1. ¹General Medicine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
2. ²Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA
3. ³Diabetes Unit, Department of Medicine and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
4. ⁴Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

Correspondence: James B. Meigs (jmeigs@partners.org)

Received 8 January 2008; Accepted 23 April 2008; Published online 24 July 2008.

Abstract

Phenotypic heterogeneity complicates detection of genomic loci predisposing to type 2 diabetes, potentially obscuring or unmasking specific loci. We conducted ordered–subsets linkage analyses (OSAs) for diabetes-related quantitative traits (fasting insulin and glucose, hemoglobin A1c (HbA1c), and 28-year-time-averaged fasting plasma glucose (FPG)) from 330 families of the Framingham Offspring Study. We calculated mean BMI, waist circumference (WC), and a diabetes "age-of-onset score" for each family. We constructed subsets by adding one family at a time in increasing (lean family to obese) or decreasing (obese to lean) adiposity order, or increasing or decreasing propensity to develop diabetes at a younger age, with the OSA LOD reported as the maximum LOD observed in any subset. Permutation P values tested the hypothesis that phenotypic ordering showed stronger linkage than random ordering. On chromosome 1, ordering by increasing family mean WC increased linkage to time-averaged FPG at 256 cM from LOD = 2.4 to 3.5 (permuted P = 0.02) and to HbA1c at 180 cM from LOD = 2.0 to 3.3 (P = 0.01). On chromosome 19, ordering by decreasing WC increased linkage to fasting insulin at 68 cM from LOD = 2.7 to 4.6 (P = 0.002), and ordering by decreasing propensity to develop diabetes at a young age increased linkage to fasting insulin at 73 cM from LOD = 2.7 to 4.0 (P = 0.046). We conclude that chromosomes 1 and 19 could harbor adiposity-interacting diabetes susceptibility genes. Such interactions might also influence trait–locus associations and may be useful to consider in diabetes genome-wide association studies.