A Genome-Wide Search for Linkage-Disequilibrium With Type 1 Diabetes in a Recent Genetically Isolated Population From the Netherlands

Abstract

Type 1 diabetes has a substantial genetic component, with consistent evidence for a susceptibility locus in the HLA-DR/DQ region (chromosome 6p) and the insulin gene region (chromosome 11p). Genome scans have identified >18 other genomic regions that may harbor putative type 1 diabetes genes. However, evidence for most regions varies in different data sets. Given the genetic heterogeneity of type 1 diabetes, studies in homogeneous genetically isolated populations may be more successful in mapping susceptibility loci than in complex outbred populations. We describe a genomewide search in a recently Dutch isolated population. We identified 43 patients that could be traced back to a common ancestor within 15 generations and performed a genome-wide scan using a combined linkage-and association-based approach. In addition to the HLA locus, evidence for type 1 diabetes loci was observed on chromosome 8q24 (marker D8S1128) and on chromosome 17q24 (marker D17S2059). Both the 8q and 17q localization are supported by allele-sharing at adjacent markers in affected individuals. Statistical evidence for a conserved ancestral haplotype was found for chromosome 8q24. Diabetes 51:856 -859, 2002

Sex-specific genetic effects influence variation in body composition

“…The aim of this programme is to identify genetic risk factors in the development of complex disorders [21][22][23]. Genealogical records demonstrated that almost all of the inhabitants of this isolated population could be traced back to about 150 individuals who founded this community about the year 1750.…”

The use of pedigree, sib-pair and association studies of common diseases for genetic mapping and epidemiology

“…Genome-wide association studies to identify risk variants for common diseases have mainly been limited, to date, to recently founded population isolates, in which microsatellites detect LD over distances up to several centimorgans 90,91 . Although some remain skeptical about genome-wide LD mapping using SNPs 92 , identification of an identical asthma-associated SNP haplotype in Finland and Quebec indicates the tremendous potential of this approach, at least in population isolates 93 .…”

Quantitative Trait Loci on Chromosome 8q24 for Pancreatic β-Cell Function and 7q11 for Insulin Sensitivity in Obese Nondiabetic White and Black Families

“…Most recently, a genome-wide linkage scan of HOMA1 insulin resistance index in the HyperGEN (12) and a meta-analysis in the FBPP (13) did not reveal promising linkage evidence at this location. The region of interest in our study (chromosome 8q24) has been shown to be linked to type 2 diabetes in a U.K. population (D8S284, 143.82 cM) (29), to type 1 diabetes in a Dutch population (D8S1128, 139.53 cM) (30), to unesterified HDL cholesterol in Mexican Americans (D8S1128) (31), to LDL cholesterol and apolipoprotein B-100 in sedentary whites (D8S1774, 137.9 cM) (32), and to systolic blood pressure in sedentary blacks (D8S1179, 135.1 cM) (33). No prominent candidate genes at this locus have been proposed, but these clusters of associated linkage results across studies and populations suggest the presence of at least one QTL of relevance to phenotypes of the metabolic syndrome.…”