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.

译文

:肥胖,糖尿病,高血压和心脏病是高度可遗传的疾病,总体而言,它们是发达国家发病率和死亡率的主要原因,也是发展中国家日益严重的问题。为了绘制致病基因,我们对科斯雷太平洋岛上的这些条件进行了种群筛选。家族史和遗传数据被用来构建该岛的血统书。家谱分析表明,所研究的代谢性状具有极高的遗传力。来自2188名参与者的DNA样品用405个微卫星标记进行基因分型,平均标记间距离为11 cM。已开发出使用loki(马尔可夫链蒙特卡洛采样方法)的协议来分析Kosraen谱系的身高(一种模型定量特征)。在10q21和1p31处发现了高度的稳健的数量性状基因座。该方案用于绘制一组代谢特征,包括血浆瘦素到染色体5q35区域。收缩压至20p12;总胆固醇达到19p13、12q24和16qter;臀围至10q25和4q23;体重指数分别为18p11和20q13;载脂蛋白B至2p24-25;权重为18q21;空腹血糖至1q31-1q43。在以前的研究中已经鉴定出了这些相同的染色体区域中的几个,从而验证了loki的使用。这些研究增加了有关代谢综合征遗传学的信息,并建立了一种用于复杂谱系连锁分析的分析方法。这些结果也为使用全基因组SNPs进行全基因组扫描奠定了基础,这些SNPs旨在鉴定致病基因。

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