Genome-wide association and meta-analysis in populations from Starr County, Texas, and Mexico City identify type 2 diabetes susceptibility loci and enrichment for expression quantitative trait loci in top signals.
Genome-wide association and meta-analysis in populations from Starr County, Texas, and Mexico City identify type 2 diabetes susceptibility loci and enrichment for expression quantitative trait loci in top signals.
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DOI：
10.1007/s00125-011-2188-3
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发表时间：
2011-08
期刊：
影响因子：
8.2
通讯作者：
Hanis, C. L.
中科院分区：
文献类型：
--
作者：
Below, J. E.;Gamazon, E. R.;Morrison, J. V.;Konkashbaev, A.;Pluzhnikov, A.;McKeigue, P. M.;Parra, E. J.;Elbein, S. C.;Hallman, D. M.;Nicolae, D. L.;Bell, G. I.;Cruz, M.;Cox, N. J.;Hanis, C. L.
关键词：
我们进行了全基因组关联研究（GWAS）和表达数量性状基因座（eQTL）分析，以识别和描述美国得克萨斯州斯塔尔县墨西哥裔美国人2型糖尿病的风险基因座。
我们在837例无关的2型糖尿病患者和436例血糖正常的对照者中使用了180万个直接检测和推算的基因型，进行了阿米蒂奇趋势检验。为了提高在这种高疾病发病率人群中的检验效能，我们还进行了有序回归分析，其中包括一个具有空腹血糖受损和/或葡萄糖耐量异常的中间类别。这些分析之后，我们与来自墨西哥墨西哥城的967例2型糖尿病患者和343例血糖正常的对照者的一项研究进行了荟萃分析。
最强信号（未调整的P值<1×10⁻⁵）包括8个基因区域（PER3、PARD3B、EPHA4、TOMM7、PTPRD、HNT[也称为RREB1]、LOC729993和IL34）中的49个单核苷酸多态性（SNP）以及6个基因间区域。其中包括时钟基因PER3中的一个错义多态性（rs10462020；Gly639Val），时钟基因是一个近期被认为与糖尿病有关的系统。我们还报告了在汉族人群中PTPRD内的第二个信号（最小P值为1.52×10⁻⁶），它独立于先前涉及的SNP。主要的荟萃分析信号包括已知区域HNF1A和KCNQ1。两项研究中主要关联信号的注释显示，在脂肪和肌肉组织中反式作用eQTL显著过多。
在迄今为止针对墨西哥人群2型糖尿病的最大规模研究中，我们发现了新的和先前报道的SNP的适度关联。此外，在我们的主要信号中，我们报告了显著过多的可预测肌肉和脂肪组织中转录水平的SNP。
We conducted genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) analyses to identify and characterise risk loci for type 2 diabetes in Mexican-Americans from Starr County, TX, USA. Using 1.8 million directly interrogated and imputed genotypes in 837 unrelated type 2 diabetes cases and 436 normoglycaemic controls, we conducted Armitage trend tests. To improve power in this population with high disease rates, we also performed ordinal regression including an intermediate class with impaired fasting glucose and/or glucose tolerance. These analyses were followed by meta-analysis with a study of 967 type 2 diabetes cases and 343 normoglycaemic controls from Mexico City, Mexico. The top signals (unadjusted p value <1×10−5) included 49 single nucleotide polymorphisms (SNPs) in eight gene regions (PER3, PARD3B, EPHA4, TOMM7, PTPRD, HNT [also known as RREB1], LOC729993 and IL34) and six intergenic regions. Among these was a missense polymorphism (rs10462020; Gly639Val) in the clock gene PER3, a system recently implicated in diabetes. We also report a second signal (minimum p value 1.52× 10−6) within PTPRD, independent of the previously implicated SNP, in a population of Han Chinese. Top meta-analysis signals included known regions HNF1A and KCNQ1. Annotation of top association signals in both studies revealed a marked excess of trans-acting eQTL in both adipose and muscle tissues. In the largest study of type 2 diabetes in Mexican populations to date, we identified modest associations of novel and previously reported SNPs. In addition, in our top signals we report significant excess of SNPs that predict transcript levels in muscle and adipose tissues.
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