Human Molecular Genetics, 2000, Vol. 9, No. 9 1291-1301
© 2000 Oxford University Press
Evaluation of fine mapping strategies for a multifactorial disease locus: systematic linkage and association analysis of IDDM1 in the HLA region on chromosome 6p21
Wellcome Trust Centre of Molecular Mechanisms in Disease, Box 139, Department of Medical Genetics, University of Cambridge, Hills Road, Cambridge CB2 2XY, UK, 1Dipartimento di Scienze Biomediche e Biotecnologie, Universita’ di Cagliari, Cagliari, Italy, 2MRC Immunochemistry Unit, University of Oxford, Oxford OX1 3QU, UK and 3Department of Medicine, University of Birmingham, Birmingham B9 5SS, UK
The positional cloning of multifactorial disease genes is a major challenge in human genetics. We have therefore empirically tested the utility of the available polymorphic microsatellite map to locate the already identified type 1 diabetes locus IDDM1 (sibling risk/population prevalence ratio 
s = 2.7) within a 14 Mb region of chromosome 6p21 linked to disease. In a two-stage approach to fine mapping, linkage was evaluated in 385 affected sib-pair families using 13 evenly spaced polymorphic microsatellite markers. The whole 14 Mb showed strong linkage. Then, each marker was analysed for evidence of allelic association, revealing evidence of disease association at one marker located within the 95% confidence interval of 1.7 cM obtained by linkage. Analysis of an additional 12 markers flanking this marker revealed a highly specific region of 570 kb associated with disease (P = 7.5 x 10–35), which included the HLA class II genes, known to be the primary determinants of IDDM1. The peak of association was as close as 85 kb centromeric of the disease-predisposing class II gene HLA-DQB1. We investigated the importance of the underlying inter-marker linkage disequilibrium, marker informativity and recombination for fine mapping and demonstrate that the majority of disease association in the region can be explained by linkage disequilibrium with the class II susceptibility genes. Recombination within the major histocompatibility complex was rare and nearly absent in the class III region. We demonstrate that fine mapping of a multifactorial disease gene is possible with high accuracy even in a region with extraordinary linkage disequilibrium across distances of several Mb. The results will be applicable to association studies of disease loci with s values <2.7 except that much larger data sets will be required.
+ Present address: Clinic of Diabetes, Institute of Diabetes, Nutrition and Metabolic Diseases ‘N. Paulescu’, Bucharest, Romania
§ Present address: Research and Development Genetics Department, Astra Zeneca, Macclesfield, Cheshire SK10 4TG, UK
¶ Present address: MRC HGMP Resource Centre, Hinxton, Cambridge CB10 1SB, UK
To whom correspondence should be addressed. Tel: +44 1223 762101; Fax: +44 1223 762102; Email: john.todd@cimr.cam.ac.uk
Present address: Department of Immunohematology and Bloodbank, Leiden University Medical Center, PO Box 9600, Leiden, The Netherlands
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R. A. Ettinger, G. K. Papadopoulos, A. K. Moustakas, G. T. Nepom, and W. W. Kwok Allelic Variation in Key Peptide-Binding Pockets Discriminates between Closely Related Diabetes-Protective and Diabetes-Susceptible HLA-DQB1*06 Alleles J. Immunol., February 1, 2006; 176(3): 1988 - 1998. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Li and T. Jiang Haplotype-based linkage disequilibrium mapping via direct data mining Bioinformatics, December 15, 2005; 21(24): 4384 - 4393. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Motzo, D. Contu, H. J. Cordell, R. Lampis, M. Congia, M. G. Marrosu, J. A. Todd, M. Devoto, and F. Cucca Heterogeneity in the Magnitude of the Insulin Gene Effect on HLA Risk in Type 1 Diabetes Diabetes, December 1, 2004; 53(12): 3286 - 3291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Deruytter, O. Boulard, and H.-J. Garchon Mapping Non-Class II H2-Linked Loci for Type 1 Diabetes in Nonobese Diabetic Mice Diabetes, December 1, 2004; 53(12): 3323 - 3327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Kralovicova, L. Hammarstrom, A. Plebani, A. D. B. Webster, and I. Vorechovsky Fine-Scale Mapping at IGAD1 and Genome-Wide Genetic Linkage Analysis Implicate HLA-DQ/DR as a Major Susceptibility Locus in Selective IgA Deficiency and Common Variable Immunodeficiency J. Immunol., March 1, 2003; 170(5): 2765 - 2775. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M A Kelly, M L Rayner, C H Mijovic, and A H Barnett Molecular aspects of type 1 diabetes Mol. Pathol., February 1, 2003; 56(1): 1 - 10. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. C.L. Johnson, F. Payne, S. Nutland, H. Stevens, E. Tuomilehto-Wolf, J. Tuomilehto, and J. A. Todd A Comprehensive, Statistically Powered Analysis of GAD2 in Type 1 Diabetes Diabetes, September 1, 2002; 51(9): 2866 - 2870. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. G. Marrosu, R. Murru, M. R. Murru, G. Costa, P. Zavattari, M. Whalen, E. Cocco, C. Mancosu, L. Schirru, E. Solla, et al. Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia Hum. Mol. Genet., December 1, 2001; 10(25): 2907 - 2916. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. T. Elder, R. P. Nair, T. Henseler, S. Jenisch, P. Stuart, N. Chia, E. Christophers, and J. J. Voorhees The Genetics of Psoriasis 2001: The Odyssey Continues Arch Dermatol, November 1, 2001; 137(11): 1447 - 1454. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Cai, J. Xie, J.-X. She, and A. L. Notkins Analysis of the Coding and Promoter Regions of the Autoantigen IA-2 in Subjects With and Without Autoantibodies to IA-2 Diabetes, October 1, 2001; 50(10): 2406 - 2409. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. SCHURMANN, P. REICHEL, B. MULLER-MYHSOK, M. SCHLAAK, J. MULLER-QUERNHEIM, and E. SCHWINGER Results from a Genome-wide Search for Predisposing Genes in Sarcoidosis Am. J. Respir. Crit. Care Med., September 1, 2001; 164(5): 840 - 846. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Zavattari, R. Lampis, C. Motzo, M. Loddo, A. Mulargia, M. Whalen, M. Maioli, E. Angius, J. A. Todd, and F. Cucca Conditional linkage disequilibrium analysis of a complex disease superlocus, IDDM1 in the HLA region, reveals the presence of independent modifying gene effects influencing the type 1 diabetes risk encoded by the major HLA-DQB1, -DRB1 disease loci Hum. Mol. Genet., April 1, 2001; 10(8): 881 - 889. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
International Molecular Genetic Study of Autism Co Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q Hum. Mol. Genet., April 1, 2001; 10(9): 973 - 982. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Zavattari, R. Lampis, A. Mulargia, M. Loddo, E. Angius, J. A. Todd, and F. Cucca Confirmation of the DRB1-DQB1 loci as the major component of IDDM1 in the isolated founder population of Sardinia Hum. Mol. Genet., December 1, 2000; 9(20): 2967 - 2972. [Abstract] [Full Text] [PDF]
|
|