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 journalArticle

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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 (US)
Article numbere1004876
JournalPLoS genetics
Volume11
Issue number1
DOIs
StatePublished - Jan 27 2015

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ASJC Scopus subject areas

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

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), [e1004876]. https://doi.org/10.1371/journal.pgen.1004876