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 (US) |
|---|---|
| Article number | e1004876 |
| Journal | PLoS genetics |
| Volume | 11 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 27 2015 |
All Science Journal Classification (ASJC) codes
- Ecology, Evolution, Behavior and Systematics
- Molecular Biology
- Genetics
- Genetics(clinical)
- Cancer Research
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In: PLoS genetics, Vol. 11, No. 1, e1004876, 27.01.2015.
Research output: Contribution to journal › Article › peer-review
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 - Seielstad, Mark
AU - Wilson, James G.
AU - Christensen, Cramer
AU - Brandslund, Ivan
AU - Rauramaa, Rainer
AU - Surdulescu, Gabriela L.
AU - Doney, Alex S.F.
AU - Lannfelt, Lars
AU - Linneberg, Allan
AU - Isomaa, Bo
AU - Tuomi, Tiinamaija
AU - Jørgensen, Marit E.
AU - Jørgensen, Torben
AU - Kuusisto, Johanna
AU - Uusitupa, Matti
AU - Salomaa, Veikko
AU - Spector, Timothy D.
AU - Morris, Andrew D.
AU - Palmer, Colin N.A.
AU - Collins, Francis S.
AU - Mohlke, Karen L.
AU - Bergman, Richard N.
AU - Ingelsson, Erik
AU - Lind, Lars
AU - Tuomilehto, Jaakko
AU - Hansen, Torben
AU - Watanabe, Richard M.
AU - Prokopenko, Inga
AU - Dupuis, Josee
AU - Karpe, Fredrik
AU - Groop, Leif
AU - Laakso, Markku
AU - Pedersen, Oluf
AU - Florez, Jose C.
AU - Morris, Andrew P.
AU - Altshuler, David
AU - Meigs, James B.
AU - Boehnke, Michael
AU - McCarthy, Mark I.
AU - Lindgren, Cecilia M.
AU - Gloyn, Anna L.
AU - Abboud, Hanna E.
AU - Afzal, Uzma
AU - Aguilar, David
AU - Arya, Rector
AU - Atzmon, Gil
AU - Aung, Tin
AU - Banks, Eric
AU - Barroso, Inês
AU - Barzilai, Nir
AU - Below, Jennifer E.
AU - Bharadwaj, Dwaipayan
AU - Blackwell, Thomas W.
AU - Bonnycastle, Lori L.
AU - Bowden, Don
AU - Carey, Jason
AU - Carneiro, Mauricio O.
AU - Chambers, John C.
AU - Chan, Edmund
AU - Chan, Juliana
AU - Chandak, Giriraj R.
AU - Chen, Peng
AU - Chen, Yuhui
AU - Chen, Han
AU - Cheng, Ching Yu
AU - Chia, Kee Seng
AU - Cho, Yoon Shin
AU - Correa, Adolfo
AU - Curran, Joanne E.
AU - Daly, Mark J.
AU - Day-Williams, Aaron G.
AU - DeFronzo, Ralph A.
AU - DePristo, Mark
AU - Donnelly, Peter J.
AU - Ebrahim, Shah B.
AU - Elliott, Paul
AU - Esko, Tõnu
AU - Fadista, João
AU - Farjoun, Yossi
AU - Farmer, Andrew J.
AU - Farook, Vidya S.
AU - Fennell, Timothy
AU - Ferreira, Teresa
AU - Fingerlin, Tasha
AU - Forsén, Tom
AU - Fowler, Sharon P.
AU - Franks, Paul W.
AU - Frayling, Timothy M.
AU - Freedman, Barry I.
AU - Froguel, Philippe
AU - Gamazon, Eric R.
AU - Gieger, Christian
AU - Glaser, Benjamin
AU - Go, Min Jin
AU - Goldstein, Jacqueline I.
AU - Grallert, Harald
AU - Grant, George
AU - Green, Todd
AU - Griswold, Michael
AU - Hale, Daniel Esten
AU - Han, Bok Ghee
AU - Hartl, Christopher
AU - Hattersley, Andrew T.
AU - Hicks, Pamela J.
AU - Hodgkiss, Dylan
AU - Horikoshi, Momoko
AU - Hrabé de Angelis, Martin
AU - Hu, Cheng
AU - Hu, Frank B.
AU - Huh, Iksoo
AU - Kamran Ikram, Mohammad
AU - Illig, Thomas
AU - Jablonski, Kathleen A.
AU - Jenkinson, Christopher P.
AU - Jia, Weiping
AU - Kang, Hyun Min
AU - Khor, Chiea Chuen
AU - Kim, Yongkang
AU - Kim, Young Jin
AU - Kim, Bong Jo
AU - Kinnunen, Leena
AU - Kooner, Jaspal Singh
AU - Kravic, Jasmina
AU - Kriebel, Jennifer
AU - Kumar, Ashish
AU - Kumar, Satish
AU - Kuulasmaa, Teemu
AU - Kwon, Min Seok
AU - Langenberg, Claudia
AU - Lauritzen, Torsten
AU - Lee, Selyeong
AU - Lee, Jaehoon
AU - Lee, Juyoung
AU - Lee, Jong Young
AU - Lehman, Donna M.
