title: Linkage and association mapping of the LRP5 locus on chromosome 11q13 in type 1 diabetes.
abstract: Linkage of chromosome 11q13 to type 1 diabetes (T1D) was first reported from genome scans (Davies et al. 1994; Hashimoto et al. 1994) resulting in P <2.2 x 10(-5) (Luo et al. 1996) and designated IDDM4 ( insulin dependent diabetes mellitus 4). Association mapping under the linkage peak using 12 polymorphic microsatellite markers suggested some evidence of association with a two-marker haplotype, D11S1917*03-H0570POLYA*02, which was under-transmitted to affected siblings and over-transmitted to unaffected siblings ( P=1.5 x 10(-6)) (Nakagawa et al. 1998). Others have reported evidence for T1D association of the microsatellite marker D11S987, which is approximately 100 kb proximal to D11S1917 (Eckenrode et al. 2000). We have sequenced a 400-kb interval surrounding these loci and identified four genes, including the low-density lipoprotein receptor related protein (LRP5) gene, which has been considered as a functional candidate gene for T1D (Hey et al. 1998; Twells et al. 2001). Consequently, we have developed a comprehensive SNP map of the LRP5 gene region, and identified 95 SNPs encompassing 269 kb of genomic DNA, characterised the LD in the region and haplotypes (Twells et al. 2003). Here, we present our refined linkage curve of the IDDM4 region, comprising 32 microsatellite markers and 12 SNPs, providing a peak MLS=2.58, P=5 x 10(-4), at LRP5 g.17646G>T. The disease association data, largely focused in the LRP5 region with 1,106 T1D families, provided no further evidence for disease association at LRP5 or at D11S987. A second dataset, comprising 1,569 families from Finland, failed to replicate our previous findings at LRP5. The continued search for the variants of the putative IDDM4 locus will greatly benefit from the future development of a haplotype map of the genome.
authors.affiliation: Department of Medical Genetics, JDRF/WT Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge CB2 2XY, UK. rebecca.twells@cimr.cam.ac.uk
authors.forename: Rebecca C J
authors.initials: RC
authors.lastname: Twells
authors.forename: Charles A
authors.initials: CA
authors.lastname: Mein
authors.forename: Felicity
authors.initials: F
authors.lastname: Payne
authors.forename: Riitta
authors.initials: R
authors.lastname: Veijola
authors.forename: Matthew
authors.initials: M
authors.lastname: Gilbey
authors.forename: Matthew
authors.initials: M
authors.lastname: Bright
authors.forename: Andrew
authors.initials: A
authors.lastname: Timms
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Hywel
authors.initials: H
authors.lastname: Snook
authors.forename: Sarah
authors.initials: S
authors.lastname: Nutland
authors.forename: Helen E
authors.initials: HE
authors.lastname: Rance
authors.forename: Philippa
authors.initials: P
authors.lastname: Carr
authors.forename: Frank
authors.initials: F
authors.lastname: Dudbridge
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Cordell
authors.forename: Jason
authors.initials: J
authors.lastname: Cooper
authors.forename: Eva
authors.initials: E
authors.lastname: Tuomilehto-Wolf
authors.forename: Jaakko
authors.initials: J
authors.lastname: Tuomilehto
authors.forename: Michael
authors.initials: M
authors.lastname: Phillips
authors.forename: Michael
authors.initials: M
authors.lastname: Metzker
authors.forename: J Fred
authors.initials: JF
authors.lastname: Hess
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
mesh_terms: D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D018895:Microsatellite Repeats; D011973:Receptors, LDL / Q000235:genetics*
chemical_list: D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D011973:Receptors, LDL