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

doi:10.1371/journal.pgen.1004876

↓ Direkt till sidans innehåll
↓ Direkt till sidans sekundära innehåll (sidomenyn)

Search: WFRF:(Rundle Jana K) > Identification and ...

1 of 1
Previous record
Next record
To hitlist

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)

(publisher)

2015
2015
English.
In: PLOS Genetics. - 1553-7390. ; 11:1

swepub:Mat__t

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.

Find in a library

PLOS Genetics (Search for host publication in LIBRIS)

To the university's database

1 of 1
Previous record
Next record
To hitlist

Find more in SwePub

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 ...; Beer, Nicola L; 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 ...; Hanis, Craig L; Seielstad, Mark; Wilson, James G; Christensen, Cra ...; Brandslund, Ivan; Rauramaa, Rainer; Surdulescu, Gabr ...; Doney, Alex S F; Lannfelt, Lars; 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; Lind, Lars; 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...

By the university: Swepub_uni:_t

Search outside SwePub

Extend your search to:: Google; Google Book Search; Google Scholar

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

LIBRIS.kb.se