Shmulewitz Dvora, Heath Simon C, Blundell Maude L, Han Zhihua, Sharma Ratnendra, Salit Jacqueline, Auerbach Steven B, Signorini Stefano, Breslow Jan L, Stoffel Markus, Friedman Jeffrey M
Department of Biostatistics, Columbia University, New York, NY 10032, USA.
Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3502-9. doi: 10.1073/pnas.0510156103. Epub 2006 Feb 28.
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.
肥胖、糖尿病、高血压和心脏病都是高度可遗传的疾病，这些疾病加在一起是发达国家发病和死亡的主要原因，并且在发展中国家也日益成为问题。为了绘制致病基因图谱，我们在太平洋科斯雷岛上对这些疾病进行了群体筛查。利用家族史和基因数据构建了该岛的谱系。对谱系的分析表明，所研究的代谢性状具有高度显著的遗传性。对2188名参与者的DNA样本进行了基因分型，使用了405个微卫星标记，平均标记间距为11厘摩。开发了一种使用马尔可夫链蒙特卡罗抽样方法loki的方案，用于分析科斯雷岛人的身高这一典型数量性状的谱系。在10q21和1p31上发现了与身高相关的稳健数量性状位点。该方案被用于绘制一组代谢性状图谱，包括血浆瘦素定位于染色体区域5q35；收缩压定位于20p12；总胆固醇定位于19p13、12q24和16qter；臀围定位于10q25和4q23；体重指数定位于18p11和20q13；载脂蛋白B定位于2p24 - 25；体重定位于18q21；空腹血糖定位于1q31 - 1q43。在之前的研究中已经鉴定出其中几个相同的染色体区域，这验证了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。这些结果也为使用密集单核苷酸多态性（SNP）进行全基因组扫描以识别致病基因奠定了基础。
