Integrating Genetic Association, Genetics of Gene Expression, and Single Nucleotide Polymorphism Set Analysis to Identify Susceptibility Loci for Type 2 Diabetes Mellitus
Integrating Genetic Association, Genetics of Gene Expression, and Single Nucleotide Polymorphism Set Analysis to Identify Susceptibility Loci for Type 2 Diabetes Mellitus
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DOI：
10.1093/aje/kws123
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发表时间：
2012-09-01
影响因子：
5
通讯作者：
Hu, Frank B.
中科院分区：
文献类型：
--
作者：
Greenawalt, Danielle M.;Sieberts, Solveig K.;Hu, Frank B.
大规模的全基因组关联研究（GWAS）已经确定了40多个与2型糖尿病显著相关的基因组区域。然而，GWAS的结果并不总是简单的解释，并且在没有广泛的随访研究的情况下，将这些位点与有意义的疾病病因联系起来通常是困难的。作者通过整合表达单核苷酸多态性（SNP）信息并应用SNP集富集分析来鉴定与基因相关的SNP集，从而扩展了先前报道的2型糖尿病GWAS，这些研究来自2个前瞻性美国队列的巢式病例对照研究，这些SNP集可以为传统的全基因组分析提供进一步的生物学见解。利用1989年至1994年在这些先前研究中收集的数据形成巢式病例对照研究，作者发现在他们的研究中与2型糖尿病最显著相关的3个SNP是淋巴细胞抗原75基因（LY75）、泛素特异性肽酶36基因（USP 36）和磷脂酰肌醇转移蛋白的表达SNP，胞质1基因（PITPNC 1）。GWAS结果的SNP集富集分析鉴定了对巨噬细胞富集模块和基因本体（GO）生物过程脂肪细胞分化人的表达SNP的富集，其包括转录因子7样2基因（TCF7L2）以及其他2型糖尿病相关基因。整合全基因组关联、基因表达和基因集分析可能为潜在的2型糖尿病易感基因位点提供有价值的生物学支持，并可能有助于确定治疗和预防2型糖尿病的新靶点或新途径。
Large-scale genome-wide association studies (GWAS) have identified over 40 genomic regions significantly associated with type 2 diabetes mellitus. However, GWAS results are not always straightforward to interpret, and linking these loci to meaningful disease etiology is often difficult without extensive follow-up studies. The authors expanded on previously reported type 2 diabetes mellitus GWAS from the nested case-control studies of 2 prospective US cohorts by incorporating expression single nucleotide polymorphism (SNP) information and applying SNP set enrichment analysis to identify sets of SNPs associated with genes that could provide further biologic insight to traditional genome-wide analysis. Using data collected between 1989 and 1994 in these previous studies to form a nested case-control study, the authors found that 3 of the most significantly associated SNPs to type 2 diabetes mellitus in their study are expression SNPs to the lymphocyte antigen 75 gene (LY75), the ubiquitin-specific peptidase 36 gene (USP36), and the phosphatidylinositol transfer protein, cytoplasmic 1 gene (PITPNC1). SNP set enrichment analysis of the GWAS results identified enrichment for expression SNPs to the macrophage-enriched module and the Gene Ontology (GO) biologic process fat cell differentiation human, which includes the transcription factor 7-like 2 gene (TCF7L2), as well as other type 2 diabetes mellitus-associated genes. Integrating genome-wide association, gene expression, and gene set analysis may provide valuable biologic support for potential type 2 diabetes mellitus susceptibility loci and may be useful in identifying new targets or pathways of interest for the treatment and prevention of type 2 diabetes mellitus.