TY - JOUR
T1 - Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion
T2 - A DIRECT study
AU - Gudmundsdottir, Valborg
AU - Pedersen, Helle Krogh
AU - Allebrandt, Karla Viviani
AU - Brorsson, Caroline
AU - van Leeuwen, Nienke
AU - Banasik, Karina
AU - Mahajan, Anubha
AU - Groves, Christopher J.
AU - van de Bunt, Martijn
AU - Dawed, Adem Y.
AU - Fritsche, Andreas
AU - Staiger, Harald
AU - Simonis-Bik, Annemarie M. C.
AU - Deelen, Joris
AU - Kramer, Mark H. H.
AU - Dietrich, Axel
AU - Hübschle, Thomas
AU - Willemsen, Gonneke
AU - Häring, Hans-Ulrich
AU - de Geus, Eco J. C.
AU - Boomsma, Dorret I.
AU - Eekhoff, Elisabeth M. W.
AU - Ferrer, Jorge
AU - McCarthy, Mark I.
AU - Pearson, Ewan R.
AU - Gupta, Ramneek
AU - Brunak, Søren
AU - 't Hart, Leen M.
N1 - The work leading to this publication has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. Sanofi (an EFPIA member) provided support in the form of salaries for authors [KA, TH, and AD] and funding of the experimentation conducted in mice. Beyond the contribution of these authors, Sanofi did not have any additional role in the study design, data collection and analysis that pertain to this manuscript, as well as on the decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. The study received funding from the Netherlands Organization for Health Research and Development (Priority Medicines Elderly Program 113102006); by BBMRI-NL, a Research Infrastructure financed by the Dutch government (NWO 184.021.007). The Netherlands Twin Register acknowledges funding from the Netherlands Organization for Scientific Research (NWO: Netherlands Twin Registry Repository: researching the interplay between genome and environment). The department of internal medicine section Endocrinology and Diabetic Center VUmc acknowledges funding from ZonMw.
PY - 2018/1/2
Y1 - 2018/1/2
N2 - Glucagon-like peptide 1 (GLP-1) stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS) of GLP-1 stimulated insulin secretion in non-diabetic individuals from the Netherlands Twin register (n = 126). This GWAS was enhanced using a tissue-specific protein-protein interaction network approach. We identified a beta-cell protein-protein interaction module that was significantly enriched for low gene scores based on the GWAS P-values and found support at the network level in an independent cohort from Tübingen, Germany (n = 100). Additionally, a polygenic risk score based on SNPs prioritized from the network was associated (P < 0.05) with glucose-stimulated insulin secretion phenotypes in up to 5,318 individuals in MAGIC cohorts. The network contains both known and novel genes in the context of insulin secretion and is enriched for members of the focal adhesion, extracellular-matrix receptor interaction, actin cytoskeleton regulation, Rap1 and PI3K-Akt signaling pathways. Adipose tissue is, like the beta-cell, one of the target tissues of GLP-1 and we thus hypothesized that similar networks might be functional in both tissues. In order to verify peripheral effects of GLP-1 stimulation, we compared the transcriptome profiling of ob/ob mice treated with liraglutide, a clinically used GLP-1 receptor agonist, versus baseline controls. Some of the upstream regulators of differentially expressed genes in the white adipose tissue of ob/ob mice were also detected in the human beta-cell network of genes associated with GLP-1 stimulated insulin secretion. The findings provide biological insight into the mechanisms through which the effects of GLP-1 may be modulated and highlight a potential role of the beta-cell expressed genes RYR2, GDI2, KIAA0232, COL4A1 and COL4A2 in GLP-1 stimulated insulin secretion.
AB - Glucagon-like peptide 1 (GLP-1) stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS) of GLP-1 stimulated insulin secretion in non-diabetic individuals from the Netherlands Twin register (n = 126). This GWAS was enhanced using a tissue-specific protein-protein interaction network approach. We identified a beta-cell protein-protein interaction module that was significantly enriched for low gene scores based on the GWAS P-values and found support at the network level in an independent cohort from Tübingen, Germany (n = 100). Additionally, a polygenic risk score based on SNPs prioritized from the network was associated (P < 0.05) with glucose-stimulated insulin secretion phenotypes in up to 5,318 individuals in MAGIC cohorts. The network contains both known and novel genes in the context of insulin secretion and is enriched for members of the focal adhesion, extracellular-matrix receptor interaction, actin cytoskeleton regulation, Rap1 and PI3K-Akt signaling pathways. Adipose tissue is, like the beta-cell, one of the target tissues of GLP-1 and we thus hypothesized that similar networks might be functional in both tissues. In order to verify peripheral effects of GLP-1 stimulation, we compared the transcriptome profiling of ob/ob mice treated with liraglutide, a clinically used GLP-1 receptor agonist, versus baseline controls. Some of the upstream regulators of differentially expressed genes in the white adipose tissue of ob/ob mice were also detected in the human beta-cell network of genes associated with GLP-1 stimulated insulin secretion. The findings provide biological insight into the mechanisms through which the effects of GLP-1 may be modulated and highlight a potential role of the beta-cell expressed genes RYR2, GDI2, KIAA0232, COL4A1 and COL4A2 in GLP-1 stimulated insulin secretion.
UR - http://www.scopus.com/inward/record.url?scp=85039965996&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0189886
DO - 10.1371/journal.pone.0189886
M3 - Article
C2 - 29293525
SN - 1932-6203
VL - 13
SP - 1
EP - 19
JO - PLoS ONE
JF - PLoS ONE
IS - 1
M1 - e0189886
ER -
