A Systems Genetics Approach Identifies Genes and Pathways for Type 2 Diabetes in Human Islets

• Published in: Cell metabolism Vol. 16; no. 1; pp. 122 - 134
• Main Authors: Taneera, Jalal, Lang, Stefan, Sharma, Amitabh, Fadista, Joao, Zhou, Yuedan, Ahlqvist, Emma, Jonsson, Anna, Lyssenko, Valeriya, Vikman, Petter, Hansson, Ola, Parikh, Hemang, Korsgren, Olle, Soni, Arvind, Krus, Ulrika, Zhang, Enming, Jing, Xing-Jun, Esguerra, Jonathan L.S., Wollheim, Claes B., Salehi, Albert, Rosengren, Anders, Renström, Erik, Groop, Leif
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.07.2012
• Subjects: Aged; Animals; Basic Medicine; Case-Control Studies; Cell and Molecular Biology; Cell Line; Cell- och molekylärbiologi; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - pathology; Female; Gene Expression Profiling; Gene Regulatory Networks; Genome-Wide Association Study; Humans; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - metabolism; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Middle Aged; Oligonucleotide Array Sequence Analysis; Polymorphism, Single Nucleotide; Protein Interaction Maps - genetics; Rats; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Systems Biology
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2012.06.006

Close to 50 genetic loci have been associated with type 2 diabetes (T2D), but they explain only 15% of the heritability. In an attempt to identify additional T2D genes, we analyzed global gene expression in human islets from 63 donors. Using 48 genes located near T2D risk variants, we identified gene coexpression and protein-protein interaction networks that were strongly associated with islet insulin secretion and HbA1c. We integrated our data to form a rank list of putative T2D genes, of which CHL1, LRFN2, RASGRP1, and PPM1K were validated in INS-1 cells to influence insulin secretion, whereas GPR120 affected apoptosis in islets. Expression variation of the top 20 genes explained 24% of the variance in HbA1c with no claim of the direction. The data present a global map of genes associated with islet dysfunction and demonstrate the value of systems genetics for the identification of genes potentially involved in T2D. ► An integrated approach identifies potential type 2 diabetes genes in human islets ► Expression of the top 20 genes explains 24% of variance in glycemia measured as HbA1c ► Silencing of CHL1, LRFN2, RASGRP1, and PPM1K influences insulin secretion ► GPR120 knockdown increases apoptosis in human islets