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Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus.

Mahajan, A and Sim, X and Ng, HJ and Manning, A and Rivas, MA and Highland, HM and Locke, AE and Grarup, N and Im, HK and Cingolani, P and Flannick, J and Fontanillas, P and Fuchsberger, C and Gaulton, KJ and Teslovich, TM and Rayner, NW and Robertson, NR and Beer, NL and Rundle, JK and Bork-Jensen, J and Ladenvall, C and Blancher, C and Buck, D and Buck, G and Burtt, NP and Gabriel, S and Gjesing, AP and Groves, CJ and Hollensted, M and Huyghe, JR and Jackson, AU and Jun, G and Justesen, JM and Mangino, M and Murphy, J and Neville, M and Onofrio, R and Small, KS and Stringham, HM and Syvänen, A-C and Trakalo, J and Abecasis, G and Bell, GI and Blangero, J and Cox, NJ and Duggirala, R and Hanis, CL and Seielstad, M and Wilson, JG and Christensen, C and Brandslund, I and Rauramaa, R and Surdulescu, GL and Doney, ASF and Lannfelt, L and Linneberg, A and Isomaa, B and Tuomi, T and Jørgensen, ME and Jørgensen, T and Kuusisto, J and Uusitupa, M and Salomaa, V and Spector, TD and Morris, AD and Palmer, CNA and Collins, FS and Mohlke, KL and Bergman, RN and Ingelsson, E and Lind, L and Tuomilehto, J and Hansen, T and Watanabe, RM and Prokopenko, I and Dupuis, J and Karpe, F and Groop, L and Laakso, M and Pedersen, O and Florez, JC and Morris, AP and Altshuler, D and Meigs, JB and Boehnke, M and McCarthy, MI and Lindgren, CM and Gloyn, AL and T2D-GENES consortium and GoT2D consortium, (2014) Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus. PLoS Genet, 11. e1004876-e1004876.

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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.

Item Type: Article
Uncontrolled Keywords: Blood Glucose Diabetes Mellitus, Type 2 Exome Gene Frequency Genome-Wide Association Study Glucagon-Like Peptide-1 Receptor Glucose-6-Phosphatase Glycemic Index Humans Insulin Polymorphism, Single Nucleotide Receptors, Glucagon
Divisions: Div D > Structures
Depositing User: Cron Job
Date Deposited: 17 Jul 2017 18:59
Last Modified: 22 Feb 2018 01:43