Ordered stratification to reduce heterogeneity in linkage to diabetes-related quantitative traits.
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.
Meigs
James B
JB
Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. jmeigs@partners.org
Manning
Alisa K
AK
Dupuis
Josée
J
Liu
Chunyu
C
Florez
Jose C
JC
Cupples
L Adrienne
LA
D017668:Age of Onset; D001786:Blood Glucose / Q000235:genetics; D015992:Body Mass Index; D049628:Body Size / Q000235:genetics; D002878:Chromosomes, Human, Pair 1; D002888:Chromosomes, Human, Pair 19; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D005838:Genotype; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics; D008126:Lod Score; D009765:Obesity / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable
D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007328:Insulin; C517652:hemoglobin A1c protein, human