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Diabetes 54:2995-3001, 2005
© 2005 by the American Diabetes Association, Inc.

Type 1 Diabetes

Evidence for Susceptibility Loci from Four Genome-Wide Linkage Scans in 1,435 Multiplex Families

Patrick Concannon1, Henry A. Erlich2, Cecile Julier3, Grant Morahan4, Jørn Nerup5, Flemming Pociot5, John A. Todd6, Stephen S. Rich7, and the Type 1 Diabetes Genetics Consortium*

1 Benaroya Research Institute, Seattle, Washington
2 Roche Molecular Systems, Alameda, California
3 Pasteur Institute, Paris, France
4 The Western Australian Institute of Medical Research, Perth, Australia
5 Steno Diabetes Center, Gentofte, Denmark
6 Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes Inflammation Laboratory, Cambridge University, Cambridge, U.K
7 Wake Forest University School of Medicine, Winston-Salem, North Carolina

Type 1 diabetes is a common, multifactorial disease with strong familial clustering (genetic risk ratio [{lambda}S] ~ 15). Approximately 40% of the familial aggregation of type 1 diabetes can be attributed to allelic variation of HLA loci in the major histocompatibility complex on chromosome 6p21 (locus-specific {lambda}S ~ 3). Three other disease susceptibility loci have been clearly demonstrated based on their direct effect on risk, INS (chromosome 11p15, allelic odds ratio [OR] ~ 1.9), CTLA4 (chromosome 2q33, allelic OR ~ 1.2), and PTPN22 (chromosome 1p13, allelic OR ~ 1.7). However, a large proportion of type 1 diabetes clustering remains unexplained. We report here on a combined linkage analysis of four datasets, three previously published genome scans, and one new genome scan of 254 families, which were consolidated through an international consortium for type 1 diabetes genetic studies (www.t1dgc.org) and provided a total sample of 1,435 families with 1,636 affected sibpairs. In addition to the HLA region (nominal P = 2.0 x 10–52), nine non–HLA-linked regions showed some evidence of linkage to type 1 diabetes (nominal P < 0.01), including three at (or near) genome-wide significance (P < 0.05): 2q31-q33, 10p14-q11, and 16q22-q24. In addition, after taking into account the linkage at the 6p21 (HLA) region, there was evidence supporting linkage for the 6q21 region (empiric P < 10–4). More than 80% of the genome could be excluded as harboring type 1 diabetes susceptibility genes of modest effect ({lambda}S ≥ 1.3) that could be detected by linkage. This study represents one of the largest linkage studies ever performed for any common disease. The results demonstrate some consistency emerging for the existence of susceptibility loci on chromosomes 2q31-q33, 6q21, 10p14-q11, and 16q22-q24 but diminished support for some previously reported locations.

Address correspondence and reprint requests to Stephen S. Rich, PhD, Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157. E-mail: srich{at}wfubmc.edu

Abbreviations: IBD, identity-by-descent; LOD, logarithm of odds; MHC, major histocompatibility complex; SNP, single nucleotide polymorphism


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2005 by the American Diabetes Association.