Genetic analysis of type II diabetes in Finnish population

2型糖尿病(T2D)是发达国家发病率和死亡率的主要原因之一。虽然饮食等环境因素起着重要作用，但家庭聚集性表明，一定有显著的遗传易感因素在起作用。15年来，我们一直在参与一项名为FUSION(芬兰-美国对NIDDM的调查)的大型合作研究，其中正在对来自芬兰的10,000多名糖尿病患者(和适当的对照)进行研究，使用糖尿病及其相关数量性状的仔细表型以及全基因组的遗传联系和关联。现在还可以从世界各地的几个合作者那里获得大量额外的样本。我们已经在实验室中开发和应用了新的高通量基因分型方法，这使得从这些芬兰糖尿病患者及其家人那里收集大量数据成为可能。利用全基因组关联研究(GWAS)的方法，我们现在已经识别了至少32个T2D基因座，并发现了其他包含变异的基因座，这些基因座对肥胖、空腹血糖、低密度脂蛋白和高密度脂蛋白、甘油三酯、血压和成人身高有重要影响。我们现在正在研究这些变异中的几个引起疾病风险的功能基础，包括TCF7L2、SLC30A8、CDKN2A/B、IGF2BP2、HMGCR和GCKR。这种分析包括对这些基因座进行高通量测序，以确定可能导致关联的常见和罕见等位基因，分析基因表达、选择性剪接、染色质结构和风险单倍型之间的关系，以及细胞培养和生化分析。有了这样的实质性进展，我们相信遗传学家的噩梦(吉姆·尼尔对糖尿病遗传学的描述)即将结束。

Type 2 diabetes (T2D) is one of the major causes of morbidity and mortality in the developed world. While environmental factors such as diet play a significant role, familial clustering indicates that there must be significant genetic susceptibility factors at work. For fifteen years we have been engaged in a large collaborative study entitled FUSION (Finland - United States Investigation of NIDDM), in which more than 10,000 individuals with diabetes (and suitable controls) from Finland are being studied, using careful phenotyping of diabetes and diabetes-associated quantitative traits, and genome-wide genetic linkage and association. Large numbers of additional samples are also now available from several collaborators around the world. We have developed and applied new high throughput genotyping approaches in the laboratory, which have allowed the collection of a massive amount of data from these Finnish diabetics and their families. Using the genome wide association study (GWAS) approach, we have now contributed to the identification of no less than 32 loci for T2D, and have identified additional loci harboring variants that have important effects on obesity, fasting glucose, LDL and HDL cholesterol, triglycerides, blood pressure, and adult height. We are now investigating the functional basis of disease risk that arises from several of these variants, including those in TCF7L2, SLC30A8, CDKN2A/B, IGF2BP2, HMGCR and GCKR. This analysis includes high throughput sequencing of these loci to identify common and rare alleles that may be driving the association, analysis of the relationship between gene expression, alternative splicing, chromatin structure, and risk haplotypes, and cell culture and biochemical assays. With this kind of substantial progress, we are confident that the geneticist's nightmare (Jim Neel's description of the genetics of diabetes) is coming to an end.