Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus

  1. Mahajan, Anubha
  2. Sim, Xueling
  3. Ng, Hui Jin
  4. Manning, Alisa
  5. Rivas, Manuel A.
  6. Highland, Heather M.
  7. Locke, Adam E.
  8. Grarup, Niels
  9. Im, Hae Kyung
  10. Cingolani, Pablo
  11. Flannick, Jason
  12. Fontanillas, Pierre
  13. Fuchsberger, Christian
  14. Gaulton, Kyle J.
  15. Teslovich, Tanya M.
  16. Rayner, N. William
  17. Robertson, Neil R.
  18. Beer, Nicola L.
  19. Rundle, Jana K.
  20. Bork-Jensen, Jette
  21. Ladenvall, Claes
  22. Blancher, Christine
  23. Buck, David
  24. Buck, Gemma
  25. Burtt, Noël P.
  26. Gabriel, Stacey
  27. Gjesing, Anette P.
  28. Groves, Christopher J.
  29. Hollensted, Mette
  30. Huyghe, Jeroen R.
  31. Jackson, Anne U.
  32. Jun, Goo
  33. Justesen, Johanne Marie
  34. Mangino, Massimo
  35. Murphy, Jacquelyn
  36. Neville, Matt
  37. Onofrio, Robert
  38. Small, Kerrin S.
  39. Stringham, Heather M.
  40. Syvänen, Ann-Christine
  41. Trakalo, Joseph
  42. Abecasis, Goncalo
  43. Bell, Graeme I.
  44. Blangero, John
  45. Cox, Nancy J.
  46. Duggirala, Ravindranath
  47. Hanis, Craig L.
  48. Seielstad, Mark
  49. Wilson, James G.
  50. Christensen, Cramer
  51. Brandslund, Ivan
  52. Rauramaa, Rainer
  53. Surdulescu, Gabriela L.
  54. Doney, Alex S. F.
  55. Lannfelt, Lars
  56. Linneberg, Allan
  57. Isomaa, Bo
  58. Tuomi, Tiinamaija
  59. Jørgensen, Marit E.
  60. Jørgensen, Torben
  61. Kuusisto, Johanna
  62. Uusitupa, Matti
  63. Salomaa, Veikko
  64. Spector, Timothy D.
  65. Morris, Andrew D.
  66. Palmer, Colin N. A.
  67. Collins, Francis S.
  68. Mohlke, Karen L.
  69. Bergman, Richard N.
  70. Ingelsson, Erik
  71. Lind, Lars
  72. Tuomilehto, Jaakko
  73. Hansen, Torben
  74. Watanabe, Richard M.
  75. Prokopenko, Inga
  76. Dupuis, Josee
  77. Karpe, Fredrik
  78. Groop, Leif
  79. Laakso, Markku
  80. Pedersen, Oluf
  81. Florez, Jose C.
  82. Morris, Andrew P.
  83. Altshuler, David
  84. Meigs, James B.
  85. Boehnke, Michael
  86. McCarthy, Mark I.
  87. Lindgren, Cecilia M.
  88. Gloyn, Anna L.
  89. Roden, Michael
  90. T2D-GENES consortium
  91. GoT2D consortium

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Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus.pdf 3,71MB
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1000 Titel
  • Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus
1000 Autor/in
  1. Mahajan, Anubha |
  2. Sim, Xueling |
  3. Ng, Hui Jin |
  4. Manning, Alisa |
  5. Rivas, Manuel A. |
  6. Highland, Heather M. |
  7. Locke, Adam E. |
  8. Grarup, Niels |
  9. Im, Hae Kyung |
  10. Cingolani, Pablo |
  11. Flannick, Jason |
  12. Fontanillas, Pierre |
  13. Fuchsberger, Christian |
  14. Gaulton, Kyle J. |
  15. Teslovich, Tanya M. |
  16. Rayner, N. William |
  17. Robertson, Neil R. |
  18. Beer, Nicola L. |
  19. Rundle, Jana K. |
  20. Bork-Jensen, Jette |
  21. Ladenvall, Claes |
  22. Blancher, Christine |
  23. Buck, David |
  24. Buck, Gemma |
  25. Burtt, Noël P. |
  26. Gabriel, Stacey |
  27. Gjesing, Anette P. |
  28. Groves, Christopher J. |
  29. Hollensted, Mette |
  30. Huyghe, Jeroen R. |
  31. Jackson, Anne U. |
  32. Jun, Goo |
  33. Justesen, Johanne Marie |
  34. Mangino, Massimo |
  35. Murphy, Jacquelyn |
  36. Neville, Matt |
  37. Onofrio, Robert |
  38. Small, Kerrin S. |
  39. Stringham, Heather M. |
  40. Syvänen, Ann-Christine |
  41. Trakalo, Joseph |
  42. Abecasis, Goncalo |
  43. Bell, Graeme I. |
  44. Blangero, John |
  45. Cox, Nancy J. |
  46. Duggirala, Ravindranath |
  47. Hanis, Craig L. |
  48. Seielstad, Mark |
  49. Wilson, James G. |
  50. Christensen, Cramer |
  51. Brandslund, Ivan |
  52. Rauramaa, Rainer |
  53. Surdulescu, Gabriela L. |
