Supporting Online Material Materials and Methods Figs. S1 to S8 Tables S1 to S10 References a Genome-wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants-猫眼课题宝

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S. Thomas;L. Scott;K. Mohlke;L. Bonnycastle;C. Willer;Yun Li;W. Duren;M. Erdos;H. Stringham

确定增加人类2型糖尿病（T2 D）风险的遗传变异一直是一个艰巨的挑战。采用全基因组关联策略，我们对1161例芬兰T2 D病例和1174例芬兰正常葡萄糖耐量（NGT）对照进行了基因分型，其中单核苷酸多态性（SNP）> 315，000，并对额外的> 200万常染色体SNP进行了基因型估算。我们对这些SNP进行了关联分析，以确定易患T2 D的遗传变异，将我们的T2 D关联结果与两项类似研究的结果进行了比较，并对另外1215例芬兰T2 D病例和1258例芬兰NGT对照中的80个SNP进行了基因分型。我们在染色体11 p12的基因间区域中鉴定了T2 D相关变异，有助于鉴定IGF 2BP 2和CDKAL 1基因附近以及CDKN 2A和CDKN 2B区域附近的T2 D相关变异，并确认TCF 7 L2，SLC 30 A8，HHEX，FTO，PPARG和KCNJ 11附近的变异与T2 D风险相关。这使得现在确信鉴定的T2 D基因座的数量达到至少10个。2型糖尿病（T2 D）是一种以胰岛素抵抗和胰腺β细胞功能受损为特征的疾病，影响全球超过1.7亿人（1）。与一般中年人群相比，一级亲属的风险约为3.5倍（2），遗传因素以及生活方式和行为因素在确定T2 D风险方面起着重要作用（3）。到目前为止，在T2 D中识别遗传风险因素的密集努力只取得有限的成功。本研究、我们的合作者的报告（4-6）以及Sladek等人最近发表的工作（7）描述了全基因组关联（GWA）研究的结果，这些研究进一步定义了T2 D的遗传结构，并确定了T2 D发病机制中涉及的生物学途径。具有≥10个拷贝的较不常见等位基因[次要等位基因频率（MAF）> 0.002]，并通过质量控制标准（8）。我们使用对数优势量表上的加性模型（表1和表S3和S4）（8）测试了这315，635个SNP与T2 D的相关性。我们观察到SNP的适度过量（观察到41个，预期为31.6个; P = 0.19），P值< 10 −4（图S1）。这些结果反对存在对T2 D疾病风险有很大影响的多种常见SNP，但与存在各自赋予适度风险的多种常见SNP一致。结果还表明，病例和对照组的出生省份，性别和年龄（8）匹配是成功的，在…

Identifying the genetic variants that increase the risk of type 2 diabetes (T2D) in humans has been a formidable challenge. Adopting a genome-wide association strategy, we genotyped 1161 Finnish T2D cases and 1174 Finnish normal glucose-tolerant (NGT) controls with >315,000 single-nucleotide polymorphisms (SNPs) and imputed genotypes for an additional >2 million autosomal SNPs. We carried out association analysis with these SNPs to identify genetic variants that predispose to T2D, compared our T2D association results with the results of two similar studies, and genotyped 80 SNPs in an additional 1215 Finnish T2D cases and 1258 Finnish NGT controls. We identify T2D-associated variants in an intergenic region of chromosome 11p12, contribute to the identification of T2D-associated variants near the genes IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings the number of T2D loci now confidently identified to at least 10. T ype 2 diabetes (T2D) is a disease characterized by insulin resistance and impaired pancreatic beta-cell function that affects >170 million people worldwide (1). With first-degree relatives having ~3.5 times as much risk as compared to individuals in the general middle-aged population (2), hereditary factors, together with lifestyle and behavioral factors, play an important role in determining T2D risk (3). To date, intense efforts to identify genetic risk factors in T2D have met with only limited success. This study, reports from our collaborators (4–6), and the recently published work of Sladek et al. (7) describe results of genome-wide association (GWA) studies that further define the genetic architecture of T2D and identify biological pathways involved in T2D pathogenesis. had ≥10 copies of the less common allele [minor allele frequency (MAF) > 0.002] and passed quality-control criteria (8). We tested these 315,635 SNPs for association with T2D using a model that is additive on the log-odds scale (Table 1 and tables S3 and S4) (8). We observed a modest excess (41 observed versus 31.6 expected; P = 0.19) of SNPs with P values < 10 −4 (fig. S1). These results argue against the existence of multiple common SNPs with a large impact on T2D disease risk but are consistent with the presence of multiple common SNPs that each confer modest risk. The results also suggest that the matching of cases and controls by birth province, sex, and age (8) has been successful; in …

Supporting Online Material Materials and Methods Figs. S1 to S8 Tables S1 to S10 References a Genome-wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants

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