Genetic analysis of type II diabetes in Finnish population

2型糖尿病（T2 D）是发达国家发病率和死亡率的主要原因之一。虽然环境因素如饮食起着重要作用，但家族聚集性表明一定有重要的遗传易感性因素在起作用。15年来，我们一直在进行一项名为FUSION（芬兰-美国NIDDM调查）的大型合作研究，其中对来自芬兰的10，000多名糖尿病患者（和合适的对照组）进行了研究，使用糖尿病和糖尿病相关数量性状的仔细表型分析以及全基因组遗传连锁和关联。世界各地的几个合作者现在也提供了大量的其他样品。我们已经在实验室开发和应用了新的高通量基因分型方法，从而可以从这些芬兰糖尿病患者及其家庭收集大量数据。使用全基因组关联研究（GWAS）方法，我们现在已经鉴定了不少于32个T2 D基因座，并鉴定了对肥胖、空腹血糖、LDL和HDL胆固醇、甘油三酯、血压和成人身高有重要影响的其他基因座变异。我们现在正在研究由这些变异中的几种引起的疾病风险的功能基础，包括TCF 7 L2，SLC 30 A8，CDKN 2A/B，IGF 2BP 2，HMGCR和GCKR。该分析包括对这些基因座进行高通量测序以鉴定可能驱动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测定。有了这种实质性的进展，我们相信遗传学家的噩梦（Jim Neel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.