet. Epidemiol. 2011. © 2011 Wiley Periodicals, Inc.35:861‐866, 2011
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FORGE and SET SCREEN TEST are meta-analytic approaches that pool SNP P values within genes or pathways while correcting for linkage disequilibrium.
“FORGE43 and SET SCREEN TEST44 are meta-analysis methods that combine P values across all the SNPs in genes or pathways while adjusting for the confound of LD.”
From Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways (2015) · cites this paper as [44]
The gene-wide analysis controlled for linkage disequilibrium and different numbers of SNPs per gene using a statistical approach by Brown (1975), adopted by Moskvina et al. (2011) and de Leeuw et al. (2015).
“The gene-wide analysis was performed based on the summary P-values while controlling for linkage disequilibrium and different numbers of SNPs per gene using a statistical approach by Brown (1975), and adopted for set-based analysis of genetic data by Moskvina et al. (2011) and de Leeuw et al. (2015).”
From Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk (2019) · cites this paper as Moskvina et al. (2011)
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- Authors
- Moskvina, V., O'Dushlaine, C., Purcell, S., Craddock, N., Holmans, P., & O'Donovan, M. C.
- Affiliations
- Cardiff University (GB)
- Broad Institute (US)
- Corresponding author
- Moskvina, Valentina
- Venue
- Genetic Epidemiology
- Publisher
- Wiley
- Published
- 2011-10-17
- Volume
- 35
- Issue
- 8
- Pages
- 861-866
- ISSN
- 0741-0395 (ISSN-L)
- 1098-2272
- PMC
- PMC3268180
- OpenAlex
- W2138237342
- Cited by
- 49
- References
- 16
- Citations by year
- 2025: 1 · 2022: 4 · 2021: 2 · 2020: 4 · 2019: 4 · 2018: 5 · 2017: 4 · 2016: 4 · 2015: 7 · 2014: 5 · 2013: 4 · 2012: 4
- FWCI
- 2.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Genetic Epidemiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- MRC (UK); NIMH (USA) CONTE (2 P50 MH066392-05A1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- genome-wide association study, Fisher's method, linkage disequilibrium, single nucleotide polymorphisms, permutation tests, type I error rate, PLINK, pathway analysis
- MeSH terms
- United Kingdom, Humans, Schizophrenia, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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