Evaluation of an approximation method for assessment of overall significance of multiple-dependent tests in a genomewide association study

Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483, O'Dushlaine, Colm, Purcell, Shaun, Craddock, Nicholas John ORCID: https://orcid.org/0000-0003-2171-0610, Holmans, Peter Alan ORCID: https://orcid.org/0000-0003-0870-9412 and O'Donovan, Michael Conlon ORCID: https://orcid.org/0000-0001-7073-2379 2011. Evaluation of an approximation method for assessment of overall significance of multiple-dependent tests in a genomewide association study. Genetic Epidemiology 35 (8) , pp. 861-866. 10.1002/gepi.20636

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine Systems Immunity Research Institute (SIURI)
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > R Medicine (General)
Uncontrolled Keywords:	GWAS; set-based analysis; multiple-dependent tests
Publisher:	Wiley
ISSN:	0741-0395
Last Modified:	19 Oct 2022 09:54
URI:	https://orca.cardiff.ac.uk/id/eprint/22597

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