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Fine mapping of the diabetes-susceptibility locus, IDDM4, on chromosome 11q13

Nakagawa, Yusuke and Kawaguchi, Yoshihiko and Twells, Rebecca C. J. and Muxworthy, Claire E. and Hunter, Kara M. D. and Wilson, Amanda J. and Merriman, Marilyn E. and Cox, Roger D. and Merriman, Tony R. and Cucca, Francesco and McKinney, Patricia A. and Shield, Julian P. and Tuomilehto, Jaakko and Tuomilehto Wolf, Eva and Ionescu Tirgoviste, Constantin and Nisticò, Lorenza and Buzzetti, Raffaella and Pozzilli, Paolo and Joner, Geir and Thorsby, Erik and Undlien, Dag Erik and Pociot, Flemming and Nerup, Jørn and Ronningen, Kjersti Skjold and Bain, Stephen Charles and Todd, John A. (1998) Fine mapping of the diabetes-susceptibility locus, IDDM4, on chromosome 11q13. American Journal of Human Genetics, Vol. 63 (2), p. 547-556. eISSN 1537-6605. Article.

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DOI: 10.1086/301974

Abstract

Genomewide linkage studies of type 1 diabetes (or insulin-dependent diabetes mellitus [IDDM]) indicate that several unlinked susceptibility loci can explain the clustering of the disease in families. One such locus has been mapped to chromosome 11q13 (IDDM4). In the present report we have analyzed 707 affected sib pairs, obtaining a peak multipoint maximum LOD score (MLS) of 2.7 (λs = 1.09) with linkage (MLS ≥ 0.7) extending over a 15-cM region. The problem is, therefore, to fine map the locus to permit structural analysis of positional candidate genes. In a two-stage approach, we first scanned the 15-cM linked region for increased or decreased transmission, from heterozygous parents to affected siblings in 340 families, of the three most common alleles of each of 12 microsatellite loci. One of the 36 alleles showed decreased transmission (50% expected, 45.1% observed [P = .02, corrected P = .72]) at marker D11S1917. Analysis of an additional 1,702 families provided further support for negative transmission (48%) of D11S1917 allele 3 to affected offspring and positive transmission (55%) to unaffected siblings (test of heterogeneity P = 3 x 10-4, corrected P = .01]). A second polymorphic marker, H0570polyA, was isolated from a cosmid clone containing D11S1917, and genotyping of 2,042 families revealed strong linkage disequilibrium between the two markers (15 kb apart), with a specific haplotype, D11S1917*03-H0570polyA*02, showing decreased transmission (46.4%) to affected offspring and increased transmission (56.6%) to unaffected siblings (test of heterogeneity P = 1.5 x 10-6, corrected P = 4.3 x 10-4). These results not only provide sufficient justification for analysis of the gene content of the D11S1917 region for positional candidates but also show that, in the mapping of genes for common multifactorial diseases, analysis of both affected and unaffected siblings is of value and that both predisposing and nonpredisposing alleles should be anticipated.

Item Type:Article
ID Code:4242
Status:Published
Refereed:Yes
Uncontrolled Keywords:Diabetes, type 1, autoimmunity, IDDM4, complex trait(s), linkage disequilibrium, chromosome 11q13
Subjects:Area 06 - Scienze mediche > MED/03 Genetica medica
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
Publisher:Cell Press / Elsevier
eISSN:1537-6605
Copyright Holders:© 1998 by The American Society of Human Genetics
Additional Information:Fra gli autori figurano due gruppi di ricerca: San-Raffaele Family Study, Istituto Scientifico San Raffaele, Università di Milano; Bart's-Oxford Family Study Group, Department of Diabetes and Metabolism, University of Bristol.
Deposited On:23 Jul 2010 10:06

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