AU - Lehne, Benjamin
AU - Levy, Jonathan C.
AU - Li, Jiang
AU - Liang, Liming
AU - Lim, Wei Yen
AU - Lin, Keng Han
AU - Liu, Jianjun
AU - Loh, Marie
AU - Ma, Ronald C.W.
AU - Ma, Clement
AU - Mägi, Reedik
AU - Maguire, Jared
AU - Maxwell, Taylor J.
AU - McVean, Gilean
AU - Meisinger, Christa
AU - Meitinger, Thomas
AU - Melander, Olle
AU - Metspalu, Andres
AU - Mihailov, Evelin
AU - Milani, Lili
AU - Moutsianas, Loukas
AU - Müller-Nurasyid, Martina
AU - K. Musani, Solomon
AU - Nagai, Yoshihiko
AU - Narisu, Narisu
AU - Neale, Benjamin M.
AU - Ng, Maggie C.Y.
AU - Nilsson, Peter
AU - O'Rahilly, Stephen P.
AU - Orho-Melander, Marju
AU - Owen, Katharine R.
AU - Palmer, Nicholette D.
AU - Park, Taesung
AU - Pasko, Dorota
AU - Pearson, Richard D.
AU - Perry, John R.B.
AU - Peters, Annette
AU - Pollin, Toni I.
AU - Poplin, Ryan
AU - Prabhakaran, Dorairaj
AU - Puppala, Sobha
AU - Purcell, Shaun
AU - Qi, Lu
AU - Qi, Qibin
AU - Roden, Michael
AU - Rolandsson, Olov
AU - Rosengren, Anders H.
AU - Sandhu, Manjinder
AU - Schwarzmayr, Thomas
AU - Scott, Laura J.
AU - Scott, Robert A.
AU - Scott, James
AU - Scott, William R.
AU - Sehmi, Jobanpreet
AU - Shakir, Khalid
AU - Sladek, Rob
AU - Smith, Joshua D.
AU - Stancáková, Alena
AU - Strauch, Konstantin
AU - Strom, Tim M.
AU - Swift, Amy
AU - Tai, E. Shyong
AU - Tajes, Juan Fernandez
AU - Tan, Sian Tsung
AU - Tandon, Nikhil
AU - Taylor, Herman A.
AU - Teo, Yik Ying
AU - Thameem, Farook
AU - Thorand, Barbara
AU - van de Bunt, Martijn
AU - Varga, Tibor V.
AU - Walker, Mark
AU - Wareham, Nicholas J.
AU - Welch, Ryan P.
AU - Wieland, Thomas
AU - Wilson, Gregory
AU - Wong, Tien Yin
AU - Wood, Andrew R.
AU - Yoon, Joon
AU - Zeggini, Eleftheria
AU - Zhang, Weihua
N1 - Funding Information: Funding: HJN was supported by the Agency for Science, Technology and Research in Singapore. CF was supported by the Austrian Science Fund (FWF) grant J-3401. JCF was supported by MGH Research Scholars Award. APM is a Wellcome Trust Senior Research Fellow in Basic and Biomedical Science. JBM was supported by NIDDK R01 DK078616 and K24 DK080140. MIM is a Wellcome Trust Senior Investigator (WT098381); and a National Institute of Health Research Senior Investigator. CML is a Wellcome Trust Research Career Development Fellow (086596/ Z/08/Z). ALG is a Wellcome Trust Senior Research Fellow in Basic and Biomedical Science (095010/Z/ 10/Z). Funding for the GoT2D and T2D-GENES studies was provided by grants NIH U01s DK085526, DK085501, DK085524, DK085545, and DK085584 (Multiethnic Study of Type 2 Diabetes Genes) and DK088389 (Low-Pass Sequencing and High-Density SNP Genotyping for Type 2 Diabetes). Analysis and genotyping of the British UK cohorts was supported by Wellcome Trust funding 090367, 098381, 090532, 083948, 085475, MRC (G0601261), EU (Framework 7) HEALTH-F4-2007-201413, and NIDDK DK098032. The Oxford Biobank is supported by the Oxford Biomedical Research Centre and part of the National NIHR Bioresource. The PIVUS/ ULSAM cohort was supported by Wellcome Trust Grants WT098017, WT064890, WT090532, Uppsala University, Uppsala University Hospital, the Swedish Research Council and the Swedish Heart-Lung Foundation. GoDARTS study was funded by The Wellcome Trust Study Cohort Wellcome Trust Functional Genomics Grant (2004-2008) (Grant No: 072960/2/ 03/2) and The Wellcome Trust Scottish Health Informatics Programme (SHIP) (2009-2012) (Grant No: 086113/Z/08/Z). TwinsUK study was funded by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/2007–2013). The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. TDS is holder of an ERC Advanced Principal Investigator award. The Danish studies were supported by the Lundbeck Foundation (Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care (LuCamp); http://www. Funding Information: Research. