Linkage analysis of quantitative traits for obesity, diabetes, hypertension, and dyslipidemia on the island of Kosrae, Federated States of Micronesia

Abstract

Obesity, diabetes, hypertension, and heart disease are highly heritable conditions that in aggregate are the major causes of morbidity and mortality in the developed world and are growing problems in developing countries. To map the causal genes, we conducted a population screen for these conditions on the Pacific Island of Kosrae. Family history and genetic data were used to construct a pedigree for the island. Analysis of the pedigree showed highly significant heritability for the metabolic traits under study. DNA samples from 2,188 participants were genotyped with 405 microsatellite markers with an average intermarker distance of 11 cM. A protocol using loki, a Markov chain Monte Carlo sampling method, was developed to analyze the Kosraen pedigree for height, a model quantitative trait. Robust quantitative trait loci for height were found on 10q21 and 1p31. This protocol was used to map a set of metabolic traits, including plasma leptin to chromosome region 5q35; systolic blood pressure to 20p12; total cholesterol to 19p13, 12q24, and 16qter; hip circumference to 10q25 and 4q23; body mass index to 18p11 and 20q13; apolipoprotein B to 2p24-25; weight to 18q21; and fasting blood sugar to 1q31-1q43. Several of these same chromosomal regions have been identified in previous studies validating the use of loki. These studies add information about the genetics of the metabolic syndrome and establish an analytical approach for linkage analysis of complex pedigrees. These results also lay the foundation for whole genome scans with dense sets of SNPs aimed to identifying causal genes.

Fig. 1.

HT loci. L-scores are on the y axis; cM (Marshfield) and markers are on the x axis. Model.HT_A (in blue), HT corrected for environmental covariates (gender, parity, smoking, and age) and LEP; Model.HT_A (no LEP) (in black), same corrections as Model.HT_A but not LEP; Model.HT_B (in red), HT corrected for environmental covariates and WT, HIP, WST, LEP, FBS, SBP, DBP, TC, TG, and apoA-I and apoB levels. _p denotes polygenic correction and _j denotes joint chromosome analysis. (A) Chromosome 1. (B) Chromosome 10. (C) Chromosome 5. (D) Chromosome 19. (E) Chromosome 15.

Fig. 2.

Selected QTLs for metabolic traits. L-scores are on the y axis; cM (Marshfield) and markers are on the x axis. _p denotes polygenic correction, and _j denotes joint chromosome analysis. Repeat refers to the same analysis repeated. (A) BMI on chromosome 18, using BMI_B, corrected for gender, parity, smoking, village, and age, and the other quantitative traits. (B) LEP on chromosome 5. Three models for LEP, all corrected for gender, smoking, village, and age, were used. Additional corrections for MAP and WT (blue), HT and MAP (red), and MAP (black), were made. (C) SBP on chromosome 20. SBP is corrected for gender, parity, smoking, village, and age. MAP is corrected for gender, parity, smoking, village, age, WST, and LE. (D) TC on chromosome 19. TC is corrected for gender, parity, village, age, and the other quantitative traits.