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; 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; Mark Seielstad; James G. Wilson; Cramer Christensen; Ivan Brandslund; Rainer Rauramaa; Gabriela L. Surdulescu; Alex S.F. Doney; Lars Lannfelt; Allan Linneberg; Bo Isomaa; Tiinamaija Tuomi; Marit E. Jørgensen; Torben Jørgensen; Johanna Kuusisto; Matti Uusitupa; Veikko Salomaa; Timothy D. Spector; Andrew D. Morris; Colin N.A. Palmer; Francis S. Collins; Karen L. Mohlke; Richard N. Bergman; Erik Ingelsson; Lars Lind; Jaakko Tuomilehto; Torben Hansen; Richard M. Watanabe; Inga Prokopenko; Josee Dupuis; Fredrik Karpe; Leif Groop; Markku Laakso; Oluf Pedersen; Jose C. Florez; Andrew P. Morris; David Altshuler; James B. Meigs; Michael Boehnke; Mark I. McCarthy; Cecilia M. Lindgren; Anna L. Gloyn; Hanna E. Abboud; Uzma Afzal; David Aguilar; Rector Arya; Gil Atzmon; Tin Aung; Eric Banks; Inês Barroso; Nir Barzilai; Jennifer E. Below; Dwaipayan Bharadwaj; Thomas W. Blackwell; Lori L. Bonnycastle; Don Bowden; Jason Carey; Mauricio O. Carneiro; John C. Chambers; Edmund Chan; Juliana Chan; Giriraj R. Chandak; Peng Chen; Yuhui Chen; Han Chen; Ching Yu Cheng; Kee Seng Chia; Yoon Shin Cho; Adolfo Correa; Joanne E. Curran; Mark J. Daly; Aaron G. Day-Williams; Ralph A. DeFronzo; Mark DePristo; Peter J. Donnelly; Shah B. Ebrahim; Paul Elliott; Tõnu Esko; João Fadista; Yossi Farjoun; Andrew J. Farmer; Vidya S. Farook; Timothy Fennell; Teresa Ferreira; Tasha Fingerlin; Tom Forsén; Sharon P. Fowler; Paul W. Franks; Timothy M. Frayling; Barry I. Freedman; Philippe Froguel; Eric R. Gamazon; Christian Gieger; Benjamin Glaser; Min Jin Go; Jacqueline I. Goldstein; Harald Grallert; George Grant; Todd Green; Michael Griswold; Daniel Esten Hale; Bok Ghee Han; Christopher Hartl; Andrew T. Hattersley; Pamela J. Hicks; Dylan Hodgkiss; Momoko Horikoshi; Martin Hrabé de Angelis; Cheng Hu; Frank B. Hu; Iksoo Huh; Mohammad Kamran Ikram; Thomas Illig; Kathleen A. Jablonski; Christopher P. Jenkinson; Weiping Jia; Hyun Min Kang; Chiea Chuen Khor; Yongkang Kim; Young Jin Kim; Bong Jo Kim; Leena Kinnunen; Jaspal Singh Kooner; Jasmina Kravic; Jennifer Kriebel; Ashish Kumar; Satish Kumar; Teemu Kuulasmaa; Min Seok Kwon; Claudia Langenberg; Torsten Lauritzen; Selyeong Lee; Jaehoon Lee; Juyoung Lee; Jong Young Lee; Donna M. Lehman; Benjamin Lehne; Jonathan C. Levy; Jiang Li; Liming Liang; Wei Yen Lim; Keng Han Lin; Jianjun Liu; Marie Loh; Ronald C.W. Ma; Clement Ma; Reedik Mägi; Jared Maguire; Taylor J. Maxwell; Gilean McVean; Christa Meisinger; Thomas Meitinger; Olle Melander; Andres Metspalu; Evelin Mihailov; Lili Milani; Loukas Moutsianas; Martina Müller-Nurasyid; Solomon K. Musani; Yoshihiko Nagai; Narisu Narisu; Benjamin M. Neale; Maggie C.Y. Ng; Peter Nilsson; Stephen P. O'Rahilly; Marju Orho-Melander; Katharine R. Owen; Nicholette D. Palmer; Taesung Park; Dorota Pasko; Richard D. Pearson; John R.B. Perry; Annette Peters; Toni I. Pollin; Ryan Poplin; Dorairaj Prabhakaran; Sobha Puppala; Shaun Purcell; Lu Qi; Qibin Qi; Michael Roden; Olov Rolandsson; Anders H. Rosengren; Manjinder Sandhu; Thomas Schwarzmayr; Laura J. Scott; Robert A. Scott; James Scott; William R. Scott; Jobanpreet Sehmi; Khalid Shakir; Rob Sladek; Joshua D. Smith; Alena Stancáková; Konstantin Strauch; Tim M. Strom; Amy Swift; E. Shyong Tai; Juan Fernandez Tajes; Sian Tsung Tan; Nikhil Tandon; Herman A. Taylor; Yik Ying Teo; Farook Thameem; Barbara Thorand; Martijn van de Bunt; Tibor V. Varga; Mark Walker; Nicholas J. Wareham; Ryan P. Welch; Thomas Wieland; Gregory Wilson; Tien Yin Wong; Andrew R. Wood; Joon Yoon; Eleftheria Zeggini; Weihua Zhang

