Linkage and Association With Type 1 Diabetes on Chromosome 1q42
- Kathryn G. Ewens1,
- Lindsey N. Johnson23,
- Beth Wapelhorst23,
- Kristin O’Brien1,
- Sarah Gutin1,
- V. Anne Morrison23,
- Craig Street1,
- Simon G. Gregory4,
- Richard S. Spielman1 and
- Patrick Concannon23
- 1Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
- 2Molecular Genetics Program, Virginia Mason Research Center, Seattle, Washington
- 3Department of Immunology, University of Washington School of Medicine, Seattle, Washington
- 4The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, U.K.
Abstract
Type 1 diabetes is a complex disorder with multiple genetic loci and environmental factors contributing to disease etiology. In the current study, a human type 1 diabetes candidate region on chromosome 1q42 was mapped at high marker density in a panel of 616 multiplex type 1 diabetic families. To facilitate the identification and evaluation of candidate genes, a physical map of the 7-cM region surrounding the maximum logarithm of odds (LOD) score (2.46, P = 0.0004) was constructed. Genes were identified in the 500-kb region surrounding the marker yielding the peak LOD score and evaluated for polymorphism by resequencing. Single-nucleotide polymorphisms (SNPs) identified in these genes as well as other anonymous markers were tested for allelic association with type 1 diabetes by both family-based and case-control methods. A haplotype formed by common alleles at three adjacent markers (D1S225, D1S2383, and D1S251) was preferentially transmitted to affected offspring in type 1 diabetic families (nominal P = 0.006). These findings extend the evidence supporting the existence of a type 1 diabetes susceptibility locus on chromosome 1q42 and identify a candidate region amenable to positional cloning efforts.
Footnotes
-
Address correspondence and reprint requests to Patrick Concannon, Molecular Genetics Program, Virginia Mason Research Center, 1201 Ninth Ave., Seattle, WA 98101. E-mail: patcon{at}vmresearch.org; or Richard Spielman, Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. E-mail: spielman{at}pobox.upenn.edu.
Received for publication 5 April 2002 and accepted in revised form 9 July 2002.
C.S. is employed by Merck Pharmaceuticals.
ASP, affected sib pair; BAC, bacterial artificial chromosome; LOD, logarithm of odds; PAC, P1 artificial chromosome; RPCI, Roswell Park Cancer Institute; SNP, single-nucleotide polymorphism; STS, sequence-tagged site; TDT, transmission/disequilibrium test.
- DIABETES
