Computational analyses of type 2 diabetes-associated loci identified by genome-wide association studies.
BACKGROUND
Genome-wide association studies (GWAS) of type 2 diabetes (T2D) have discovered a number of loci that contribute to susceptibility to the disease. Future challenges include elucidation of functional mechanisms through which these GWAS-identified loci modulate T2D disease risk. The aim of the present study was to comprehensively characterize T2D associated single nucleotide polymorphisms (SNPs) and genes through computational approaches.


METHODS
Computational biology approaches used in the present study included comparative genomic analyses and functional annotation using GWAS3D and RegulomeDB, investigation of the effects of T2D-associated SNPs on miRNA binding and protein phosphorylation, and gene ontology, pathway enrichment, protein-protein interaction (PPI) networks and functional module analysis of T2D-associated genes from previously published GWAS.


RESULTS
Computational analysis identified a number of T2D GWAS-associated SNPs that were located at protein binding sites, including CCCTC-binding factor (CTCF), E1A binding protein p300 (EP300), hepatocyte nuclear factor 4alpha (HNF4A), transcription factor 7 like 2 (TCF7L2), forkhead box A1 (FOXA1) and A2 (FOXA2), and potentially affected the binding of miRNAs and protein phosphorylation. Pathway enrichment analysis confirmed two well-known maturity onset diabetes of the young and T2D pathways, whereas PPI network analysis identified highly interconnected "hub" genes, such as TCF7L2, melatonin receptor 1B (MTNR1B), and solute carrier family 30 (zinc transporter), member 8 (SLC30A8), that created two tight subnetworks.


CONCLUSIONS
The results provide objectives and clues for future experimental studies and further insights into the molecular pathogenesis of T2D.
College of Life Sciences, Central China Normal University, Wuhan, China.
Mengrong
M
Cheng
College of Life Sciences, Central China Normal University, Wuhan, China.
Xinhong
X
Liu
College of Life Sciences, Central China Normal University, Wuhan, China.
Mei
M
Yang
College of Life Sciences, Central China Normal University, Wuhan, China.|Institute of Public Health and Molecular Medicine Analysis, Central China Normal University, Wuhan, China.
Lanchun
L
Han
Li Cha Chung Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Aimin
A
Xu
College of Life Sciences, Central China Normal University, Wuhan, China.|Institute of Public Health and Molecular Medicine Analysis, Central China Normal University, Wuhan, China.
Qingyang
Q
Huang
D000076246:CCCTC-Binding Factor; D019295:Computational Biology / Q000379:methods*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008957:Models, Genetic; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D060066:Protein Interaction Maps / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; C496499:FOXA1 protein, human; C496502:FOXA2 protein, human; C496592:HNF4A protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D051557:Hepatocyte Nuclear Factor 4; D035683:MicroRNAs; D012097:Repressor Proteins; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051542:Hepatocyte Nuclear Factor 3-beta; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human
2型糖尿病; computational biology; genome-wide association studies; single nucleotide polymorphisms; type 2 diabetes; “hub” genes; 全基因组关联研究; 关键节点基因; 单核苷酸多态性; 计算生物学