  54. Doney, Alex S. F. |
  55. Lannfelt, Lars |
  56. Linneberg, Allan |
  57. Isomaa, Bo |
  58. Tuomi, Tiinamaija |
  59. Jørgensen, Marit E. |
  60. Jørgensen, Torben |
  61. Kuusisto, Johanna |
  62. Uusitupa, Matti |
  63. Salomaa, Veikko |
  64. Spector, Timothy D. |
  65. Morris, Andrew D. |
  66. Palmer, Colin N. A. |
  67. Collins, Francis S. |
  68. Mohlke, Karen L. |
  69. Bergman, Richard N. |
  70. Ingelsson, Erik |
  71. Lind, Lars |
  72. Tuomilehto, Jaakko |
  73. Hansen, Torben |
  74. Watanabe, Richard M. |
  75. Prokopenko, Inga |
  76. Dupuis, Josee |
  77. Karpe, Fredrik |
  78. Groop, Leif |
  79. Laakso, Markku |
  80. Pedersen, Oluf |
  81. Florez, Jose C. |
  82. Morris, Andrew P. |
  83. Altshuler, David |
  84. Meigs, James B. |
  85. Boehnke, Michael |
  86. McCarthy, Mark I. |
  87. Lindgren, Cecilia M. |
  88. Gloyn, Anna L. |
  89. Roden, Michael |
1000 Mitwirkende/r
  1. T2D-GENES consortium |
  2. GoT2D consortium |
1000 Erscheinungsjahr 2015
1000 LeibnizOpen
1000 Art der Datei
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2015-01-27
1000 Erschienen in
1000 Quellenangabe
  • 11(1):e1004876
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2015
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1371/journal.pgen.1004876 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4307976/ |
1000 Ergänzendes Material
  • http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004876#sec005 |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • 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.
1000 Sacherschließung
lokal Genomic signal processing
lokal Haplotypes
lokal Genome-wide association studies
lokal Genetic loci
lokal Alleles
lokal Insulin
lokal Meta-analysis
lokal Variant genotypes
1000 Fachgruppe
  1. Medizin |
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
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1000 (Academic) Editor
1000 Förderer
  1. Agency for Science, Technology and Research (Singapore) |
  2. Austrian Science Fund (FWF) |
  3. Massachusetts General Hospital Research Scholars Award |
  4. Wellcome Trust |
  5. National Institute of Diabetes and Digestive and Kidney Diseases |
  6. Medical Research Council |
  7. EU |
  8. Oxford Biomedical Research Centre |
  9. Uppsala University |
  10. Uppsala University Hospital |
  11. Swedish Research Council |
  12. Swedish Heart-Lung Foundation |
  13. National Institute for Health Research (NIHR) |
  14. BioResource Clinical Research Facility |
  15. Biomedical Research Centre |
  16. Lundbeck Foundation |
  17. Danish Council for Independent Research |
  18. The Novo Nordisk Foundation Center for Basic Metabolic Research |
  19. Academy of Finland |
  20. Finnish Heart Foundation |
  21. Commission of the European Community |
  22. US National Institutes of Health |
  23. Finnish Foundation for Cardiovascular Research |
  24. Finnish National Public Health Institute (current National Institute for Health and Welfare) |
  25. Finnish Diabetes Association |
  26. Ministry of Social Affairs and Health in Finland |
  27. Directorate C-Public Health |
  28. Finland’s Slottery Machine Association |
  29. Kuopio University Hospital from Ministry of Health and Social Affairs |
  30. Finnish Funding Agency for Technology and Innovation |
  31. Nordic Centre of Excellence |
  32. The Finnish Diabetes Research Foundation |
  33. Yrjö Jahnsson Foundation |
  34. Sigrid Juselius Foundation |
  35. Ministry of Education and Culture of Finland |
  36. Kuopio University Hospital |
  37. Finnish Diabetes Association |
  38. Finnish Heart Association |
  39. Päivikki and Sakari Sohlberg Foundation |
  40. City of Kuopio |
