title: Genome-wide and fine-mapping linkage studies of type 2 diabetes and glucose traits in the Old Order Amish: evidence for a new diabetes locus on chromosome 14q11 and confirmation of a locus on chromosome 1q21-q24.
abstract: We conducted a genome scan using a 10-cM map to search for genes linked to type 2 diabetes in 691 individuals from a founder population, the Old Order Amish. We then saturated two regions on chromosomes 1 and 14 showing promising linkage signals with additional markers to produce a approximately 2-cM map for fine mapping. Analyses of both discrete traits (type 2 diabetes and the composite trait of type 2 diabetes and/or impaired glucose homeostasis [IGH]), and quantitative traits (glucose levels during a 75-g oral glucose challenge, designated glucose 0-180 and HbA(1c)) were performed. We obtained significant evidence for linkage to type 2 diabetes in a novel region on chromosome 14q11 (logarithm of odds [LOD] for diabetes = 3.48, P = 0.00005). Furthermore, we observed evidence for the existence of a diabetes-related locus on chromosome 1q21-q24 (LOD for type 2 diabetes/IGH = 2.35, P = 0.0008), a region shown to be linked to diabetes in several other studies. Suggestive evidence for linkage to glucose traits was observed on three other regions: 14q11-q13 (telomeric to that above with LOD = 1.82-1.85 for glucose 150 and 180), 1p31 (LOD = 1.28-2.30 for type 2 diabetes and glucose 120-180), and 18p (LOD = 3.07, P = 0.000085 for HbA(1c) and LOD = 1.50 for glucose 0). In conclusion, our findings provide evidence that type 2 diabetes susceptibility genes reside on chromosomes 1, 14, and 18.
authors.affiliation: Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas, USA.
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Hsueh
authors.forename: Pamela L
authors.initials: PL
authors.lastname: St  Jean
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.forename: Toni I
authors.initials: TI
authors.lastname: Pollin
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.forename: Margaret G
authors.initials: MG
authors.lastname: Ehm
authors.forename: Callum J
authors.initials: CJ
authors.lastname: Bell
authors.forename: Hakan
authors.initials: H
authors.lastname: Sakul
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wagner
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Burns
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
mesh_terms: D001786:Blood Glucose / Q000378:metabolism*; D002874:Chromosome Mapping / Q000379:methods; D002878:Chromosomes, Human, Pair 1; D002883:Chromosomes, Human, Pair 14; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D015894:Genome, Human; D006801:Humans; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D040641:Quantitative Trait Loci / Q000235:genetics; D012680:Sensitivity and Specificity; D014481:United States
chemical_list: D001786:Blood Glucose