Rheumatology Advance Access originally published online on January 27, 2007
Rheumatology 2007 46(5):763-771; doi:10.1093/rheumatology/kel443
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Combined analysis of three whole genome linkage scans for Ankylosing Spondylitis
Laboratory for Genetic Epidemiology, Western Australian Institute for Medical Research, UWA Centre for Medical Research, University of Western Australia, Ground Floor, B Block, Hospital Avenue, Nedlands, Western Australia 6009, Australia, 1Department of Human Genetics, The University of Chicago, Chicago, USA, 2Botnar Research Centre, Institute of Musculoskeletal Sciences, University of Oxford, Nuffield Orthopaedic Centre, Windmill Road, Headington, OX3 7LD, UK, 3Laboratoire de Génétique des Maladies Inflammatoires de l’Intestin et Fondation Jean Dausset/CEPH, Paris, 4INSERM U535, Villejuif, 5INSERM AVENIR U458 and AP-HP, Hôpital Robert Debré, 48 Bd Sérurier, 75019 Paris, 6Département d’Immunologie, Institut Cochin, INSERM U567, CNRS UMR 8104, IFR116, and Hôpital Ambroise Paré, Assistance Publique-Hôpitaux de Paris, Université Paris, Ile de France Ouest Paris, France, 7The University of Texas Health Science Center at Houston, Houston, Texas, USA and 8Centre for Immunology and Cancer Research, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia.
Correspondence to: K. W. Carter. E-mail: kcarter{at}cyllene.uwa.edu.au
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Abstract |
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Objective. Ankylosing spondylitis (AS) is a debilitating chronic inflammatory condition with a high degree of familiality (
s = 82) and heritability (>90%) that primarily affects spinal and sacroiliac joints. Whole genome scans for linkage to AS phenotypes have been conducted, although results have been inconsistent between studies and all have had modest sample sizes. One potential solution to these issues is to combine data from multiple studies in a retrospective meta-analysis.
Methods. The International Genetics of Ankylosing Spondylitis Consortium combined data from three whole genome linkage scans for AS (n = 3744 subjects) to determine chromosomal markers that show evidence of linkage with disease. Linkage markers typed in different centres were integrated into a consensus map to facilitate effective data pooling. We performed a weighted meta-analysis to combine the linkage results, and compared them with the three individual scans and a combined pooled scan.
Results. In addition to the expected region surrounding the HLA-B27 gene on chromosome 6, we determined that several marker regions showed significant evidence of linkage with disease status. Regions on chromosome 10q and 16q achieved ‘suggestive’ evidence of linkage, and regions on chromosomes 1q, 3q, 5q, 6q, 9q, 17q and 19q showed at least nominal linkage in two or more scans and in the weighted meta-analysis. Regions previously associated with AS on chromosome 2q (the IL-1 gene cluster) and 22q (CYP2D6) exhibited nominal linkage in the meta-analysis, providing further statistical support for their involvement in susceptibility to AS.
Conclusion. These findings provide a useful guide for future studies aiming to identify the genes involved in this highly heritable condition.
KEY WORDS: Ankylosing Spondylitis, genome scans, meta-analysis
Submitted 26 June 2006;
revised version accepted 12 December 2006.
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