doi: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

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-JensenClaes 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, Mark Seielstad, James G. Wilson, Cramer Christensen, Ivan Brandslund, Rainer Rauramaa, Gabriela L. Surdulescu, Alex S.F. Doney, Lars Lannfelt, Allan Linneberg, Bo Isomaa, Tiinamaija Tuomi, Marit E. Jørgensen, Torben Jørgensen, Johanna Kuusisto, Matti Uusitupa, Veikko Salomaa, Timothy D. Spector, Andrew D. Morris, Colin N.A. Palmer, Francis S. Collins, Karen L. Mohlke, Richard N. Bergman, Erik Ingelsson, Lars Lind, Jaakko Tuomilehto, Torben Hansen, Richard M. Watanabe, Inga Prokopenko, Josee Dupuis, Fredrik Karpe, Leif Groop, Markku Laakso, Oluf Pedersen, Jose C. Florez, Andrew P. Morris, David Altshuler, James B. Meigs, Michael Boehnke, Mark I. McCarthy, Cecilia M. Lindgren, Anna L. Gloyn, Hanna E. Abboud, Uzma Afzal, David Aguilar, Rector Arya, Gil Atzmon, Tin Aung, Eric Banks, Inês Barroso, Nir Barzilai, Jennifer E. Below, Dwaipayan Bharadwaj, Thomas W. Blackwell, Lori L. Bonnycastle, Don Bowden, Jason Carey, Mauricio O. Carneiro, John C. Chambers, Edmund Chan, Juliana Chan, Giriraj R. Chandak, Peng Chen, Yuhui Chen, Han Chen, Ching Yu Cheng, Kee Seng Chia, Yoon Shin Cho, Adolfo Correa, Joanne E. Curran, Mark J. Daly, Aaron G. Day-Williams, Ralph A. DeFronzo, Mark DePristo, Peter J. Donnelly, Shah B. Ebrahim, Paul Elliott, Tõnu Esko, João Fadista, Yossi Farjoun, Andrew J. Farmer, Vidya S. Farook, Timothy Fennell, Teresa Ferreira, Tasha Fingerlin, Tom Forsén, Sharon P. Fowler, Paul W. Franks, Timothy M. Frayling, Barry I. Freedman, Philippe Froguel, Eric R. Gamazon, Christian Gieger, Benjamin Glaser, Min Jin Go, Jacqueline I. Goldstein, Harald Grallert, George Grant, Todd Green, Michael Griswold, Daniel Esten Hale, Bok Ghee Han, Christopher Hartl, Andrew T. Hattersley, Pamela J. Hicks, Dylan Hodgkiss, Momoko Horikoshi, Martin Hrabé de Angelis, Cheng Hu, Frank B. Hu, Iksoo Huh, Mohammad Kamran Ikram, Thomas Illig, Kathleen A. Jablonski, Christopher P. Jenkinson, Weiping Jia, Hyun Min Kang, Chiea Chuen Khor, Yongkang Kim, Young Jin Kim, Bong Jo Kim, Leena Kinnunen, Jaspal Singh Kooner, Jasmina Kravic, Jennifer Kriebel, Ashish Kumar, Satish Kumar, Teemu Kuulasmaa, Min Seok Kwon, Claudia Langenberg, Torsten Lauritzen, Selyeong Lee, Jaehoon Lee, Juyoung Lee, Jong Young Lee, Donna M. Lehman, Benjamin Lehne, Jonathan C. Levy, Jiang Li, Liming Liang, Wei Yen Lim, Keng Han Lin, Jianjun Liu, Marie Loh, Ronald C.W. Ma, Clement Ma, Reedik Mägi, Jared Maguire, Taylor J. Maxwell, Gilean McVean, Christa Meisinger, Thomas Meitinger, Olle Melander, Andres Metspalu, Evelin Mihailov, Lili Milani, Loukas Moutsianas, Martina Müller-Nurasyid, Solomon K. Musani, Yoshihiko Nagai, Narisu Narisu, Benjamin M. Neale, Maggie C.Y. Ng, Peter Nilsson, Stephen P. O'Rahilly, Marju Orho-Melander, Katharine R. Owen, Nicholette D. Palmer, Taesung Park, Dorota Pasko, Richard D. Pearson, John R.B. Perry, Annette Peters, Toni I. Pollin, Ryan Poplin, Dorairaj Prabhakaran, Sobha Puppala, Shaun Purcell, Lu Qi, Qibin Qi, Michael Roden, Olov Rolandsson, Anders H. Rosengren, Manjinder Sandhu, Thomas Schwarzmayr, Laura J. Scott, Robert A. Scott, James Scott, William R. Scott, Jobanpreet Sehmi, Khalid Shakir, Rob Sladek, Joshua D. Smith, Alena Stancáková, Konstantin Strauch, Tim M. Strom, Amy Swift, E. Shyong Tai, Juan Fernandez Tajes, Sian Tsung Tan, Nikhil Tandon, Herman A. Taylor, Yik Ying Teo, Farook Thameem, Barbara Thorand, Martijn van de Bunt, Tibor V. Varga, Mark Walker, Nicholas J. Wareham, Ryan P. Welch, Thomas Wieland, Gregory Wilson, Tien Yin Wong, Andrew R. Wood, Joon Yoon, Eleftheria Zeggini, Weihua Zhang

