遗传 ›› 2016, Vol. 38 ›› Issue (6): 543-559.doi: 10.16288/j.yczz.16-091

• 研究报告 • 上一篇    下一篇

2型糖尿病易感候选基因在世界不同人群中的多样性比较分析

弓弦1,2,张超2,3,伊利亚斯·艾萨1,时瑛4,杨雪唯1,努尔斯曼古丽奥斯曼1,关亚群1,徐书华2,3,5,6   

  1. 1. 新疆医科大学基础医学院生物化学与分子生物学教研室,乌鲁木齐830000;
    2. 中科院−马普学会计算生物学伙伴研究所,中国科学院计算生物学重点实验室,上海200031;
    3. 中国科学院大学,北京100049; 
    4. 新疆医科大学第一附属医院医学检验中心,乌鲁木齐830000; 
    5. 上海科技大学生命科学与技术学院,上海201210; 
    6. 遗传与发育协同创新中心,上海200438
  • 收稿日期:2016-03-16 修回日期:2016-04-21 出版日期:2016-06-20 发布日期:2016-05-31
  • 通讯作者: 徐书华,研究员,研究方向:群体基因组学。E-mail:xushua@picb.ac.cn 关亚群,教授,研究方向:肥胖及 2 型糖尿病。E-mail:yaqunguan@163.com
  • 作者简介:弓弦,硕士研究生,专业方向:2 型糖尿病群体遗传学。E-mail:gongxian1989@foxmail.com
  • 基金资助:
    国家自然科学基金项目(编号:91331204, 31260263)资助

A comparative analysis of genetic diversity of candidate genes associated with type 2 diabetes in worldwide populations

Xian Gong 1,2, Chao Zhang 2,3, Aisa Yiliyasi 1, Ying Shi 4, Xuewei Yang 1, Aosiman Nuersimanguli 1, Yaqun Guan 1, Shuhua Xu 2,3,5,6   

  1. 1. Department of Biochemistry, Preclinical Medicine College, Xinjiang Medical University, Urumqi 830000, China; 
    2. Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Max Planck Independent Research Group on Population Genomics, CAS-MPG Partner Institute for Computational Biology (PICB), Shanghai Institutes for Biological Sciences, CAS, Shanghai 200031, China; 
    3. University of Chinese Academy of Sciences, Beijing 100049, China; 
    4. Clinical laboratory of The First Affiliated Hospital, Xinjiang Medical University, Urumqi 830000, China; 
    5. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; 
    6. Collaborative Innovation Center of Genetics and Development, Shanghai 200438, China
  • Received:2016-03-16 Revised:2016-04-21 Online:2016-06-20 Published:2016-05-31
  • Supported by:
    Supported by the National Natural Science Foundation of China (Nos. 91331204, 31260263)

摘要: 近10年来兴起的全基因组关联分析(Genome-wide association study, GWAS)相关研究结果获得了大量与2型糖尿病相关的候选易感基因,了解这些候选基因在正常人群中的遗传多样性程度以及在不同人群间的遗传差异,不但有助于阐明2型糖尿病的遗传机理,而且对于今后在特定人群中进行2型糖尿病发病机制的深入研究具有指导意义。本研究通过对GWAS数据库和相关文献的搜索和整理确定了170个与2型糖尿病相关的基因或基因区域;随后基于千人基因组计划的全基因组测序数据对这些候选基因在世界范围内14个人群间的遗传多样性进行了比较分析;进一步确定了在人群间存在显著差异的易感基因,并分析了这些基因的多样性特征。在所研究的14个世界人群中,2型糖尿病候选易感基因的遗传多样性与基因组范围的平均水平没有显著差异;但其中8个易感基因IL20RA、RNMTL1-NXN、NOTCH2、ADRA2A-BTBD7P2、TBC1D4、RBM38-HMGB1P1、UBE2E2和PPARD在群体间呈现显著差异,其中最明显的是IL20RA基因 (FST=0.152),该易感基因在非洲人群和非非洲人群间存在显著等位基因频率和单倍型频率差异。14个人群中易感基因遗传结构差异的主要原因是由于非洲人群与非非洲人群之间的群体遗传结构的不同所造成的。进一步比较东西方人群间的2型糖尿病候选基因遗传结构差异,发现在东西方人群中同样存在明显的群体遗传结构差别,其中DGKB-AGMO(FST=0.173)和JAZF1(FST=0.182)是差异最显著的易感基因。本研究通过对群体间2型糖尿病易感基因遗传结构进行比较,鉴别出一些差异特别显著的易感基因,对今后2型糖尿病易感基因与不同人群间发病率和易感性差异的相关研究提供重要参考。

关键词: 2型糖尿病, 易感基因, 遗传多样性, 单核苷酸多态性, 世界人群

Abstract: Over the last decade, a larger number of type 2 diabetes mellitus (T2DM) susceptible candidate genes have been reported by numerous genome-wide association studies (GWAS). Understanding the genetic diversity of these candidate genes among worldwide populations not only facilitates to elucidating the genetic mechanism of T2DM, but also provides guidance to further studies of pathogenesis of T2DM in any certain population. In this study, we identified 170 genes or genomic regions associated with T2DM by searching the GWAS databases and related literatures. We next analyzed the genetic diversity of these genes (or genomic regions) among present-day human populations by curetting the 1000 Genomes Projects phase1 dataset covering 14 worldwide populations. We further compared the characteristics of T2DM genes in different populations. No significant differences of genetic diversity were observed among the 14 worldwide populations between the T2DM candidate genes and the non-T2DM genes in terms of overall pattern. However, we observed some genes, such as IL20RA, RNMTL1-NXN, NOTCH2, ADRA2A-BTBD7P2, TBC1D4, RBM38-HMGB1P1, UBE2E2, and PPARD, show considerable differentiation between populations. In particular, IL20RA (FST=0.1521) displays the greatest population difference which is mainly contributed by that between Africans and non-Africans. Moreover, we revealed genetic differences between East Asians and Europeans on some candidate genes such as DGKB-AGMO (FST=0.173) and JAZF1 (FST=0.182). Our results indicate that some T2DM susceptible candidate genes harbor highly-differentiated variants between populations. These analyses, despite preliminary, should advance our understanding of the population difference of susceptibility to T2DM and provide insightful reference that future studies can relay on.

Key words: Type 2 diabetes mellitus, Candidate Gene, Genetic diversity, Single nucleotide polymorphism, Worldwide populations