Biological Sciences Division
Published January 27, 2015 | Version v1
Journal article Open

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

Creators

  • 1. University of Oxford
  • 2. University of Michigan
  • 3. Broad Institute
  • 4. University of Texas Health Science Center at Houston
  • 5. University of Copenhagen
  • 6. University of Chicago
  • 7. McGill University
  • 8. Massachusetts General Hospital
  • 9. Lund University
  • 10. King's College London
  • 11. Uppsala University
  • 12. Texas Biomedical Research Institute

Description

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.

Notes

Due to the large number of authors, only the first 20 and the University of Chicago authors are included on the above author list. Please download the article for the complete list of authors.

Data availability

This is a meta-analysis that was conducted on summary level results. Individual level data was not shared amongst the authors of the manuscript, and the corresponding authors are not in a position to make the individual level data available. For most of the samples included, individual level data deposition is precluded by existing consents, and other issues related to individual privacy. Summary level data from the meta-analysis are available from the DIAGRAM (http://www.diagram-consortium.org/Mahajan_2014_ExomeChip/) and LocusZoom (http://csg.sph.umich.edu/locuszoom/) website.

Files

journal.pgen.1004876.pdf

Files (4.8 MB)

Name Size Download all
Article
md5:624aad64f050660607b412f4db37377b
3.9 MB Preview Download
md5:87a0d42489d948aa028a274e8edc431b
869.1 kB Preview Download

Additional details

Identifiers

DOI
10.1371/journal.pgen.1004876
Other
oai:uchicago.tind.io:10885

Funding

Agency for Science, Technology and Research
FWF Austrian Science Fund
J-3401
Massachusetts General Hospital
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 Institutes of Health
Wellcome Trust
Research Career Development Fellowship
Wellcome Trust
Senior Research Fellowship in Basic and Biomedical Science
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
Medical Research Council
G0601261
European Union
Framework 7
National Institute of Diabetes and Digestive and Kidney Diseases
DK098032
Oxford Biomedical Research
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
Wellcome Trust
Scottish Health Informatics Programme
European Commission
Seventh Framework Programme
National Institute for Health and Care Research
European Research Council
Advanced Principal Investigator award
Lundbeck Foundation
Danmarks Frie Forskningsfond
Novo Nordisk Foundation
Research Council of Finland
124243
Finnish Foundation for Cardiovascular Research
Finnish Diabetes Association
Tekes
1510/31/06
European Commission
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
National Institutes of Health
DK093757
National Institutes of Health
DK072193
National Institutes of Health
DK062370
National Institutes of Health
1Z01 HG000024
Finnish Foundation for Cardiovascular Research
Research Council of Finland
139635
Finnish Institute for Health and Welfare
Finnish Diabetes Association
Ministry of Social Affairs and Health
Research Council of Finland
129293
European Commission
2004310
Unknown funder
Finnish Slot Machine Association
Research Council of Finland
117844
Research Council of Finland
40758
Research Council of Finland
211497
Research Council of Finland
118590
Ministry of Social Affairs and Health
5254
Tekes
40058/07
NordForsk
070014
Diabetes Tutkimussaatio
Yrjö Jahnsson Foundation
56358
Sigrid Jusélius Foundation
Tekes
70103/06
Tekes
40058/07
Ministry of Education and Culture
627;2004-2011
Research Council of Finland
102318
Research Council of Finland
123885
Kuopio University Hospital
Finnish Heart Association
Päivikki and Sakari Sohlberg Foundation
European Commission
FP6 Integrated Project
Social Insurance Institution
LSHM-CT-2004-005272
City of Kuopio
Pirkanmaa Hospital District
Etelä-Pohjanmaan Sairaanhoitopiiri
Central Finland Health Care District

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Human Genetics, Medicine, Public Health Sciences