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

Genes & Immunity volume 8, pages 57–68 (2007)Cite this article

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 203 269 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 1.7 Mb 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.

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Acknowledgements

This work was supported by the Health Research Council of New Zealand, the Arthritis and Rheumatism Council in the United Kingdom, Myriad Genetics Inc. and NHS Research and Development funding for recruitment carried out at Guy's and St Thomas' and Lewisham hospitals. We thank NZ research nurses Gael Hewett and Sue Yeoman, UK research nurse Janet Grumley, and Bhaneeta Lad for technical assistance, and Cathryn Lewis and Sheila Fisher for statistical advice.

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Author notes

  1. S Steer and V Abkevich: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Rheumatology, Kings College London School of Medicine at Guy's, King's and St Thomas', London, UK

    S Steer

  2. Myriad Genetics Inc., Salt Lake City, UT, USA

    V Abkevich, A Gutin, L Fitzgerald, D Iliev, A Kouzmine, T Tran, M H Skolnick, K M Timms & J S Lanchbury

  3. Institute of Human Genetics, University of Newcastle, Newcastle, UK

    H J Cordell

  4. Department of Biochemistry, University of Otago, Dunedin, New Zealand

    K L Gendall, M E Merriman, R A Rodger, K A Rowley & T R Merriman

  5. Department of Rheumatology, Christchurch Hospital, Christchurch, New Zealand

    P Chapman, J O'Donnell & L Stamp

  6. Department of Rheumatology, Middlemore Hospital, Auckland, New Zealand

    P Gow

  7. Wellington School of Medicine, University of Otago, Wellington, New Zealand

    A A Harrison

  8. Otago School of Medicine, University of Otago, Dunedin, New Zealand

    J Highton

  9. Department of Rheumatology, QE Hospital, Rotorua, New Zealand

    P B B Jones

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  1. S Steer
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Correspondence to T R Merriman.

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Steer, S., Abkevich, V., Gutin, A. et al. Genomic DNA pooling for whole-genome association scans in complex disease: empirical demonstration of efficacy in rheumatoid arthritis. Genes Immun 8, 57–68 (2007). https://doi.org/10.1038/sj.gene.6364359

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  • DOI: https://doi.org/10.1038/sj.gene.6364359

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