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

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Fältnamn	Indikatorer	Metadata
000		08114naa a2201465 4500
001		oai:lup.lub.lu.se:92e5271a-2f84-40bf-9352-b6d46d93d415
003		SwePub
008		160401s2015 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
009		oai:DiVA.org:uu-242802
024	7	a https://lup.lub.lu.se/record/50394642 URI
024	7	a https://doi.org/10.1371/journal.pgen.10048762 DOI
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2428022 URI
040		a (SwePub)lud (SwePub)uu
041		a engb eng
042		9 SwePub
072	7	a art2 swepub-publicationtype
072	7	a ref2 swepub-contenttype
100	1	a Mahajan, Anubha4 aut
245	1 0	a Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus.
264		c 2015-01-27
264	1	b Public Library of Science (PLoS),c 2015
338		a electronic2 rdacarrier
520		a 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.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Endokrinologi och diabetes0 (SwePub)302052 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Endocrinology and Diabetes0 (SwePub)302052 hsv//eng
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Medicinsk genetik0 (SwePub)301072 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Medical Genetics0 (SwePub)301072 hsv//eng
700	1	a Sim, Xueling4 aut
700	1	a Ng, Hui Jin4 aut
700	1	a Manning, Alisa4 aut
700	1	a Rivas, Manuel A4 aut
700	1	a Highland, Heather M4 aut
700	1	a Locke, Adam E4 aut
700	1	a Grarup, Niels4 aut
700	1	a Im, Hae Kyung4 aut
700	1	a Cingolani, Pablo4 aut
700	1	a Flannick, Jason4 aut
700	1	a Fontanillas, Pierre4 aut
700	1	a Fuchsberger, Christian4 aut
700	1	a Gaulton, Kyle J4 aut
700	1	a Teslovich, Tanya M4 aut
700	1	a Rayner, N William4 aut
700	1	a Robertson, Neil R4 aut
700	1	a Lannfelt, Larsu Uppsala universitet,Geriatrik4 aut0 (Swepub:uu)lalan021
700	1	a Rundle, Jana K4 aut
700	1	a Bork-Jensen, Jette4 aut
700	1	a Ladenvall, Claesu Lund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups4 aut0 (Swepub:lu)med-cll
700	1	a Blancher, Christine4 aut
700	1	a Buck, David4 aut
700	1	a Buck, Gemma4 aut
700	1	a Burtt, Noël P4 aut
700	1	a Gabriel, Stacey4 aut
700	1	a Gjesing, Anette P4 aut
700	1	a Groves, Christopher J4 aut
700	1	a Hollensted, Mette4 aut
700	1	a Huyghe, Jeroen R4 aut
700	1	a Jackson, Anne U4 aut
700	1	a Jun, Goo4 aut
700	1	a Justesen, Johanne Marie4 aut
700	1	a Mangino, Massimo4 aut
700	1	a Murphy, Jacquelyn4 aut
700	1	a Neville, Matt4 aut
700	1	a Onofrio, Robert4 aut
700	1	a Small, Kerrin S4 aut
700	1	a Stringham, Heather M4 aut
700	1	a Syvänen, Ann-Christineu Uppsala universitet,Molekylär medicin,Science for Life Laboratory, SciLifeLab4 aut0 (Swepub:uu)anncsyva
700	1	a Trakalo, Joseph4 aut
700	1	a Abecasis, Goncalo4 aut
700	1	a Bell, Graeme I4 aut
700	1	a Blangero, John4 aut
700	1	a Cox, Nancy J4 aut
700	1	a Duggirala, Ravindranath4 aut
700	1	a Lind, Larsu Uppsala universitet,Kardiovaskulär epidemiologi4 aut0 (Swepub:uu)larslind
700	1	a Seielstad, Mark4 aut
700	1	a Wilson, James G4 aut
700	1	a Christensen, Cramer4 aut
700	1	a Brandslund, Ivan4 aut
700	1	a Rauramaa, Rainer4 aut
700	1	a Surdulescu, Gabriela L4 aut
700	1	a Doney, Alex S F4 aut
700	1	a Lannfelt, Lars4 aut
700	1	a Linneberg, Allan4 aut
700	1	a Isomaa, Bo4 aut
700	1	a Tuomi, Tiinamaija4 aut
700	1	a Jørgensen, Marit E4 aut
700	1	a Jørgensen, Torben4 aut
700	1	a Kuusisto, Johanna4 aut
700	1	a Uusitupa, Matti4 aut
700	1	a Salomaa, Veikko4 aut
700	1	a Spector, Timothy D4 aut
700	1	a Morris, Andrew D4 aut
700	1	a Palmer, Colin N A4 aut
700	1	a Collins, Francis S4 aut
700	1	a Mohlke, Karen L4 aut
700	1	a Bergman, Richard N4 aut
700	1	a Ingelsson, Eriku Uppsala universitet,Molekylär epidemiologi,Science for Life Laboratory, SciLifeLab4 aut0 (Swepub:uu)ering425
700	1	a Lind, Lars4 aut
700	1	a Tuomilehto, Jaakko4 aut
700	1	a Hansen, Torben4 aut
700	1	a Watanabe, Richard M4 aut
700	1	a Prokopenko, Inga4 aut
700	1	a Dupuis, Josee4 aut
700	1	a Karpe, Fredrik4 aut
700	1	a Groop, Leifu Lund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups4 aut0 (Swepub:lu)endo-lgr
700	1	a Laakso, Markku4 aut
700	1	a Pedersen, Oluf4 aut
700	1	a Florez, Jose C4 aut
700	1	a Morris, Andrew P4 aut
700	1	a Altshuler, David4 aut
700	1	a Meigs, James B4 aut
700	1	a Boehnke, Michael4 aut
700	1	a McCarthy, Mark I4 aut
700	1	a Lindgren, Cecilia M4 aut
700	1	a Gloyn, Anna L4 aut
710	2	a Uppsala universitetb Geriatrik4 org
773	0	t PLoS Geneticsd : Public Library of Science (PLoS)g 11:1q 11:1x 1553-7404x 1553-7390
856	4	u https://portal.research.lu.se/files/1681182/7753969.pdfx primaryx freey FULLTEXT
856	4	u http://www.ncbi.nlm.nih.gov/pubmed/25625282?dopt=Abstractx freey FULLTEXT
856	4	u http://dx.doi.org/10.1371/journal.pgen.1004876x freey FULLTEXT
856	4	u https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1004876&type=printable
856	4	u https://doi.org/10.1371/journal.pgen.1004876y Fulltext
856	4	u https://uu.diva-portal.org/smash/get/diva2:785134/FULLTEXT01.pdfx primaryx Raw objecty fulltext:print
856	4 8	u https://lup.lub.lu.se/record/5039464
856	4 8	u https://doi.org/10.1371/journal.pgen.1004876
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-242802

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Av författaren/redakt...: Mahajan, Anubha; Sim, Xueling; Ng, Hui Jin; Manning, Alisa; Rivas, Manuel A; Highland, Heathe ...; visa fler...; 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; visa färre...

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Endokrinologi oc ...

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