Mohlke Karen L, Boehnke Michael
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA and
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
Hum Mol Genet. 2015 Oct 15;24(R1):R85-92. doi: 10.1093/hmg/ddv264. Epub 2015 Jul 9.
Genome-wide association (GWAS) and sequencing studies are providing new insights into the genetic basis of type 2 diabetes (T2D) and the inter-individual variation in glycemic traits, including levels of glucose, insulin, proinsulin and hemoglobin A1c (HbA1c). At the end of 2011, established loci (P < 5 × 10(-8)) totaled 55 for T2D and 32 for glycemic traits. Since then, most new loci have been detected by analyzing common [minor allele frequency (MAF)>0.05] variants in increasingly large sample sizes from populations around the world, and in trans-ancestry studies that successfully combine data from diverse populations. Most recently, advances in sequencing have led to the discovery of four loci for T2D or glycemic traits based on low-frequency (0.005 < MAF ≤ 0.05) variants, and additional low-frequency, potentially functional variants have been identified at GWAS loci. Established published loci now total ∼88 for T2D and 83 for one or more glycemic traits, and many additional loci likely remain to be discovered. Future studies will build on these successes by identifying additional loci and by determining the pathogenic effects of the underlying variants and genes.
全基因组关联(GWAS)研究和测序研究正在为2型糖尿病(T2D)的遗传基础以及血糖性状的个体间差异提供新的见解,这些血糖性状包括葡萄糖、胰岛素、胰岛素原和糖化血红蛋白A1c(HbA1c)的水平。截至2011年底,已确定的T2D相关位点(P < 5 × 10(-8))共有55个,血糖性状相关位点共有32个。从那时起,大多数新位点是通过分析来自世界各地人群的越来越大样本量中的常见[次要等位基因频率(MAF)>0.05]变异,以及通过成功整合不同人群数据的跨祖先研究发现的。最近,测序技术的进步使得基于低频(0.005 < MAF ≤ 0.05)变异发现了4个T2D或血糖性状相关位点,并且在GWAS位点还鉴定出了其他低频的、可能具有功能的变异。目前已发表的确定位点中,T2D相关位点约有88个,一种或多种血糖性状相关位点有83个,可能还有许多其他位点有待发现。未来的研究将基于这些成果,通过识别更多位点以及确定潜在变异和基因的致病作用来继续推进。