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Ordered Stratification to Reduce Heterogeneity in Linkage to Diabetes‐related Quantitative Traits
Author(s) -
Meigs James B.,
Manning Alisa K.,
Dupuis Josée,
Liu Chunyu,
Florez Jose C.,
Cupples L. Adrienne
Publication year - 2008
Publication title -
obesity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.438
H-Index - 199
eISSN - 1930-739X
pISSN - 1930-7381
DOI - 10.1038/oby.2008.354
Subject(s) - quantitative trait locus , diabetes mellitus , medicine , waist , genetic linkage , type 2 diabetes , locus (genetics) , endocrinology , lod score , genetics , linkage (software) , obesity , biology , chromosome , gene , gene mapping
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.