Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus

Anubha Mahajan, Xueling Sim, Hui Jin Ng, Alisa Manning, Manuel A. Rivas, Heather M. Highland, Adam E. Locke, Niels Grarup, Hae Kyung Im, Pablo Cingolani, Jason Flannick, Pierre Fontanillas, Christian Fuchsberger, Kyle J. Gaulton, Tanya M. Teslovich, N. William Rayner, Neil R. Robertson, Nicola L. Beer, Jana K. Rundle, Jette Bork-Jensen & 31 others Claes Ladenvall, Christine Blancher, David Buck, Gemma Buck, Noël P. Burtt, Stacey Gabriel, Anette P. Gjesing, Christopher J. Groves, Mette Hollensted, Jeroen R. Huyghe, Anne U. Jackson, Goo Jun, Johanne Marie Justesen, Massimo Mangino, Jacquelyn Murphy, Matt Neville, Robert Onofrio, Kerrin S. Small, Heather M. Stringham, Ann-Christine Syvänen, Joseph Trakalo, Goncalo Abecasis, Graeme I. Bell, John Blangero, Nancy J. Cox, Ravindranath Duggirala, Craig L. Hanis, Alex S. F. Doney, Andrew D. Morris, Colin N. A. Palmer, On Behalf of the T2D-GENES consortium and GoT2D consortium

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    Abstract

    Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.

    Original languageEnglish
    Article numbere1004876
    Number of pages25
    JournalPLoS Genetics
    Volume11
    Issue number1
    DOIs
    Publication statusPublished - 27 Jan 2015

    Fingerprint

    Genome-Wide Association Study
    genome
    fasting
    allele
    glucose
    loci
    Exome
    Glucose
    Fasting
    diabetes
    noninsulin-dependent diabetes mellitus
    Gene Frequency
    Type 2 Diabetes Mellitus
    gene frequency
    insulin
    Alleles
    Insulin
    alleles
    gene
    genetic variance

    Cite this

    Mahajan, A., Sim, X., Ng, H. J., Manning, A., Rivas, M. A., Highland, H. M., ... On Behalf of the T2D-GENES consortium and GoT2D consortium (2015). Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus. PLoS Genetics, 11(1), [e1004876]. https://doi.org/10.1371/journal.pgen.1004876
    Mahajan, Anubha ; Sim, Xueling ; Ng, Hui Jin ; Manning, Alisa ; Rivas, Manuel A. ; Highland, Heather M. ; Locke, Adam E. ; Grarup, Niels ; Im, Hae Kyung ; Cingolani, Pablo ; Flannick, Jason ; Fontanillas, Pierre ; Fuchsberger, Christian ; Gaulton, Kyle J. ; Teslovich, Tanya M. ; Rayner, N. William ; Robertson, Neil R. ; Beer, Nicola L. ; Rundle, Jana K. ; Bork-Jensen, Jette ; Ladenvall, Claes ; Blancher, Christine ; Buck, David ; Buck, Gemma ; Burtt, Noël P. ; Gabriel, Stacey ; Gjesing, Anette P. ; Groves, Christopher J. ; Hollensted, Mette ; Huyghe, Jeroen R. ; Jackson, Anne U. ; Jun, Goo ; Justesen, Johanne Marie ; Mangino, Massimo ; Murphy, Jacquelyn ; Neville, Matt ; Onofrio, Robert ; Small, Kerrin S. ; Stringham, Heather M. ; Syvänen, Ann-Christine ; Trakalo, Joseph ; Abecasis, Goncalo ; Bell, Graeme I. ; Blangero, John ; Cox, Nancy J. ; Duggirala, Ravindranath ; Hanis, Craig L. ; Doney, Alex S. F. ; Morris, Andrew D. ; Palmer, Colin N. A. ; On Behalf of the T2D-GENES consortium and GoT2D consortium. / Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus. In: PLoS Genetics. 2015 ; Vol. 11, No. 1.
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    title = "Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus",
    abstract = "Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8{\%} and 1.2{\%} of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5{\%}) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1{\%}) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.",
    author = "Anubha Mahajan and Xueling Sim and Ng, {Hui Jin} and Alisa Manning and Rivas, {Manuel A.} and Highland, {Heather M.} and Locke, {Adam E.} and Niels Grarup and Im, {Hae Kyung} and Pablo Cingolani and Jason Flannick and Pierre Fontanillas and Christian Fuchsberger and Gaulton, {Kyle J.} and Teslovich, {Tanya M.} and Rayner, {N. William} and Robertson, {Neil R.} and Beer, {Nicola L.} and Rundle, {Jana K.} and Jette Bork-Jensen and Claes Ladenvall and Christine Blancher and David Buck and Gemma Buck and Burtt, {No{\"e}l P.} and Stacey Gabriel and Gjesing, {Anette P.} and Groves, {Christopher J.} and Mette Hollensted and Huyghe, {Jeroen R.} and Jackson, {Anne U.} and Goo Jun and Justesen, {Johanne Marie} and Massimo Mangino and Jacquelyn Murphy and Matt Neville and Robert Onofrio and Small, {Kerrin S.} and Stringham, {Heather M.} and Ann-Christine Syv{\"a}nen and Joseph Trakalo and Goncalo Abecasis and Bell, {Graeme I.} and John Blangero and Cox, {Nancy J.} and Ravindranath Duggirala and Hanis, {Craig L.} and Doney, {Alex S. F.} and Morris, {Andrew D.} and Palmer, {Colin N. A.} and {On Behalf of the T2D-GENES consortium and GoT2D consortium}",
    year = "2015",
    month = "1",
    day = "27",
    doi = "10.1371/journal.pgen.1004876",
    language = "English",
    volume = "11",
    journal = "PLoS Genetics",
    issn = "1553-7390",
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    Mahajan, A, Sim, X, Ng, HJ, Manning, A, Rivas, MA, Highland, HM, Locke, AE, Grarup, N, Im, HK, Cingolani, P, Flannick, J, Fontanillas, P, Fuchsberger, C, Gaulton, KJ, Teslovich, TM, Rayner, NW, Robertson, NR, Beer, NL, Rundle, JK, Bork-Jensen, J, Ladenvall, C, Blancher, C, Buck, D, Buck, G, Burtt, NP, Gabriel, S, Gjesing, AP, Groves, CJ, Hollensted, M, Huyghe, JR, Jackson, AU, Jun, G, Justesen, JM, Mangino, M, Murphy, J, Neville, M, Onofrio, R, Small, KS, Stringham, HM, Syvänen, A-C, Trakalo, J, Abecasis, G, Bell, GI, Blangero, J, Cox, NJ, Duggirala, R, Hanis, CL, Doney, ASF, Morris, AD, Palmer, CNA & On Behalf of the T2D-GENES consortium and GoT2D consortium 2015, 'Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus', PLoS Genetics, vol. 11, no. 1, e1004876. https://doi.org/10.1371/journal.pgen.1004876

    Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus. / Mahajan, Anubha; Sim, Xueling; Ng, Hui Jin; Manning, Alisa; Rivas, Manuel A.; Highland, Heather M.; Locke, Adam E.; Grarup, Niels; Im, Hae Kyung; Cingolani, Pablo; Flannick, Jason; Fontanillas, Pierre; Fuchsberger, Christian; Gaulton, Kyle J.; Teslovich, Tanya M.; Rayner, N. William; Robertson, Neil R.; Beer, Nicola L.; Rundle, Jana K.; Bork-Jensen, Jette; Ladenvall, Claes; Blancher, Christine; Buck, David; Buck, Gemma; Burtt, Noël P.; Gabriel, Stacey; Gjesing, Anette P.; Groves, Christopher J.; Hollensted, Mette; Huyghe, Jeroen R.; Jackson, Anne U.; Jun, Goo; Justesen, Johanne Marie; Mangino, Massimo; Murphy, Jacquelyn; Neville, Matt; Onofrio, Robert; Small, Kerrin S.; Stringham, Heather M.; Syvänen, Ann-Christine; Trakalo, Joseph; Abecasis, Goncalo; Bell, Graeme I.; Blangero, John; Cox, Nancy J.; Duggirala, Ravindranath; Hanis, Craig L.; Doney, Alex S. F. ; Morris, Andrew D.; Palmer, Colin N. A.; On Behalf of the T2D-GENES consortium and GoT2D consortium.

    In: PLoS Genetics, Vol. 11, No. 1, e1004876, 27.01.2015.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus

    AU - Mahajan, Anubha

    AU - Sim, Xueling

    AU - Ng, Hui Jin

    AU - Manning, Alisa

    AU - Rivas, Manuel A.

    AU - Highland, Heather M.

    AU - Locke, Adam E.

    AU - Grarup, Niels

    AU - Im, Hae Kyung

    AU - Cingolani, Pablo

    AU - Flannick, Jason

    AU - Fontanillas, Pierre

    AU - Fuchsberger, Christian

    AU - Gaulton, Kyle J.

    AU - Teslovich, Tanya M.

    AU - Rayner, N. William

    AU - Robertson, Neil R.

    AU - Beer, Nicola L.

    AU - Rundle, Jana K.

    AU - Bork-Jensen, Jette

    AU - Ladenvall, Claes

    AU - Blancher, Christine

    AU - Buck, David

    AU - Buck, Gemma

    AU - Burtt, Noël P.

    AU - Gabriel, Stacey

    AU - Gjesing, Anette P.

    AU - Groves, Christopher J.

    AU - Hollensted, Mette

    AU - Huyghe, Jeroen R.

    AU - Jackson, Anne U.

    AU - Jun, Goo

    AU - Justesen, Johanne Marie

    AU - Mangino, Massimo

    AU - Murphy, Jacquelyn

    AU - Neville, Matt

    AU - Onofrio, Robert

    AU - Small, Kerrin S.

    AU - Stringham, Heather M.

    AU - Syvänen, Ann-Christine

    AU - Trakalo, Joseph

    AU - Abecasis, Goncalo

    AU - Bell, Graeme I.

    AU - Blangero, John

    AU - Cox, Nancy J.

    AU - Duggirala, Ravindranath

    AU - Hanis, Craig L.

    AU - Doney, Alex S. F.

    AU - Morris, Andrew D.

    AU - Palmer, Colin N. A.

    AU - On Behalf of the T2D-GENES consortium and GoT2D consortium

    PY - 2015/1/27

    Y1 - 2015/1/27

    N2 - Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.

    AB - Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.

    U2 - 10.1371/journal.pgen.1004876

    DO - 10.1371/journal.pgen.1004876

    M3 - Article

    VL - 11

    JO - PLoS Genetics

    JF - PLoS Genetics

    SN - 1553-7390

    IS - 1

    M1 - e1004876

    ER -