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen, partially funded by an unrestricted donation from the Novo Nordisk Foundation (http://www.metabol.ku.dk/). Funding Information: HJN was supported by the Agency for Science, Technology and Research in Singapore. CF was supported by the Austrian Science Fund (FWF) grant J-3401. JCF was supported by MGH Research Scholars Award. APM is a Wellcome Trust Senior Research Fellow in Basic and Biomedical Science. JBM was supported by NIDDK R01 DK078616 and K24 DK080140. MIM is a Wellcome Trust Senior Investigator (WT098381); and a National Institute of Health Research Senior Investigator. CML is a Wellcome Trust Research Career Development Fellow (086596/ Z/08/Z). ALG is a Wellcome Trust Senior Research Fellow in Basic and Biomedical Science (095010/Z/ 10/Z). Funding for the GoT2D and T2D-GENES studies was provided by grants NIH U01s DK085526, DK085501, DK085524, DK085545, and DK085584 (Multiethnic Study of Type 2 Diabetes Genes) and DK088389 (Low-Pass Sequencing and High-Density SNP Genotyping for Type 2 Diabetes). Analysis and genotyping of the British UK cohorts was supported by Wellcome Trust funding 090367, 098381, 090532, 083948, 085475, MRC (G0601261), EU (Framework 7) HEALTH-F4-2007-201413, and NIDDK DK098032. The Oxford Biobank is supported by the Oxford Biomedical Research Centre and part of the National NIHR Bioresource. The PIVUS/ ULSAM cohort was supported by Wellcome Trust Grants WT098017, WT064890, WT090532, Uppsala University, Uppsala University Hospital, the Swedish Research Council and the Swedish Heart-Lung Foundation. GoDARTS study was funded by The Wellcome Trust Study Cohort Wellcome Trust Functional Genomics Grant (2004-2008) (Grant No: 072960/2/ 03/2) and The Wellcome Trust Scottish Health Informatics Programme (SHIP) (2009-2012) (Grant No: 086113/Z/08/Z). TwinsUK study was funded by the Wellcome Trust; European Community?s Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy''s and St Thomas'' NHS Foundation Trust and King''s College London. TDS is holder of an ERC Advanced Principal Investigator award. The Danish studies were supported by the Lundbeck Foundation (Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care (LuCamp); http://www. lucamp.org/) and the Danish Council for Independent Research. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen, partially funded by an unrestricted donation from the Novo Nordisk Foundation (http://www.metabol.ku.dk/). The METSIM study was supported by the Academy of Finland (contract 124243), the Finnish Heart Foundation, the Finnish Diabetes Foundation, Tekes (contract 1510/31/06), and the Commission of the European Community (HEALTH-F2-2007-201681), and the US National Institutes of Health grants DK093757, DK072193, DK062370, and 1Z01 HG000024. The FUSION study was supported by DK093757, DK072193, DK062370, and 1Z01 HG000024. Genotyping of the METSIM and DPS studies was conducted at the Genetic Resources Core Facility (GRCF) at the Johns Hopkins Institute of Genetic Medicine. VS is funded by the Finnish Foundation for Cardiovascular Research and the Academy of Finland (grant # 139635). The FIN-D2D 2007 study has been financially supported by the hospital districts of Pirkanmaa, South Ostrobothnia, and Central Finland, the Finnish National Public Health Institute (current National Institute for Health and Welfare), the Finnish Diabetes Association, the Ministry of Social Affairs and Health in Finland, the Academy of Finland (grant number 129293), Commission of the European Communities, Directorate C-Public Health (grant agreement no. 2004310) and Finland?s Slottery Machine Association. The DPS has been financially supported by grants from the Academy of Finland (117844 and 40758, 211497, and 118590 (MU); The EVO funding of the Kuopio University Hospital from Ministry of Health and Social Affairs (5254), Finnish Funding Agency for Technology and Innovation (40058/07), Nordic Centre of Excellence on ?Systems biology in controlled dietary interventions and cohort studies, SYSDIET (070014), The Finnish Diabetes Research Foundation, Yrj? Jahnsson Foundation (56358), Sigrid Juselius Foundation and TEKES grants 70103/06 and 40058/07. The DR''s EXTRA Study was supported by grants to RR by the Ministry of Education and Culture of Finland (627;2004-2011), Academy of Finland (102318; 123885), Kuopio University Hospital, Finnish Diabetes Association, Finnish Heart Association, P?ivikki and Sakari Sohlberg Foundation and by grants from European Commission FP6 Integrated Project (EXGENESIS); LSHM-CT-2004-005272, City of Kuopio and Social Insurance Institution of Finland (4/26/ 2010). The Broad Genomics Platform for genotyping of the FIN-D2D 2007, FINRISK 2007, DR''sEXTRA, FUSION, and PPP studies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: The METSIM study was supported by the Academy Publisher Copyright: © 2015, Public Library of Science, All Rights Reserved.
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
UR - http://www.scopus.com/inward/citedby.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 -