Dataset Information

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.

SUBMITTER: Mahajan A

PROVIDER: S-EPMC4307976 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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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 A Sim Xueling X Ng Hui Jin HJ Manning Alisa A Rivas Manuel A MA Highland Heather M HM Locke Adam E AE Grarup Niels N Im Hae Kyung HK Cingolani Pablo P Flannick Jason J Fontanillas Pierre P Fuchsberger Christian C Gaulton Kyle J KJ Teslovich Tanya M TM Rayner N William NW Robertson Neil R NR Beer Nicola L NL Rundle Jana K JK Bork-Jensen Jette J Ladenvall Claes C Blancher Christine C Buck David D Buck Gemma G Burtt Noël P NP Gabriel Stacey S Gjesing Anette P AP Groves Christopher J CJ Hollensted Mette M Huyghe Jeroen R JR Jackson Anne U AU Jun Goo G Justesen Johanne Marie JM Mangino Massimo M Murphy Jacquelyn J Neville Matt M Onofrio Robert R Small Kerrin S KS Stringham Heather M HM Syvänen Ann-Christine AC Trakalo Joseph J Abecasis Goncalo G Bell Graeme I GI Blangero John J Cox Nancy J NJ Duggirala Ravindranath R Hanis Craig L CL Seielstad Mark M Wilson James G JG Christensen Cramer C Brandslund Ivan I Rauramaa Rainer R Surdulescu Gabriela L GL Doney Alex S F AS Lannfelt Lars L Linneberg Allan A Isomaa Bo B Tuomi Tiinamaija T Jørgensen Marit E ME Jørgensen Torben T Kuusisto Johanna J Uusitupa Matti M Salomaa Veikko V Spector Timothy D TD Morris Andrew D AD Palmer Colin N A CN Collins Francis S FS Mohlke Karen L KL Bergman Richard N RN Ingelsson Erik E Lind Lars L Tuomilehto Jaakko J Hansen Torben T Watanabe Richard M RM Prokopenko Inga I Dupuis Josee J Karpe Fredrik F Groop Leif L Laakso Markku M Pedersen Oluf O Florez Jose C JC Morris Andrew P AP Altshuler David D Meigs James B JB Boehnke Michael M McCarthy Mark I MI Lindgren Cecilia M CM Gloyn Anna L AL

PLoS genetics 20150127 1

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 ...[more]

PMID: 25625282

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Project description:Background and aimsFruit traits and their inter-relationships can affect foraging choices by frugivores, and hence the probability of mutualistic interactions. Certain combinations of fruit traits that determine the interaction with specific seed dispersers are known as dispersal syndromes. The dispersal syndrome hypothesis (DSH) states that seed dispersers influence the combination of fruit traits found in fruits. Therefore, fruit traits can predict the type of dispersers with which plant species interact. Here, we analysed whether relationships of fruit traits can be explained by the DSH. To do so, we estimated the inter-relationships between morphological, chemical and display groups of fruit traits. In addition, we tested the importance of each trait group defining seed dispersal syndromes.MethodsUsing phylogenetically corrected fruit trait data and fruit-seed disperser networks, we tested the relationships among morphological, chemical and display fruit traits with Pearson's correlations and phenotypic integration indices. Then, we used perMANOVA to test if the fruit traits involved in the analysis supported the functional types of seed dispersers.Key resultsMorphological traits showed strong intragroup relationships, in contrast to chemical and display traits whose intragroup trait relationships were weak or null. Accordingly, only the morphological group of traits supported three broad seed disperser functional types (birds, terrestrial mammals and bats), consistent with the DSH.ConclusionsAltogether, our results give some support to the DSH. Here, the three groups of traits interacted in different ways with seed disperser biology. Broad functional types of seed dispersers would adjust fruit consumption to anatomical limitations imposed by fruit morphology. Once this anatomical filter is sovercome, seed dispersers use almost all the range of variation in chemical and display fruit traits. This suggests that the effect of seed dispersers on fruit traits is modulated by hierarchical decisions. First, morphological constraints define which interactions can actually occur; subsequently, display and composition determine fruit preferences.

Dataset Information

Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus.

Publications

Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus.

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