1. ¹King's College London School of Medicine, Department of Medical and Molecular Genetics, London, UK
2. ²Istituto di Genetica delle Popolazioni-CNR, Alghero, Italy
3. ³INSERM, U794, Evry, France
4. ⁴Department of Medicine, Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco, CA, USA
5. ⁵King's College London, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, London, UK

Correspondence: Professor CM Lewis, King's College London School of Medicine, Department of Medical and Molecular Genetics, 8th Floor, Guy's Tower, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK. Tel: +44 20 7188 2601; Fax: +44 20 7188 2585; E-mail: cathryn.lewis@kcl.ac.uk

Received 11 June 2008; Revised 23 July 2008; Accepted 7 August 2008; Published online 10 September 2008.

Abstract

Autoimmune diseases are chronic disorders initiated by a loss of immunologic tolerance to self-antigens. They cluster within families, and patients may be diagnosed with more than one disease, suggesting pleiotropic genes are involved in the aetiology of different diseases. To identify potential loci, which confer susceptibility to autoimmunity independent of disease phenotype, we pooled results from genome-wide linkage studies, using the genome scan meta-analysis method (GSMA). The meta-analysis included 42 independent studies for 11 autoimmune diseases, using 7350 families with 18 291 affected individuals. In addition to the HLA region, which showed highly significant genome-wide evidence for linkage, we obtained suggestive evidence for linkage on chromosome 16, with peak evidence at 10.0–19.8 Mb. This region may harbour a pleiotropic gene (or genes) conferring risk for several diseases, although no such gene has been identified through association studies. We did not identify evidence for linkage at several genes known to confer increased risk to different autoimmune diseases (PTPN22, CTLA4), even in subgroups of diseases consistently found to be associated with these genes. The relative risks conferred by variants in these genes are modest (<1.5 in most cases), and even a large study like this meta-analysis lacks power to detect linkage. This study illustrates the concept that linkage and association studies have power to identify very different types of disease-predisposing variants.