Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus.
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Authors
Mahajan, Anubha
Sim, Xueling
Ng, Hui Jin
Manning, Alisa
Rivas, Manuel A
Highland, Heather M
Locke, Adam E
Grarup, Niels
Im, Hae Kyung
Cingolani, Pablo
Flannick, Jason
Fontanillas, Pierre
Fuchsberger, Christian
Gaulton, Kyle J
Teslovich, Tanya M
Rayner, N William
Robertson, Neil R
Beer, Nicola L
Rundle, Jana K
Bork-Jensen, Jette
Ladenvall, Claes
Blancher, Christine
Buck, David
Buck, Gemma
Burtt, Noël P
Gabriel, Stacey
Gjesing, Anette P
Groves, Christopher J
Hollensted, Mette
Huyghe, Jeroen R
Jackson, Anne U
Jun, Goo
Justesen, Johanne Marie
Mangino, Massimo
Murphy, Jacquelyn
Neville, Matt
Onofrio, Robert
Small, Kerrin S
Stringham, Heather M
Syvänen, Ann-Christine
Trakalo, Joseph
Abecasis, Goncalo
Bell, Graeme I
Blangero, John
Cox, Nancy J
Duggirala, Ravindranath
Hanis, Craig L
Seielstad, Mark
Wilson, James G
Christensen, Cramer
Brandslund, Ivan
Rauramaa, Rainer
Surdulescu, Gabriela L
Doney, Alex SF
Lannfelt, Lars
Linneberg, Allan
Isomaa, Bo
Tuomi, Tiinamaija
Jørgensen, Marit E
Jørgensen, Torben
Kuusisto, Johanna
Uusitupa, Matti
Salomaa, Veikko
Spector, Timothy D
Morris, Andrew D
Palmer, Colin NA
Collins, Francis S
Mohlke, Karen L
Bergman, Richard N
Ingelsson, Erik
Lind, Lars
Tuomilehto, Jaakko
Hansen, Torben
Watanabe, Richard M
Prokopenko, Inga
Dupuis, Josee
Karpe, Fredrik
Groop, Leif
Laakso, Markku
Pedersen, Oluf
Florez, Jose C
Morris, Andrew P
Altshuler, David
Meigs, James B
Boehnke, Michael
McCarthy, Mark I
Lindgren, Cecilia M
Gloyn, Anna L
T2D-GENES, consortium and GoT2D consortium
Publication Date
2015-01-27Journal Title
PLoS genetics
ISSN
1553-7390
Volume
11
Pages
e1004876
Language
English
Type
Article
This Version
VoR
Physical Medium
Electronic-eCollection
Metadata
Show full item recordCitation
Mahajan, A., Sim, X., Ng, H. J., Manning, A., Rivas, M. A., Highland, H. M., Locke, A. E., et al. (2015). Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus.. PLoS genetics, 11 e1004876. https://doi.org/10.1371/journal.pgen.1004876
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.
Keywords
T2D-GENES consortium and GoT2D consortium, Humans, Diabetes Mellitus, Type 2, Insulin, Glucose-6-Phosphatase, Blood Glucose, Receptors, Glucagon, Glycemic Index, Gene Frequency, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Exome, Glucagon-Like Peptide-1 Receptor
Sponsorship
MRC (MC_UU_12015/1)
Identifiers
External DOI: https://doi.org/10.1371/journal.pgen.1004876
This record's URL: https://www.repository.cam.ac.uk/handle/1810/260089
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