Genome-Wide Linkage Analysis of Type 2 Diabetes-Related Quantitative Traits in the FUSION Study. R.M. Watanabe1, C.D. Langefeld1, M. Epstein1, T. Valle1, S. Ghosh1, F.S. Collins1, R.N. Bergman4, M. Boehnke1, The FUSION Study Investigators1,2,3,4. 1) Dept. of Biostatistics, Univ. of Michigan School of Public Health, Ann Arbor, MI; 2) National Public Health Institutes, Helsinki, Finland; 3) National Human Genome Research Insititute, Bethesda, MD; 4) Dept. of Physiology & Biophysics, Univ. of Southern California, Los Angeles, CA.
The FUSION study is an effort to positionally clone genes for type 2 diabetes and related quantitative traits in a Finnish cohort. We sampled 580 families with type 2 diabetes (1240 affected subjects, 2095 total subjects) ascertained through affected sibling pairs, and have genotyped these subjects for >400 genetic markers spaced ~10 cM apart throughout the genome. Quantitative trait locus (QTL) linkage analysis was performed using variance components (VC) analysis of intact families using the program USERFQTL which combines elements of SIBLINK for identity-by-descent estimation in relative pairs and FISHER for VC estimation. We analyzed body mass index (BMI), waist-to-hip ratio (WHR), fasting and 2-hour glucose (GLU) and insulin (INS), fasting C-peptide, minimal model-derived measures of glucose effectiveness and insulin resistance, and acute insulin response (AIR) after adjusting for age and gender. Analyses were also done with and without additional adjustment for BMI or WHR, due to the known relationship between adiposity and type 2 diabetes. Affected (AFF) and unaffected (UAF) individuals were analyzed independently, because disease status may differentially affect trait values. Also, unaffected offspring (OFF) were analyzed as an additional "at-risk" group. Our most interesting results to date include: AIR on chr. 10 (UAF, LOD=3.11, distance from pter d=21 cM), fasting INS on chr. 14 (AFF, LOD=2.67, d=102 cM), fasting GLU on chr. 14 (OFF, LOD=2.66, d=23 cM), 2-hour GLU on chr. 20 (OFF, LOD=2.11, d=9.5 cM). These initial results provide evidence for several quantitative trait loci along the genome. In addition, because these traits are closely related to type 2 diabetes, these QTL linkage results may provide information regarding the location of type 2 diabetes susceptibility loci.