  41. Social Insurance Institution of Finland |
1000 Fördernummer
  1. -
  2. J-3401
  3. -
  4. WT098381; 086596/Z/08/Z; 095010/Z/10/Z; 090367; 098381; 090532; 083948; 085475; WT098017; WT064890; WT090532; 072960/2/03/2; 086113/Z/08/Z
  5. DK078616; DK080140; DK098032; DK085526; DK085501; DK085524; DK085545; DK085584; DK088389
  6. G0601261
  7. HEALTH-F4-2007-201413; FP7/2007–2013
  8. -
  9. -
  10. -
  11. -
  12. -
  13. -
  14. -
  15. -
  16. -
  17. -
  18. -
  19. 124243; 139635; 129293; 117844; 40758; 211497; 118590; 102318; 123885
  20. -
  21. HEALTH-F2-2007-201681; LSHM-CT-2004-005272
  22. DK093757; DK072193; DK062370; 1Z01 HG000024
  23. -
  24. -
  25. -
  26. -
  27. no2004310
  28. -
  29. 5254
  30. 40058/07; 1510/31/06; 70103/06; 40058/07
  31. 070014
  32. -
  33. 56358
  34. -
  35. -
  36. -
  37. -
  38. -
  39. -
  40. -
  41. 4/26/2010
1000 Förderprogramm
  1. -
  2. -
  3. -
  4. -
  5. -
  6. -
  7. Framework 7
  8. -
  9. -
  10. -
  11. -
  12. -
  13. -
  14. -
  15. -
  16. -
  17. -
  18. -
  19. -
  20. -
  21. FP6 Integrated Project (EXGENESIS)
  22. -
  23. -
  24. -
  25. -
  26. -
  27. -
  28. -
  29. -
  30. -
  31. -
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  39. -
  40. -
  41. -
1000 Dateien
  1. Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer Agency for Science, Technology and Research (Singapore) |
    1000 Förderprogramm -
    1000 Fördernummer -
  2. 1000 joinedFunding-child
    1000 Förderer Austrian Science Fund (FWF) |
    1000 Förderprogramm -
    1000 Fördernummer J-3401
  3. 1000 joinedFunding-child
    1000 Förderer Massachusetts General Hospital Research Scholars Award |
    1000 Förderprogramm -
    1000 Fördernummer -
  4. 1000 joinedFunding-child
    1000 Förderer Wellcome Trust |
    1000 Förderprogramm -
    1000 Fördernummer WT098381; 086596/Z/08/Z; 095010/Z/10/Z; 090367; 098381; 090532; 083948; 085475; WT098017; WT064890; WT090532; 072960/2/03/2; 086113/Z/08/Z
  5. 1000 joinedFunding-child
    1000 Förderer National Institute of Diabetes and Digestive and Kidney Diseases |
    1000 Förderprogramm -
    1000 Fördernummer DK078616; DK080140; DK098032; DK085526; DK085501; DK085524; DK085545; DK085584; DK088389
  6. 1000 joinedFunding-child
    1000 Förderer Medical Research Council |
    1000 Förderprogramm -
    1000 Fördernummer G0601261
  7. 1000 joinedFunding-child
    1000 Förderer EU |
    1000 Förderprogramm Framework 7
    1000 Fördernummer HEALTH-F4-2007-201413; FP7/2007–2013
  8. 1000 joinedFunding-child
    1000 Förderer Oxford Biomedical Research Centre |
    1000 Förderprogramm -
    1000 Fördernummer -
  9. 1000 joinedFunding-child
    1000 Förderer Uppsala University |
    1000 Förderprogramm -
    1000 Fördernummer -
  10. 1000 joinedFunding-child
    1000 Förderer Uppsala University Hospital |
    1000 Förderprogramm -
    1000 Fördernummer -
  11. 1000 joinedFunding-child
    1000 Förderer Swedish Research Council |
    1000 Förderprogramm -
    1000 Fördernummer -
  12. 1000 joinedFunding-child
    1000 Förderer Swedish Heart-Lung Foundation |
    1000 Förderprogramm -
    1000 Fördernummer -
  13. 1000 joinedFunding-child
    1000 Förderer National Institute for Health Research (NIHR) |
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1000 @id frl:6408167.rdf
1000 Erstellt am 2018-05-30T10:54:26.945+0200
1000 Erstellt von 218
1000 beschreibt frl:6408167
1000 Bearbeitet von 218
1000 Zuletzt bearbeitet Tue Sep 04 10:31:31 CEST 2018
1000 Objekt bearb. Tue Sep 04 10:31:31 CEST 2018
1000 Vgl. frl:6408167
1000 Oai Id
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1000 Sichtbarkeit Metadaten public
1000 Sichtbarkeit Daten public
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