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Genomic DNA pooling for whole-genome association scans in complex disease: Empirical demonstration of efficacy in rheumatoid arthritis

Lookup NU author(s): Professor Heather Cordell, Pamela Chapman

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Abstract

A pragmatic approach that balances the benefit of a whole-genome association (WGA) experiment against the cost of individual genotyping is to use pooled genomic DNA samples. We aimed to determine the feasibility of this approach in a WGA scan in rheumatoid arthritis (RA) using the validated human leucocyte antigen (HLA) and PTPN22 associations as test loci. A total of 203269 single-nucleotide polymorphisms (SNPs) on the Affymetrix 100K GeneChip and Illumina Infinium microarrays were examined. A new approach to the estimation of allele frequencies from Affymetrix hybridization intensities was developed involving weighting for quality signals from the probe quartets. SNPs were ranked by z-scores, combined from United Kingdom and New Zealand case-control cohorts. Within a 1.7Mb HLA region, 33 of the 257 SNPs and at PTPN22, 21 of the 45 SNPs, were ranked within the top 100 associated SNPs genome wide. Within PTPN22, individual genotyping of SNP rs1343125 within MAGI3 confirmed association and provided some evidence for association independent of the PTPN22 620W variant (P=0.03). Our results emphasize the feasibility of using genomic DNA pooling for the detection of association with complex disease susceptibility alleles. The results also underscore the importance of the HLA and PTPN22 loci in RA aetiology.

Publication metadata

Author(s): Steer S, Abkevich V, Gutin A, Cordell HJ, Gendall KL, Merriman ME, Rodger RA, Rowley KA, Chapman P, Gow P, Harrison AA, Highton J, Jones PBB, O'Donnell J, Stamp L, Fitzgerald L, Iliev D, Kouzmine A, Tran T, Skolnick MH, Timms KM, Lanchbury JS, Merriman TR

Publication type: Article

Publication status: Published

Journal: Genes and Immunity

Year: 2007

Volume: 8

Issue: 1

Pages: 57-68

ISSN (print): 1466-4879

ISSN (electronic): 1476-5470

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/sj.gene.6364359

DOI: 10.1038/sj.gene.6364359

PubMed id: 17159887

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