A Quantitative Trait Locus Influencing Type 2 Diabetes Susceptibility Maps to a Region on 5q in an Extended French Family

Abstract

Type 2 diabetes is a heterogeneous disorder of glucose metabolism characterized by insulin resistance, β-cell dysfunction, and increased glucose production by the liver. Given the high degree of genetic heterogeneity, multiple genes with small to moderate effects may influence susceptibility to diabetes. To circumvent this limitation, we searched for quantitative trait loci (QTLs) that explain the variation in susceptibility of type 2 diabetes in a single extended family, as these individuals are likely to share polymorphisms. We collected genotypic and phenotypic data on 152 individuals ascertained through a multimedia campaign in France to find diabetes-prone families for genetic studies. The effects of genes and covariates (age and sex) on diabetes status were estimated using a threshold model and a maximum likelihood variance component approach. We obtained suggestive evidence of linkage (logarithm of odds [LOD] = 2.4) for diabetes status on chromosome 5q. Within the 1-LOD unit support interval, there are two strong candidates: PCSK1 and CAST. Furthermore, we have obtained a replication (LOD = 1.6) for a QTL for type 2 diabetes on chromosome 11 detected by Hanson and colleagues (1998).