Research output: Contribution to journal › Article › peer-review

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 language	English
Article number	e1004876
Journal	PLoS Genetics
Volume	11
Issue number	1
DOIs	https://doi.org/10.1371/journal.pgen.1004876
State	Published - 27 Jan 2015
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2015, Public Library of Science, All Rights Reserved.

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1371/journal.pgen.1004876

Cite this

Mahajan, A., Sim, X., Ng, H. J., Manning, A., Rivas, M. A., Highland, H. M., Locke, A. E., Grarup, N., Im, H. K., Cingolani, P., Flannick, J., Fontanillas, P., Fuchsberger, C., Gaulton, K. J., Teslovich, T. M., Rayner, N. W., Robertson, N. R., Beer, N. L., Rundle, J. K., ... Zhang, W. (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), Article e1004876. https://doi.org/10.1371/journal.pgen.1004876

@article{f82ec10df7ba43a388cdce8cf1f42551,

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 Syv{\"a}nen, {Ann Christine} 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 Mark Seielstad and Wilson, {James G.} and Cramer Christensen and Ivan Brandslund and Rainer Rauramaa and Surdulescu, {Gabriela L.} and Doney, {Alex S.F.} and Lars Lannfelt and Allan Linneberg and Bo Isomaa and Tiinamaija Tuomi and J{\o}rgensen, {Marit E.} and Torben J{\o}rgensen and Johanna Kuusisto and Matti Uusitupa and Veikko Salomaa and Spector, {Timothy D.} and Morris, {Andrew D.} and Palmer, {Colin N.A.} and Collins, {Francis S.} and Mohlke, {Karen L.} and Bergman, {Richard N.} and Erik Ingelsson and Lars Lind and Jaakko Tuomilehto and Torben Hansen and Watanabe, {Richard M.} and Inga Prokopenko and Josee Dupuis and Fredrik Karpe and Leif Groop and Markku Laakso and Oluf Pedersen and Florez, {Jose C.} and Morris, {Andrew P.} and David Altshuler and Meigs, {James B.} and Michael Boehnke and McCarthy, {Mark I.} and Lindgren, {Cecilia M.} and Gloyn, {Anna L.} and Abboud, {Hanna E.} and Uzma Afzal and David Aguilar and Rector Arya and Gil Atzmon and Tin Aung and Eric Banks and In{\^e}s Barroso and Nir Barzilai and Below, {Jennifer E.} and Dwaipayan Bharadwaj and Blackwell, {Thomas W.} and Bonnycastle, {Lori L.} and Don Bowden and Jason Carey and Carneiro, {Mauricio O.} and Chambers, {John C.} and Edmund Chan and Juliana Chan and Chandak, {Giriraj R.} and Peng Chen and Yuhui Chen and Han Chen and Cheng, {Ching Yu} and Chia, {Kee Seng} and Cho, {Yoon Shin} and Adolfo Correa and Curran, {Joanne E.} and Daly, {Mark J.} and Day-Williams, {Aaron G.} and DeFronzo, {Ralph A.} and Mark DePristo and Donnelly, {Peter J.} and Ebrahim, {Shah B.} and Paul Elliott and T{\~o}nu Esko and Jo{\~a}o Fadista and Yossi Farjoun and Farmer, {Andrew J.} and Farook, {Vidya S.