RESEARCH - Combined analysis of three whole genome linkage scans for ankylosing spondylitis

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Rheumatology Advance Access originally published online on January 27, 2007

Rheumatology 2007 46(5):763-771; doi:10.1093/rheumatology/kel443

Combined analysis of three whole genome linkage scans for Ankylosing

Spondylitis

K. W. , A. Pluzhnikov1, A. E. Timms2, C. Miceli-3, C.

Bourgain4, B. P. Wordsworth2, H. Jean-Pierre5, N. J. 1, L. J. Palmer, M.

Breban6, J. D. Reveille7 and M. A. Brown2,8

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 Dausset/CEPH, Paris, 4INSERM

U535, Villejuif, 5INSERM AVENIR U458 and AP-HP, Hôpital 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

andra Hospital, Woolloongabba, Queensland, Australia.

Abstract

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.

http://rheumatology.oxfordjournals.org/cgi/content/abstract/46/5/763?etoc

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