Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus
dc.contributor.author | Mahajan, A | |
dc.contributor.author | Sim, X | |
dc.contributor.author | Ng, HJ | |
dc.contributor.author | Manning, A | |
dc.contributor.author | Rivas, MA | |
dc.contributor.author | Highland, HM | |
dc.contributor.author | Locke, AE | |
dc.contributor.author | Grarup, N | |
dc.contributor.author | Im, HK | |
dc.contributor.author | Cingolani, P | |
dc.contributor.author | Flannick, J | |
dc.contributor.author | Fontanillas, P | |
dc.contributor.author | Fuchsberger, C | |
dc.contributor.author | Gaulton, KJ | |
dc.contributor.author | Teslovich, TM | |
dc.contributor.author | Rayner, NW | |
dc.contributor.author | Robertson, NR | |
dc.contributor.author | Beer, NL | |
dc.contributor.author | Rundle, JK | |
dc.contributor.author | Bork-Jensen, J | |
dc.contributor.author | Ladenvall, C | |
dc.contributor.author | Blancher, C | |
dc.contributor.author | Buck, D | |
dc.contributor.author | Buck, G | |
dc.contributor.author | Burtt, NP | |
dc.contributor.author | Gabriel, S | |
dc.contributor.author | Gjesing, AP | |
dc.contributor.author | Groves, CJ | |
dc.contributor.author | Hollensted, M | |
dc.contributor.author | Huyghe, JR | |
dc.contributor.author | Jackson, AU | |
dc.contributor.author | Jun, G | |
dc.contributor.author | Justesen, JM | |
dc.contributor.author | Mangino, M | |
dc.contributor.author | Murphy, J | |
dc.contributor.author | Neville, M | |
dc.contributor.author | Onofrio, R | |
dc.contributor.author | Small, KS | |
dc.contributor.author | Stringham, HM | |
dc.contributor.author | Syvänen, AC | |
dc.contributor.author | Trakalo, J | |
dc.contributor.author | Abecasis, G | |
dc.contributor.author | Bell, GI | |
dc.contributor.author | Blangero, J | |
dc.contributor.author | Cox, NJ | |
dc.contributor.author | Duggirala, R | |
dc.contributor.author | Hanis, CL | |
dc.contributor.author | Seielstad, M | |
dc.contributor.author | Wilson, JG | |
dc.contributor.author | Christensen, C | |
dc.contributor.author | Brandslund, I | |
dc.contributor.author | Rauramaa, R | |
dc.contributor.author | Surdulescu, GL | |
dc.contributor.author | Doney, ASF | |
dc.contributor.author | Lannfelt, L | |
dc.contributor.author | Linneberg, A | |
dc.contributor.author | Isomaa, B | |
dc.contributor.author | Tuomi, T | |
dc.contributor.author | Jørgensen, ME | |
dc.contributor.author | Jørgensen, T | |
dc.contributor.author | Kuusisto, J | |
dc.contributor.author | Uusitupa, M | |
dc.contributor.author | Salomaa, V | |
dc.contributor.author | Spector, TD | |
dc.contributor.author | Morris, AD | |
dc.contributor.author | Palmer, CNA | |
dc.contributor.author | Collins, FS | |
dc.contributor.author | Mohlke, KL | |
dc.contributor.author | Bergman, RN | |
dc.contributor.author | Ingelsson, E | |
dc.contributor.author | Lind, L | |
dc.contributor.author | Tuomilehto, J | |
dc.contributor.author | Hansen, T | |
dc.contributor.author | Watanabe, RM | |
dc.contributor.author | Prokopenko, I | |
dc.contributor.author | Dupuis, J | |
dc.contributor.author | Karpe, F | |
dc.contributor.author | Groop, L | |
dc.contributor.author | Laakso, M | |
dc.contributor.author | Pedersen, O | |
dc.contributor.author | Florez, JC | |
dc.contributor.author | Morris, AP | |
dc.contributor.author | Altshuler, D | |
dc.contributor.author | Meigs, JB | |
dc.contributor.author | Boehnke, M | |
dc.contributor.author | McCarthy, MI | |
dc.contributor.author | Lindgren, CM | |
dc.contributor.author | Gloyn, AL | |
dc.contributor.author | Abboud, HE | |
dc.contributor.author | Afzal, U | |
dc.contributor.author | Aguilar, D | |
dc.contributor.author | Arya, R | |
dc.contributor.author | Atzmon, G | |
dc.contributor.author | Aung, T | |
dc.contributor.author | Banks, E | |
dc.contributor.author | Barroso, I | |
dc.contributor.author | Barzilai, N | |
dc.contributor.author | Below, JE | |
dc.contributor.author | Bharadwaj, D | |
dc.contributor.author | Blackwell, TW | |
dc.date.accessioned | 2020-10-22T12:01:33Z | |
dc.date.issued | 2015-01-27 | |
dc.description.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. | en_GB |
dc.identifier.citation | Vol. 11 (1), article e1004876 | en_GB |
dc.identifier.doi | 10.1371/journal.pgen.1004876 | |
dc.identifier.uri | http://hdl.handle.net/10871/123331 | |
dc.language.iso | en | en_GB |
dc.publisher | Public Library of Science (PLoS) | en_GB |
dc.relation.url | http://www.diagram-consortium.org/Mahajan_2014_ExomeChip/ | en_GB |
dc.relation.url | http://csg.sph.umich.edu/locuszoom/ | en_GB |
dc.rights | This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication | en_GB |
dc.title | Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2020-10-22T12:01:33Z | |
dc.identifier.issn | 1553-7390 | |
dc.description | This is the final version. Available on open access from the Public Library of Science via the DOI in this record | en_GB |
dc.description | 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. | en_GB |
dc.identifier.journal | PLoS Genetics | en_GB |
dc.rights.uri | https://creativecommons.org/publicdomain/zero/1.0/ | en_GB |
pubs.euro-pubmed-id | MED:25625282 | |
dcterms.dateAccepted | 2014-11-04 | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2015-01-27 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2020-10-22T11:58:52Z | |
refterms.versionFCD | VoR | |
refterms.dateFOA | 2020-10-22T12:01:46Z | |
refterms.panel | A | en_GB |
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