} and Timothy Fennell and Teresa Ferreira and Tasha Fingerlin and Tom Fors{\'e}n and Fowler, {Sharon P.} and Franks, {Paul W.} and Frayling, {Timothy M.} and Freedman, {Barry I.} and Philippe Froguel and Gamazon, {Eric R.} and Christian Gieger and Benjamin Glaser and Go, {Min Jin} and Goldstein, {Jacqueline I.} and Harald Grallert and George Grant and Todd Green and Michael Griswold and Hale, {Daniel Esten} and Han, {Bok Ghee} and Christopher Hartl and Hattersley, {Andrew T.} and Hicks, {Pamela J.} and Dylan Hodgkiss and Momoko Horikoshi and {Hrab{\'e} de Angelis}, Martin and Cheng Hu and Hu, {Frank B.} and Iksoo Huh and {Kamran Ikram}, Mohammad and Thomas Illig and Jablonski, {Kathleen A.} and Jenkinson, {Christopher P.} and Weiping Jia and Kang, {Hyun Min} and Khor, {Chiea Chuen} and Yongkang Kim and Kim, {Young Jin} and Kim, {Bong Jo} and Leena Kinnunen and Kooner, {Jaspal Singh} and Jasmina Kravic and Jennifer Kriebel and Ashish Kumar and Satish Kumar and Teemu Kuulasmaa and Kwon, {Min Seok} and Claudia Langenberg and Torsten Lauritzen and Selyeong Lee and Jaehoon Lee and Juyoung Lee and Lee, {Jong Young} and Lehman, {Donna M.} and Benjamin Lehne and Levy, {Jonathan C.} and Jiang Li and Liming Liang and Lim, {Wei Yen} and Lin, {Keng Han} and Jianjun Liu and Marie Loh and Ma, {Ronald C.W.} and Clement Ma and Reedik M{\"a}gi and Jared Maguire and Maxwell, {Taylor J.} and Gilean McVean and Christa Meisinger and Thomas Meitinger and Olle Melander and Andres Metspalu and Evelin Mihailov and Lili Milani and Loukas Moutsianas and Martina M{\"u}ller-Nurasyid and {K. Musani}, Solomon and Yoshihiko Nagai and Narisu Narisu and Neale, {Benjamin M.} and Ng, {Maggie C.Y.} and Peter Nilsson and O'Rahilly, {Stephen P.} and Marju Orho-Melander and Owen, {Katharine R.} and Palmer, {Nicholette D.} and Taesung Park and Dorota Pasko and Pearson, {Richard D.} and Perry, {John R.B.} and Annette Peters and Pollin, {Toni I.} and Ryan Poplin and Dorairaj Prabhakaran and Sobha Puppala and Shaun Purcell and Lu Qi and Qibin Qi and Michael Roden and Olov Rolandsson and Rosengren, {Anders H.} and Manjinder Sandhu and Thomas Schwarzmayr and Scott, {Laura J.} and Scott, {Robert A.} and James Scott and Scott, {William R.} and Jobanpreet Sehmi and Khalid Shakir and Rob Sladek and Smith, {Joshua D.} and Alena Stanc{\'a}kov{\'a} and Konstantin Strauch and Strom, {Tim M.} and Amy Swift and Tai, {E. Shyong} and Tajes, {Juan Fernandez} and Tan, {Sian Tsung} and Nikhil Tandon and Taylor, {Herman A.} and Teo, {Yik Ying} and Farook Thameem and Barbara Thorand and {van de Bunt}, Martijn and Varga, {Tibor V.} and Mark Walker and Wareham, {Nicholas J.} and Welch, {Ryan P.} and Thomas Wieland and Gregory Wilson and Wong, {Tien Yin} and Wood, {Andrew R.} and Joon Yoon and Eleftheria Zeggini and Weihua Zhang",

