A Dense (1 Million SNP) Genome-Wide Association Study in Pima Indians

皮马印第安人密集（100 万个 SNP）全基因组关联研究

• 批准号: 8553602
• 负责人: Leslie J Baier
• 金额: $ 39.23万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8553602
• 关键词: Acute; Affect; Age; Age of Onset; American Indians; BRD2 gene; Body fat; Body mass index; Data; Diabetes Mellitus; Disease; Ethnic group; Euglycemic Clamping; Family; Genes; Genetic; Genotype; Glucose; Glucose Clamp; High Prevalence; Insulin; Intravenous Bolus; Maps; Measures; Native Americans; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Phase; Phenotype; Pima Indian; Population; Predisposition; Sampling; Siblings; Signal Transduction; Techniques; Technology; Variant; case control; design; diabetic; early onset; genome wide association study; genome-wide; high throughput technology; non-diabetic; population based; response; trait

We completed genotyping subjects with both the Affymetrix 100,000 SNP chip and the 1 million SNP chip technologies. Phase 1 was designed to detect potential associations with young-onset type 2 diabetes, by genotyping 300 early-onset type 2 diabetes subjects (onset age<25 yrs) and 329 non-diabetic controls (age >45 yrs), and 271 additional subjects who were diabetic and non-diabetic siblings of the selected subjects. Associations with diabetes were calculated using both a case/control analysis (N= 629) and a within-family analysis (482 siblings from 169 sibships), and SNPs that had the strongest association for the combined associations were prioritized. Phase 2 of the GWA was designed to detect associations with pre-diabetic traits (% body fat, insulin action as measured by the hyperinsulinemic euglycemic clamp technique, and the acute insulin response to an intravenous bolus of glucose). Six hundred non-diabetic subjects who had been metabolically phenotyped for these predictors of diabetes were genotyped. Measures of BMI were available on all samples from Phase 1 and Phase 2. SNPs that provided the best associations for diabetes and/or a pre-diabetic trait (including BMI) were selected for additional genotyping in a population-based sample of 3501 full-heritage Pima Indians. This genotyping utilized a new high throughput technology (Bead Express). We recently completed genotyping the best signals from our genome-wide association analysis in a sample of 3501 full hertiage Pima Indians and are currently replicating the best SNPs from this sample in a second population-based sample of 3784 mixed heritage Native Americans. To date the strongest assocations in the combined samples for diabetes are with SNPs in DNER (P= 1 x 10-8) and with KCNQ1 (P= 5 x 10-9). The strongest associations in the combined samples for BMI are with SNPs in BRD2, HEATR5B, UBE2E, GSTA5, NOVA1, FTO, MAP2K3, and CYB5A (all P between 10-6 and 10-7). Studies are ongoing to identify the casual variant that underlies each of these associations.

我们使用Affyss 100，000 SNP芯片和100万SNP芯片技术完成了受试者的基因分型。第1阶段旨在检测与早发性2型糖尿病的潜在关联，通过对300名早发性2型糖尿病受试者（发病年龄<25岁）和329名非糖尿病对照者（年龄>45岁）以及271名其他受试者进行基因分型，这些受试者是所选受试者的糖尿病和非糖尿病同胞。使用病例/对照分析（N= 629）和家族内分析（来自169个兄弟姐妹的482个兄弟姐妹）计算与糖尿病的关联，并优先考虑与组合关联最强的SNP。GWA的第2阶段旨在检测与糖尿病前期特征（%体脂、通过高胰岛素正葡萄糖钳夹技术测量的胰岛素作用以及对静脉推注葡萄糖的急性胰岛素反应）的相关性。对600名非糖尿病受试者进行了这些糖尿病预测因子的代谢表型分型。可获得I期和II期所有样本的BMI测量值。选择与糖尿病和/或糖尿病前期性状（包括BMI）相关性最好的SNP，在3501名全遗传皮马印第安人的人群样本中进行额外的基因分型。该基因分型利用了新的高通量技术（Bead Express）。我们最近完成了基因分型的最佳信号，从我们的全基因组关联分析在3501个完整的遗传皮马印第安人的样本，目前正在复制最好的SNP从这个样本中的第二个人口为基础的样本3784混合遗产美洲原住民。迄今为止，糖尿病合并样本中最强的关联是DNER（P= 1 x 10-8）和KCNQ 1（P= 5 x 10-9）中的SNP。在合并样本中，BMI与BRD 2、HEATR 5 B、UBE 2 E、GSTA 5、NOVA 1、FTO、MAP 2K 3和CYB 5A中的SNP的关联最强（所有P值均在10-6和10-7之间）。目前正在进行研究，以确定这些关联背后的因果变量。