Ordered stratification to reduce heterogeneity in linkage to diabetes-related quantitative traits.
Ordered stratification to reduce heterogeneity in linkage to diabetes-related quantitative traits.
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DOI：
10.1038/oby.2008.354
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发表时间：
2008-10
期刊：
影响因子：
--
通讯作者：
Cupples LA
中科院分区：
文献类型：
--
作者：
Meigs JB;Manning AK;Dupuis J;Liu C;Florez JC;Cupples LA
Phenotypic heterogeneity complicates detection of genomic loci predisposing to type 2 diabetes, potentially obscuring or unmasking specific loci. We conducted ordered subsets linkage analyses (OSA) for diabetes-related quantitative traits (fasting insulin and glucose, HbA1c and 28-year time averaged fasting plasma glucose (tFPG)) from 330 families of the Framingham Offspring Study. We calculated mean body mass index (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 tFPG 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.
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