Ghosh, S., et al. 1999. Proceedings of the National Academy of Science, USA 96(5):2198–2203.
We are conducting a genome scan at an average resolution of 10 centimorgans (cM) for type 2 diabetes susceptibility genes in 716 affected sib pairs from 477 Finnish families. To date, our best evidence for linkage is on chromosome 20 with potentially separable peaks located on both the long and short arms. The unweighted multipoint maximum logarithm of odds score (MLS) was 3.08 on 20p (location, x̂ = 19.5 cM) under an additive model, whereas the weighted MLS was 2.06 on 20q (x̂ = 57 cM, recurrence risk, λ̂s = 1.25, P = 0.009). Weighted logarithm of odds scores of 2.00 (x̂ = 69.5 cM, P = 0.010) and 1.92 (x̂ = 18.5 cM, P = 0.013) were also observed. Ordered subset analyses based on sibships with extreme mean values of diabetes-related quantitative traits yielded sets of families who contributed disproportionately to the peaks. Two-hour glucose levels in offspring of diabetic individuals gave a MLS of 2.12 (P = 0.0018) at 9.5 cM. Evidence from this and other studies suggests at least two diabetes-susceptibility genes on chromosome 20. We have also screened the gene for maturity-onset diabetes of the young 1, hepatic nuclear factor 4-a (HNF-4α) in 64 affected sibships with evidence for high chromosomal sharing at its location on chromosome 20q. We found no evidence that sequence changes in this gene accounted for the linkage results we observed.
Type 2 diabetes is a common multifactorial heterogeneous disease with both genetic and environmental determinants and an uncertain mode of inheritance. At least three groups have recently completed genome scans for type 2 diabetes and many are nearing completion. Hanis et al. reported genome-wide significance on chromosome 2q37 on a combined data set of 440 Mexican-American affected sib pairs (ASPs). In a sample from Botnia, Western Finland, a small number of selected pedigrees with the lowest quartile for mean 30-min insulin levels after oral glucose tolerance tests showed significant evidence for linkage to type 2 diabetes on chromosome 12q. More recently, evidence for linkage was obtained on chromosome 11q for both diabetes and body mass index (BMI) in 264 Pima Indian families.
In contrast, maturity-onset diabetes of the young (MODY) is a rare monogenic form of type 2 diabetes that has an autosomal dominant mode of inheritance. At least five different genes, located on chromosomes 20, 7, 12, 13, and 17, independently cause MODY within single pedigrees. MODY genes may also play a minor role in the common form of type 2 diabetes.
Several groups have reported modest evidence for linkage on chromosome 20 for type 2 diabetes. All of these linkage peaks cover broad regions and appear to include the MODY1 gene (hepatic nuclear factor-4a or HNF-4α). Here, we report our results from chromosome 20 as part of an ongoing genome scan in a large Finnish sample of affected sibships and extended families. Together with results from previous studies, our findings support the evidence for more than one diabetes-predisposing gene on chromosome 20. We also show that variants in the HNF-4α gene for MODY1 do not explain the suggestive logarithm of odds (lod) scores detected on chromosome 20q.