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

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title = "Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus.",
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.",
author = "Anubha Mahajan and Xueling Sim and Ng, {Hui Jin} and Alisa Manning and Rivas, {Manuel A} and Highland, {Heather M} and Locke, {Adam E} and Niels Grarup and Im, {Hae Kyung} and Pablo Cingolani and Jason Flannick and Pierre Fontanillas and Christian Fuchsberger and Gaulton, {Kyle J} and Teslovich, {Tanya M} and Rayner, {N William} and Robertson, {Neil R} and Beer, {Nicola L} and Rundle, {Jana K} and Jette Bork-Jensen and Claes Ladenvall and Christine Blancher and David Buck and Gemma Buck and Burtt, {No{\"e}l P} and Stacey Gabriel and Gjesing, {Anette P} and Groves, {Christopher J} and Mette Hollensted and Huyghe, {Jeroen R} and Jackson, {Anne U} and Goo Jun and Justesen, {Johanne Marie} and Massimo Mangino and Jacquelyn Murphy and Matt Neville and Robert Onofrio and Small, {Kerrin S} and Stringham, {Heather M} and Ann-Christine Syv{\"a}nen and Joseph Trakalo and Goncalo Abecasis and Bell, {Graeme I} and John Blangero and Cox, {Nancy J} and Ravindranath Duggirala and Hanis, {Craig L} and Mark Seielstad and Wilson, {James G} and Cramer Christensen and Ivan Brandslund and Rainer Rauramaa and Surdulescu, {Gabriela L} and Doney, {Alex S F} and Lars Lannfelt and Allan Linneberg and Bo Isomaa and Tiinamaija Tuomi and J{\o}rgensen, {Marit E} and Torben J{\o}rgensen and Johanna Kuusisto and Matti Uusitupa and Veikko Salomaa and Spector, {Timothy D} and Morris, {Andrew D} and Palmer, {Colin N A} and Collins, {Francis S} and Mohlke, {Karen L} and Bergman, {Richard N} and Erik Ingelsson and Lars Lind and Jaakko Tuomilehto and Torben Hansen and Watanabe, {Richard M} and Inga Prokopenko and Josee Dupuis and Fredrik Karpe and Leif Groop and Markku Laakso and Oluf Pedersen and Florez, {Jose C} and Morris, {Andrew P} and David Altshuler and Meigs, {James B} and Michael Boehnke and McCarthy, {Mark I} and Lindgren, {Cecilia M} and Gloyn, {Anna L}",
year = "2015",
doi = "10.1371/journal.pgen.1004876",
language = "English",
volume = "11",
journal = "PLoS Genetics",
issn = "1553-7404",
publisher = "Public Library of Science",
number = "1",