title: A systems genetics approach identifies genes and pathways for type 2 diabetes in human islets.
abstract: 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.
authors: Lund University Diabetes Center, Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital Malmö, Lund University, Malmö 20502, Sweden. jalal.taneera@med.lu.se
authors: Jalal
authors: J
authors: Taneera
authors: Stefan
authors: S
authors: Lang
authors: Amitabh
authors: A
authors: Sharma
authors: Joao
authors: J
authors: Fadista
authors: Yuedan
authors: Y
authors: Zhou
authors: Emma
authors: E
authors: Ahlqvist
authors: Anna
authors: A
authors: Jonsson
authors: Valeriya
authors: V
authors: Lyssenko
authors: Petter
authors: P
authors: Vikman
authors: Ola
authors: O
authors: Hansson
authors: Hemang
authors: H
authors: Parikh
authors: Olle
authors: O
authors: Korsgren
authors: Arvind
authors: A
authors: Soni
authors: Ulrika
authors: U
authors: Krus
authors: Enming
authors: E
authors: Zhang
authors: Xing-Jun
authors: XJ
authors: Jing
authors: Jonathan L S
authors: JL
authors: Esguerra
authors: Claes B
authors: CB
authors: Wollheim
authors: Albert
authors: A
authors: Salehi
authors: Anders
authors: A
authors: Rosengren
authors: Erik
authors: E
authors: Renström
authors: Leif
authors: L
authors: Groop
mesh_terms: D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D060066:Protein Interaction Maps / Q000235:genetics*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D049490:Systems Biology
chemical_list: C519853:FFAR4 protein, human; D007328:Insulin; D043562:Receptors, G-Protein-Coupled