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
Mahajan, Anubha : University of Oxford
Sim, Xueling : University of Michigan
Ng, Hui Jin : University of Oxford
Manning, Alisa : Broad Institute
Rivas, Manuel A. : University of Oxford
Highland, Heather M. : University of Texas Health Science Center at Houston
Locke, Adam E. : University of Michigan
Garup, Niels : University of Copenhagen
Im, Hae Kyung : University of Chicago
Cingolani, Pablo : McGill University
Flannick, Jason : Massachusetts General Hospital
Fontanillas, Pierre : Broad Institute
Fuchsberger, Christian : University of Michigan
Gaulton, Kyle J. : University of Oxford
Teslovich, Tanya M. : University of Michigan
Rayner, N. William : University of Oxford
Robertson, Neil R. : University of Oxford
Beer, Nicola L. : University of Oxford
Rundle, Jana K. : University of Oxford
Bork-Jensen, Jette : University of Copenhagen
Ladenvall, Claes : Lund University
Blancher, Christine : University of Oxford
Buck, David : University of Oxford
Buck, Gemma : University of Oxford
Burtt, Noël P. : Broad Institute
Gabriel, Stacey : Broad Institute
Gjesing, Anette P. : University of Copenhagen
Groves, Christopher J. : University of Oxford
Hollensted, Mette : University of Copenhagen
Huyghe, Jeroen R. : University of Michigan
Jackson, Anne U. : University of Michigan
Jun, Goo : University of Michigan
Justesen, Johanne Marie : University of Copenhagen
Mangino, Massimo : King's College London
Murphy, Jacquelyn : Broad Institute
Neville, Matt : University of Oxford
Onofrio, Robert : Broad Institute
Small, Kerrin S. : King's College London
Stringham, Heather M. : University of Michigan
Syvänen, Ann-Christine : Uppsala University
Trakalo, Joseph : University of Oxford
Abecasis, Goncalo : University of Michigan
Bell, Graeme I. : University of Chicago
Blangero, John : Texas Biomedical Research Institute
Cox, Nancy J. : University of Chicago
Funding Information
Agency for Science, Technology and Research in Singapore
Austrian Science Fund, J-3401
MGH, Research Scholars Award
Wellcome Trust, Senior Research Fellowship in Basic and Biomedical Science
National Institute of Diabetes and Digestive and Kidney Diseases, R01 DK078616
National Institute of Diabetes and Digestive and Kidney Diseases, K24 DK080140
Wellcome Trust, WT098381
National Institute of Health
Wellcome Trust, Research Career Development Fellowship, 086596/Z/08/Z
Wellcome Trust, Senior Research Fellowship in Basic and Biomedical Science, 095010/Z/10/Z
National Institutes of Health, DK085526
National Institutes of Health, DK085501
National Institutes of Health, DK085524
National Institutes of Health, DK085545
National Institutes of Health, DK085584
National Institutes of Health, DK088389
Wellcome Trust, 090367
Wellcome Trust, 098381
Wellcome Trust, 090532
Wellcome Trust, 083948
Wellcome Trust, 085475
MRC, G0601261
European Union, Framework 7, HEALTH-F4-2007-201413
National Institute of Diabetes and Digestive and Kidney Diseases, DK098032
Oxford Biomedical Research Centre
Wellcome Trust, WT098017
Wellcome Trust, WT064890
Wellcome Trust, WT090532
Uppsala University
Uppsala University Hospital
Swedish Research Council
Swedish Heart-Lung Foundation
Wellcome Trust, Study Cohort Wellcome Trust Functional Genomics Grant, 072960/2/03/2
Wellcome Trust, Scottish Health Informatics Programme, 086113/Z/08/Z
European Community, Seventh Framework Programme, FP7/2007–2013
National Institute for Health Research
ERC, Advanced Principal Investigator award
Lundbeck Foundation
Danish Council for Independent Research
Novo Nordisk Foundation
Academy of Finland, 124243
Finnish Heart Foundation
Finnish Diabetes Foundation
Tekes, 1510/31/06
Commission of the European Community, HEALTH-F2-2007-201681
National Institutes of Health, DK093757
National Institutes of Health, DK072193
National Institutes of Health, DK062370
National Institutes of Health, 1Z01 HG000024
DK093757
DK072193
DK062370
1Z01 HG000024
Finnish Foundation for Cardiovascular Research
Academy of Finland, 139635
hospital districts of Pirkanmaa, South Ostrobothnia, and Central Finland
Finnish National Public Health Institute
Finnish Diabetes Association
Ministry of Social Affairs and Health in Finland
Academy of Finland, 129293
Commission of the European Communities, 2004310
Finland’s Slottery Machine Association
Academy of Finland, 117844
Academy of Finland, 40758
Academy of Finland, 211497
Academy of Finland, 118590
Ministry of Health and Social Affairs, 5254
Finnish Funding Agency for Technology and Innovation, 40058/07
Nordic Centre of Excellence, 070014
Finnish Diabetes Research Foundation
Yrjö Jahnsson Foundation, 56358
Sigrid Juselius Foundation
TEKES, 70103/06
TEKES, 40058/07
Ministry of Education and Culture of Finland, 627;2004-2011
Academy of Finland, 102318
Academy of Finland, 123885
Kuopio University Hospital
Finnish Diabetes Association
Finnish Heart Association
Päivikki and Sakari Sohlberg Foundation
European Commission, FP6 Integrated Project
LSHM-CT-2004-005272
City of Kuopio
Social Insurance Institution of Finland
FIN-D2D 2007
FINRISK 2007
