Streamlined analysis of pooled genotype data in SNP-based association studies

Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483, Norton, Nadine ORCID: https://orcid.org/0000-0002-3848-4288, Williams, Nigel Melville ORCID: https://orcid.org/0000-0003-1177-6931, Holmans, Peter Alan ORCID: https://orcid.org/0000-0003-0870-9412, Owen, Michael John ORCID: https://orcid.org/0000-0003-4798-0862 and O'Donovan, Michael Conlon ORCID: https://orcid.org/0000-0001-7073-2379 2005. Streamlined analysis of pooled genotype data in SNP-based association studies. Genetic Epidemiology 28 (3) , pp. 273-282. 10.1002/gepi.20062

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Abstract

Several groups have developed methods for estimating allele frequencies in DNA pools as a fast and cheap way for detecting allelic association between genetic markers and disease. To obtain accurate estimates of allele frequencies, a correction factor k for the degree to which measurement of allele-specific products is biased is generally applied. Factor k is usually obtained as the ratio of the two allele-specific signals in samples from heterozygous individuals, a step that can significantly impair throughput and increase cost. We have systematically investigated the properties of k through the use of empirical and simulated data. We show that for the dye terminator primer extension genotyping method we have applied, the correction factor k is substantially influenced by the dye terminators incorporated, but also by the terminal 3' base of the extension primer. We also show that the variation in k is large enough to result in unacceptable error rates if association studies are conducted without regard to k. We show that the impact of ignoring k can be neutralized by applying a correction factor k(max) that can be easily derived, but this at the potential cost of an increase in type I error. Finally, based upon observed distributions for k we derive a method allowing the estimation of the probability pooled data reflects significant differences in the allele frequencies between the subjects comprising the pools. By controlling the error rates in the absence of knowledge of the appropriate SNP-specific correction factors, each approach enhances the performance of DNA pooling, while considerably streamlining the method by reducing time and cost.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI) MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Neuroscience and Mental Health Research Institute (NMHRI)
Uncontrolled Keywords:	DNA pool ; association ; SNP ; case-control differential amplification
Publisher:	John Wiley & Sons
ISSN:	0741-0395
Last Modified:	01 Dec 2022 09:48
URI:	https://orca.cardiff.ac.uk/id/eprint/592

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