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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, Anubha; Sim, Xueling; Ng, Hui Jin; Manning, Alisa; Rivas, Manuel A; Highland, Heather M; Locke, Adam E; Grarup, Niels; Im, Hae Kyung and Cingolani, Pablo, et al. (2015) In PLoS Genetics 11(1).
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)... (More)
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. (Less)
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  • pmid:25625282
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1553-7404
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10.1371/journal.pgen.1004876
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@article{92e5271a-2f84-40bf-9352-b6d46d93d415,
  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&lt;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.},
  articleno    = {e1004876},
  author       = {Mahajan, Anubha and Sim, Xueling and Ng, Hui Jin and Manning, Alisa and Rivas, Manuel A and Highland, Heather M and Locke, Adam E and Grarup, Niels and Im, Hae Kyung and Cingolani, Pablo and Flannick, Jason and Fontanillas, Pierre and Fuchsberger, Christian 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 Bork-Jensen, Jette and Ladenvall, Claes and Blancher, Christine and Buck, David and Buck, Gemma and Burtt, Noël P and Gabriel, Stacey and Gjesing, Anette P and Groves, Christopher J and Hollensted, Mette and Huyghe, Jeroen R and Jackson, Anne U and Jun, Goo and Justesen, Johanne Marie and Mangino, Massimo and Murphy, Jacquelyn and Neville, Matt and Onofrio, Robert and Small, Kerrin S and Stringham, Heather M and Syvänen, Ann-Christine and Trakalo, Joseph and Abecasis, Goncalo and Bell, Graeme I and Blangero, John and Cox, Nancy J and Duggirala, Ravindranath and Hanis, Craig L and Seielstad, Mark and Wilson, James G and Christensen, Cramer and Brandslund, Ivan and Rauramaa, Rainer and Surdulescu, Gabriela L and Doney, Alex S F and Lannfelt, Lars and Linneberg, Allan and Isomaa, Bo and Tuomi, Tiinamaija and Jørgensen, Marit E and Jørgensen, Torben and Kuusisto, Johanna and Uusitupa, Matti and Salomaa, Veikko 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 Ingelsson, Erik and Lind, Lars and Tuomilehto, Jaakko and Hansen, Torben and Watanabe, Richard M and Prokopenko, Inga and Dupuis, Josee and Karpe, Fredrik and Groop, Leif and Laakso, Markku and Pedersen, Oluf and Florez, Jose C and Morris, Andrew P and Altshuler, David and Meigs, James B and Boehnke, Michael and McCarthy, Mark I and Lindgren, Cecilia M and Gloyn, Anna L},
  issn         = {1553-7404},
  language     = {eng},
  number       = {1},
  publisher    = {Public Library of Science},
  series       = {PLoS Genetics},
  title        = {Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus.},
  url          = {http://dx.doi.org/10.1371/journal.pgen.1004876},
  volume       = {11},
  year         = {2015},
}