Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study

Valborg Gudmundsdottir, Helle Krogh Pedersen, Karla Viviani Allebrandt, Caroline Anna Brorsson, Nienke van Leeuwen, Karina Banasik, Anubha Mahajan, Christopher J Groves, Martijn van de Bunt, Adem Y Dawed, Andreas Fritsche, Harald Staiger, Annemarie M C Simonis-Bik, Joris Deelen, Mark H H Kramer, Axel Dietrich, Thomas Hübschle, Gonneke Willemsen, Hans-Ulrich Häring, Eco J C de GeusDorret I Boomsma, Elisabeth M W Eekhoff, Jorge Ferrer, Mark I McCarthy, Ewan R Pearson, Ramneek Gupta, Søren Brunak, Leen M 't Hart*

*Corresponding author for this work

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    Abstract

    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.
    Original languageEnglish
    Article numbere0189886
    JournalP L o S One
    Volume13
    Issue number1
    Number of pages12
    ISSN1932-6203
    DOIs
    Publication statusPublished - 2018

    Cite this

    Gudmundsdottir, Valborg ; Pedersen, Helle Krogh ; Allebrandt, Karla Viviani ; Brorsson, Caroline Anna ; van Leeuwen, Nienke ; Banasik, Karina ; Mahajan, Anubha ; Groves, Christopher J ; van de Bunt, Martijn ; Dawed, Adem Y ; Fritsche, Andreas ; Staiger, Harald ; Simonis-Bik, Annemarie M C ; Deelen, Joris ; Kramer, Mark H H ; Dietrich, Axel ; Hübschle, Thomas ; Willemsen, Gonneke ; Häring, Hans-Ulrich ; de Geus, Eco J C ; Boomsma, Dorret I ; Eekhoff, Elisabeth M W ; Ferrer, Jorge ; McCarthy, Mark I ; Pearson, Ewan R ; Gupta, Ramneek ; Brunak, Søren ; 't Hart, Leen M. / Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study. In: P L o S One. 2018 ; Vol. 13, No. 1.
    @article{25f85a124b3649c5b903a9a96f18e66b,
    title = "Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study",
    abstract = "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 T{\"u}bingen, 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.",
    author = "Valborg Gudmundsdottir and Pedersen, {Helle Krogh} and Allebrandt, {Karla Viviani} and Brorsson, {Caroline Anna} and {van Leeuwen}, Nienke and Karina Banasik and Anubha Mahajan and Groves, {Christopher J} and {van de Bunt}, Martijn and Dawed, {Adem Y} and Andreas Fritsche and Harald Staiger and Simonis-Bik, {Annemarie M C} and Joris Deelen and Kramer, {Mark H H} and Axel Dietrich and Thomas H{\"u}bschle and Gonneke Willemsen and Hans-Ulrich H{\"a}ring and {de Geus}, {Eco J C} and Boomsma, {Dorret I} and Eekhoff, {Elisabeth M W} and Jorge Ferrer and McCarthy, {Mark I} and Pearson, {Ewan R} and Ramneek Gupta and S{\o}ren Brunak and {'t Hart}, {Leen M}",
    year = "2018",
    doi = "10.1371/journal.pone.0189886",
    language = "English",
    volume = "13",
    journal = "P L o S One",
    issn = "1932-6203",
    publisher = "Public Library of Science",
    number = "1",

    }

    Gudmundsdottir, V, Pedersen, HK, Allebrandt, KV, Brorsson, CA, van Leeuwen, N, Banasik, K, Mahajan, A, Groves, CJ, van de Bunt, M, Dawed, AY, Fritsche, A, Staiger, H, Simonis-Bik, AMC, Deelen, J, Kramer, MHH, Dietrich, A, Hübschle, T, Willemsen, G, Häring, H-U, de Geus, EJC, Boomsma, DI, Eekhoff, EMW, Ferrer, J, McCarthy, MI, Pearson, ER, Gupta, R, Brunak, S & 't Hart, LM 2018, 'Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study', P L o S One, vol. 13, no. 1, e0189886. https://doi.org/10.1371/journal.pone.0189886

    Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study. / Gudmundsdottir, Valborg; Pedersen, Helle Krogh; Allebrandt, Karla Viviani; Brorsson, Caroline Anna; van Leeuwen, Nienke; Banasik, Karina; Mahajan, Anubha; Groves, Christopher J; van de Bunt, Martijn; Dawed, Adem Y; Fritsche, Andreas; Staiger, Harald; Simonis-Bik, Annemarie M C; Deelen, Joris; Kramer, Mark H H; Dietrich, Axel; Hübschle, Thomas; Willemsen, Gonneke; Häring, Hans-Ulrich; de Geus, Eco J C; Boomsma, Dorret I; Eekhoff, Elisabeth M W; Ferrer, Jorge; McCarthy, Mark I; Pearson, Ewan R; Gupta, Ramneek; Brunak, Søren; 't Hart, Leen M.

    In: P L o S One, Vol. 13, No. 1, e0189886, 2018.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study

    AU - Gudmundsdottir, Valborg

    AU - Pedersen, Helle Krogh

    AU - Allebrandt, Karla Viviani

    AU - Brorsson, Caroline Anna

    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

    PY - 2018

    Y1 - 2018

    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.

    U2 - 10.1371/journal.pone.0189886

    DO - 10.1371/journal.pone.0189886

    M3 - Journal article

    C2 - 29293525

    VL - 13

    JO - P L o S One

    JF - P L o S One

    SN - 1932-6203

    IS - 1

    M1 - e0189886

    ER -