title: Identification of novel type 2 diabetes candidate genes involved in the crosstalk between the mitochondrial and the insulin signaling systems.
abstract: Type 2 Diabetes (T2D) is a highly prevalent chronic metabolic disease with strong co-morbidity with obesity and cardiovascular diseases. There is growing evidence supporting the notion that a crosstalk between mitochondria and the insulin signaling cascade could be involved in the etiology of T2D and insulin resistance. In this study we investigated the molecular basis of this crosstalk by using systems biology approaches. We combined, filtered, and interrogated different types of functional interaction data, such as direct protein-protein interactions, co-expression analyses, and metabolic and signaling dependencies. As a result, we constructed the mitochondria-insulin (MITIN) network, which highlights 286 genes as candidate functional linkers between these two systems. The results of internal gene expression analysis of three independent experimental models of mitochondria and insulin signaling perturbations further support the connecting roles of these genes. In addition, we further assessed whether these genes are involved in the etiology of T2D using the genome-wide association study meta-analysis from the DIAGRAM consortium, involving 8,130 T2D cases and 38,987 controls. We found modest enrichment of genes associated with T2D amongst our linker genes (p = 0.0549), including three already validated T2D SNPs and 15 additional SNPs, which, when combined, were collectively associated to increased fasting glucose levels according to MAGIC genome wide meta-analysis (p = 8.12×10(-5)). This study highlights the potential of combining systems biology, experimental, and genome-wide association data mining for identifying novel genes and related variants that increase vulnerability to complex diseases.
authors.affiliation: Joint IRB-BSC Program on Computational Biology, Barcelona Supercomputing Center, Barcelona, Catalonia, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Mercader
authors.forename: Montserrat
authors.initials: M
authors.lastname: Puiggros
authors.forename: Ayellet V
authors.initials: AV
authors.lastname: Segrè
authors.forename: Evarist
authors.initials: E
authors.lastname: Planet
authors.forename: Eleonora
authors.initials: E
authors.lastname: Sorianello
authors.forename: David
authors.initials: D
authors.lastname: Sebastian
authors.forename: Sergio
authors.initials: S
authors.lastname: Rodriguez-Cuenca
authors.forename: Vicent
authors.initials: V
authors.lastname: Ribas
authors.forename: Sílvia
authors.initials: S
authors.lastname: Bonàs-Guarch
authors.forename: Sorin
authors.initials: S
authors.lastname: Draghici
authors.forename: Chenjing
authors.initials: C
authors.lastname: Yang
authors.forename: Sílvia
authors.initials: S
authors.lastname: Mora
authors.forename: Antoni
authors.initials: A
authors.lastname: Vidal-Puig
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
authors.forename: David
authors.initials: D
authors.lastname: Torrents
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D053858:Metabolic Networks and Pathways; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D049490:Systems Biology
chemical_list: D007328:Insulin; D005947:Glucose