A systems genetics approach identifies genes and pathways for type 2 diabetes in human islets
Research output: Contribution to journal › Journal article › Research › peer-review
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 HbA(1c). 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 HbA(1c) 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.
Original language | English |
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Journal | Cell Metabolism |
Volume | 16 |
Issue number | 1 |
Pages (from-to) | 122-34 |
Number of pages | 13 |
ISSN | 1550-4131 |
DOIs | |
Publication status | Published - 3 Jul 2012 |
- Aged, Animals, Case-Control Studies, Cell Line, Diabetes Mellitus, Type 2, Female, Gene Expression Profiling, Gene Regulatory Networks, Genome-Wide Association Study, Humans, Insulin, Islets of Langerhans, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Protein Interaction Maps, Rats, Receptors, G-Protein-Coupled, Systems Biology
Research areas
ID: 46404026