Type 2 Diabetes: Evidence for Linkage on Chromosome 20 in 716 Finnish Affected Sib Pairs

• Published in: Proceedings of the National Academy of Sciences - PNAS 1999-03, Vol.96 (5), p.2198-2203
• Main Authors: Ghosh, Soumitra, Watanabe, Richard M., Hauser, Elizabeth R., Valle, Timo, Magnuson, Victoria L., Erdos, Michael R., Langefeld, Carl D., Balow, James, Ally, Delphine S., Kohtamaki, Kimmo, Chines, Peter, Birznieks, Gunther, Kaleta, Hong-Shi, Musick, Anjene, Te, Catherine, Tannenbaum, Joyce, Eldridge, William, Shapiro, Shane, Martin, Colin, Witt, Alyson, So, Alistair, Chang, Jennie, Shurtleff, Ben, Porter, Rachel, Kudelko, Kristina, Unni, Arun, Segal, Leonid, Sharaf, Ravi, Blaschak-Harvan, Jillian, Eriksson, Johan, Tenkula, Tuula, Vidgren, Gabriele, Ehnholm, Christian, Tuomilehto-Wolf, Eva, Hagopian, William, Buchanan, Thomas A., Tuomilehto, Jaakko, Bergman, Richard N., Collins, Francis S., Boehnke, Michael
• Format: Article
• Language: English
• Subjects: Adult; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Biological Sciences; Blood Glucose - metabolism; Body mass index; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 20; Diabetes; Diabetes complications; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - genetics; DNA-Binding Proteins - genetics; Exons; Fasting; Female; Finland; Genes; Genetic Linkage; Genetic loci; Genetic Markers; Genetic Predisposition to Disease - genetics; Genetic Variation; Genetics; Glucose Tolerance Test; Hepatocyte Nuclear Factor 4; Humans; Introns; Lod score; Male; Middle Aged; Models, Genetic; Nuclear Family; Odds Ratio; Phosphoproteins - genetics; Point Mutation; Polymorphism, Single-Stranded Conformational; Quantitative traits; Sequence Deletion; Siblings; Spouses; Studies; Transcription Factors - genetics; Type 2 diabetes mellitus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.5.2198

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 = 6.95 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.