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

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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 (author)

Sim, Xueling (author)

Ng, Hui Jin (author)

Manning, Alisa (author)

Rivas, Manuel A (author)

Highland, Heather M (author)

Locke, Adam E (author)

Grarup, Niels (author)

Im, Hae Kyung (author)

Cingolani, Pablo (author)

Flannick, Jason (author)

Fontanillas, Pierre (author)

Fuchsberger, Christian (author)

Gaulton, Kyle J (author)

Teslovich, Tanya M (author)

Rayner, N William (author)

Robertson, Neil R (author)

Lannfelt, Lars (author): Uppsala universitet,Geriatrik

Rundle, Jana K (author)

Bork-Jensen, Jette (author)

Ladenvall, Claes (author): Lund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups

Blancher, Christine (author)

Buck, David (author)

Buck, Gemma (author)

Burtt, Noël P (author)

Gabriel, Stacey (author)

Gjesing, Anette P (author)

Groves, Christopher J (author)

Hollensted, Mette (author)

Huyghe, Jeroen R (author)

Jackson, Anne U (author)

Jun, Goo (author)

Justesen, Johanne Marie (author)

Mangino, Massimo (author)

Murphy, Jacquelyn (author)

Neville, Matt (author)

Onofrio, Robert (author)

Small, Kerrin S (author)

Stringham, Heather M (author)

Syvänen, Ann-Christine (author): Uppsala universitet,Molekylär medicin,Science for Life Laboratory, SciLifeLab

Trakalo, Joseph (author)

Abecasis, Goncalo (author)

Bell, Graeme I (author)

Blangero, John (author)

Cox, Nancy J (author)

Duggirala, Ravindranath (author)

Lind, Lars (author): Uppsala universitet,Kardiovaskulär epidemiologi

Seielstad, Mark (author)

Wilson, James G (author)

Christensen, Cramer (author)

Brandslund, Ivan (author)

Rauramaa, Rainer (author)

Surdulescu, Gabriela L (author)

Doney, Alex S F (author)

Lannfelt, Lars (author)

Linneberg, Allan (author)

Isomaa, Bo (author)

Tuomi, Tiinamaija (author)

Jørgensen, Marit E (author)

Jørgensen, Torben (author)

Kuusisto, Johanna (author)

Uusitupa, Matti (author)

Salomaa, Veikko (author)

Spector, Timothy D (author)

Morris, Andrew D (author)

Palmer, Colin N A (author)

Collins, Francis S (author)

Mohlke, Karen L (author)

Bergman, Richard N (author)

Ingelsson, Erik (author): Uppsala universitet,Molekylär epidemiologi,Science for Life Laboratory, SciLifeLab

Lind, Lars (author)

Tuomilehto, Jaakko (author)

Hansen, Torben (author)

Watanabe, Richard M (author)

Prokopenko, Inga (author)

Dupuis, Josee (author)

Karpe, Fredrik (author)

Groop, Leif (author): Lund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups

Laakso, Markku (author)

Pedersen, Oluf (author)

Florez, Jose C (author)

Morris, Andrew P (author)

Altshuler, David (author)

Meigs, James B (author)

Boehnke, Michael (author)

McCarthy, Mark I (author)

Lindgren, Cecilia M (author)

Gloyn, Anna L (author)

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(creator_code:org_t)

2015-01-27
2015
English.
In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 11:1

Related links:: https://portal.resea... (primary) (free); show more...; http://www.ncbi.nlm.... (free); http://dx.doi.org/10... (free); https://journals.plo...; https://doi.org/10.1...; https://uu.diva-port... (primary) (Raw object); https://lup.lub.lu.s...; https://doi.org/10.1...; https://urn.kb.se/re...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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.

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By the author/editor: Mahajan, Anubha; Sim, Xueling; Ng, Hui Jin; Manning, Alisa; Rivas, Manuel A; Highland, Heathe ...; show more...; Locke, Adam E; Grarup, Niels; Im, Hae Kyung; Cingolani, Pablo; Flannick, Jason; Fontanillas, Pie ...; Fuchsberger, Chr ...; Gaulton, Kyle J; Teslovich, Tanya ...; Rayner, N Willia ...; Robertson, Neil ...; Lannfelt, Lars; Rundle, Jana K; Bork-Jensen, Jet ...; Ladenvall, Claes; Blancher, Christ ...; Buck, David; Buck, Gemma; Burtt, Noël P; Gabriel, Stacey; Gjesing, Anette ...; Groves, Christop ...; Hollensted, Mett ...; Huyghe, Jeroen R; Jackson, Anne U; Jun, Goo; Justesen, Johann ...; Mangino, Massimo; Murphy, Jacquely ...; Neville, Matt; Onofrio, Robert; Small, Kerrin S; Stringham, Heath ...; Syvänen, Ann-Chr ...; Trakalo, Joseph; Abecasis, Goncal ...; Bell, Graeme I; Blangero, John; Cox, Nancy J; Duggirala, Ravin ...; Lind, Lars; Seielstad, Mark; Wilson, James G; Christensen, Cra ...; Brandslund, Ivan; Rauramaa, Rainer; Surdulescu, Gabr ...; Doney, Alex S F; Linneberg, Allan; Isomaa, Bo; Tuomi, Tiinamaij ...; Jørgensen, Marit ...; Jørgensen, Torbe ...; Kuusisto, Johann ...; Uusitupa, Matti; Salomaa, Veikko; Spector, Timothy ...; Morris, Andrew D; Palmer, Colin N ...; Collins, Francis ...; Mohlke, Karen L; Bergman, Richard ...; Ingelsson, Erik; Tuomilehto, Jaak ...; Hansen, Torben; Watanabe, Richar ...; 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, Cecili ...; Gloyn, Anna L; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Endocrinology an ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Medical Genetics

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

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