title: Genomic DNA pooling for whole-genome association scans in complex disease: empirical demonstration of efficacy in rheumatoid arthritis.
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.
authors.affiliation: Kings College London School of Medicine at Guy's, Department of Rheumatology, King's and St Thomas', London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Steer
authors.forename: V
authors.initials: V
authors.lastname: Abkevich
authors.forename: A
authors.initials: A
authors.lastname: Gutin
authors.forename: H J
authors.initials: HJ
authors.lastname: Cordell
authors.forename: K L
authors.initials: KL
authors.lastname: Gendall
authors.forename: M E
authors.initials: ME
authors.lastname: Merriman
authors.forename: R A
authors.initials: RA
authors.lastname: Rodger
authors.forename: K A
authors.initials: KA
authors.lastname: Rowley
authors.forename: P
authors.initials: P
authors.lastname: Chapman
authors.forename: P
authors.initials: P
authors.lastname: Gow
authors.forename: A A
authors.initials: AA
authors.lastname: Harrison
authors.forename: J
authors.initials: J
authors.lastname: Highton
authors.forename: P B B
authors.initials: PB
authors.lastname: Jones
authors.forename: J
authors.initials: J
authors.lastname: O'Donnell
authors.forename: L
authors.initials: L
authors.lastname: Stamp
authors.forename: L
authors.initials: L
authors.lastname: Fitzgerald
authors.forename: D
authors.initials: D
authors.lastname: Iliev
authors.forename: A
authors.initials: A
authors.lastname: Kouzmine
authors.forename: T
authors.initials: T
authors.lastname: Tran
authors.forename: M H
authors.initials: MH
authors.lastname: Skolnick
authors.forename: K M
authors.initials: KM
authors.lastname: Timms
authors.forename: J S
authors.initials: JS
authors.lastname: Lanchbury
authors.forename: T R
authors.initials: TR
authors.lastname: Merriman
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D023281:Genomics / Q000379:methods*; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases / Q000235:genetics
chemical_list: D006680:HLA Antigens; D004247:DNA; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases