Although linkages to various chromosomal regions have been reported for these disorders in the general population, further studies will be necessary to identify the causal genes ( 3– 5). Although the genes for uncommon monogenic forms of obesity, insulin resistance/diabetes, hypertension, and dyslipidemia have been identified, these gene variants do not account for most of the heritability of these conditions in the general population. Familial aggregation, adoption, twin, and segregation analysis studies all indicate that the component disorders of Syndrome X are highly heritable with substantial genetic effects, interacting with environmental factors, leading to the development of disease. In aggregate, these disorders represent major causes of morbidity and mortality in industrialized countries and are growing problems in the developing world ( 2). The metabolic syndrome (also known as Syndrome X) includes central obesity, insulin resistance, hypertension, and dyslipidemia, all of which are risk factors for diabetes and vascular heart disease ( 1). These results also lay the foundation for whole genome scans with dense sets of SNPs aimed to identifying causal genes. These studies add information about the genetics of the metabolic syndrome and establish an analytical approach for linkage analysis of complex pedigrees. Several of these same chromosomal regions have been identified in previous studies validating the use of loki. 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. Robust quantitative trait loci for height were found on 10q21 and 1p31. A protocol using loki, a Markov chain Monte Carlo sampling method, was developed to analyze the Kosraen pedigree for height, a model quantitative trait.
DNA samples from 2,188 participants were genotyped with 405 microsatellite markers with an average intermarker distance of 11 cM. Analysis of the pedigree showed highly significant heritability for the metabolic traits under study. Family history and genetic data were used to construct a pedigree for the island. To map the causal genes, we conducted a population screen for these conditions on the Pacific Island of Kosrae. 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.
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