year = "2015",

month = jan,

day = "27",

doi = "10.1371/journal.pgen.1004876",

language = "English",

volume = "11",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "1",

}

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, AC, Trakalo, J, Abecasis, G, Bell, GI, Blangero, J, Cox, NJ, Duggirala, R, Hanis, CL, Seielstad, M, Wilson, JG, Christensen, C, Brandslund, I, Rauramaa, R, Surdulescu, GL, Doney, ASF, Lannfelt, L, Linneberg, A, Isomaa, B, Tuomi, T, Jørgensen, ME, Jørgensen, T, Kuusisto, J, Uusitupa, M, Salomaa, V, Spector, TD, Morris, AD, Palmer, CNA, Collins, FS, Mohlke, KL, Bergman, RN, Ingelsson, E, Lind, L, Tuomilehto, J, Hansen, T, Watanabe, RM, Prokopenko, I, Dupuis, J, Karpe, F, Groop, L, Laakso, M, Pedersen, O, Florez, JC, Morris, AP, Altshuler, D, Meigs, JB, Boehnke, M, McCarthy, MI, Lindgren, CM, Gloyn, AL, Abboud, HE, Afzal, U, Aguilar, D, Arya, R, Atzmon, G, Aung, T, Banks, E, Barroso, I, Barzilai, N, Below, JE, Bharadwaj, D, Blackwell, TW, Bonnycastle, LL, Bowden, D, Carey, J, Carneiro, MO, Chambers, JC, Chan, E, Chan, J, Chandak, GR, Chen, P, Chen, Y, Chen, H, Cheng, CY, Chia, KS, Cho, YS, Correa, A, Curran, JE, Daly, MJ, Day-Williams, AG, DeFronzo, RA, DePristo, M, Donnelly, PJ, Ebrahim, SB, Elliott, P, Esko, T, Fadista, J, Farjoun, Y, Farmer, AJ, Farook, VS, Fennell, T, Ferreira, T, Fingerlin, T, Forsén, T, Fowler, SP, Franks, PW, Frayling, TM, Freedman, BI, Froguel, P, Gamazon, ER, Gieger, C, Glaser, B, Go, MJ, Goldstein, JI, Grallert, H, Grant, G, Green, T, Griswold, M, Hale, DE, Han, BG, Hartl, C, Hattersley, AT, Hicks, PJ, Hodgkiss, D, Horikoshi, M, Hrabé de Angelis, M, Hu, C, Hu, FB, Huh, I, Kamran Ikram, M, Illig, T, Jablonski, KA, Jenkinson, CP, Jia, W, Kang, HM, Khor, CC, Kim, Y, Kim, YJ, Kim, BJ, Kinnunen, L, Kooner, JS, Kravic, J, Kriebel, J, Kumar, A, Kumar, S, Kuulasmaa, T, Kwon, MS, Langenberg, C, Lauritzen, T, Lee, S, Lee, J, Lee, J, Lee, JY, Lehman, DM, Lehne, B, Levy, JC, Li, J, Liang, L, Lim, WY, Lin, KH, Liu, J, Loh, M, Ma, RCW, Ma, C, Mägi, R, Maguire, J, Maxwell, TJ, McVean, G, Meisinger, C, Meitinger, T, Melander, O, Metspalu, A, Mihailov, E, Milani, L, Moutsianas, L, Müller-Nurasyid, M, K. Musani, S, Nagai, Y, Narisu, N, Neale, BM, Ng, MCY, Nilsson, P, O'Rahilly, SP, Orho-Melander, M, Owen, KR, Palmer, ND, Park, T, Pasko, D, Pearson, RD, Perry, JRB, Peters, A, Pollin, TI, Poplin, R, Prabhakaran, D, Puppala, S, Purcell, S, Qi, L, Qi, Q, Roden, M, Rolandsson, O, Rosengren, AH, Sandhu, M, Schwarzmayr, T, Scott, LJ, Scott, RA, Scott, J, Scott, WR, Sehmi, J, Shakir, K, Sladek, R, Smith, JD, Stancáková, A, Strauch, K, Strom, TM, Swift, A, Tai, ES, Tajes, JF, Tan, ST, Tandon, N, Taylor, HA, Teo, YY, Thameem, F, Thorand, B, van de Bunt, M, Varga, TV, Walker, M, Wareham, NJ, Welch, RP, Wieland, T, Wilson, G, Wong, TY, Wood, AR, Yoon, J, Zeggini, E & Zhang, W 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

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

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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.

UR - http://www.scopus.com/inward/record.url?scp=84929200986&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1004876

DO - 10.1371/journal.pgen.1004876

M3 - Article

C2 - 25625282

AN - SCOPUS:84929200986

SN - 1553-7390

VL - 11

JO - PLoS Genetics

JF - PLoS Genetics

IS - 1

M1 - e1004876

ER -

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

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