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

Anubha Mahajan; Xueling Sim; Hui Jin Ng; Alisa Manning; Manuel A Rivas; Heather M Highland; Adam E Locke; Niels Grarup; Hae Kyung Im; Pablo Cingolani; Jason Flannick; Pierre Fontanillas; Christian Fuchsberger; Kyle J Gaulton; Tanya M Teslovich; N William Rayner; Neil R Robertson; Nicola L Beer; Jana K Rundle; Jette Bork-Jensen; Claes Ladenvall; Christine Blancher; David Buck; Gemma Buck; Noël P Burtt; Stacey Gabriel; Anette P Gjesing; Christopher J Groves; Mette Hollensted; Jeroen R Huyghe; Anne U Jackson; Goo Jun; Johanne Marie Justesen; Massimo Mangino; Jacquelyn Murphy; Matt Neville; Robert Onofrio; Kerrin S Small; Heather M Stringham; Ann-Christine Syvänen; Joseph Trakalo; Goncalo Abecasis; Graeme I Bell; John Blangero; Nancy J Cox; Ravindranath Duggirala; Craig L Hanis; Mark Seielstad; James G Wilson; Cramer Christensen; Ivan Brandslund; Rainer Rauramaa; Gabriela L Surdulescu; Alex S F Doney; Lars Lannfelt; Allan Linneberg; Bo Isomaa; Tiinamaija Tuomi; Marit E Jørgensen; Torben Jørgensen; Johanna Kuusisto; Matti Uusitupa; Veikko Salomaa; Timothy D Spector; Andrew D Morris; Colin N A Palmer; Francis S Collins; Karen L Mohlke; Richard N Bergman; Erik Ingelsson; Lars Lind; Jaakko Tuomilehto; Torben Hansen; Richard M Watanabe; Inga Prokopenko; Josee Dupuis; Fredrik Karpe; Leif Groop; Markku Laakso; Oluf Pedersen; Jose C Florez; Andrew P Morris; David Altshuler; James B Meigs; Michael Boehnke; Mark I McCarthy; Cecilia M Lindgren; Anna L Gloyn; T2D-GENES consortium and GoT2D consortium

doi:10.1371/journal.pgen.1004876

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

Anubha Mahajan, Xueling Sim, Hui Jin Ng, Alisa Manning, Manuel A Rivas, Heather M Highland, Adam E Locke, Niels Grarup, Hae Kyung Im, Pablo Cingolani, …

PLoS genetics, Vol.11(1), pp.e1004876-e1004876

01/01/2015

DOI: https://doi.org/10.1371/journal.pgen.1004876

PMID: 25625282

Abstract

Blood Glucose - genetics

Diabetes Mellitus, Type 2 - blood

Diabetes Mellitus, Type 2 - genetics

Diabetes Mellitus, Type 2 - pathology

Exome - genetics

Gene Frequency

Genome-Wide Association Study

Glucagon-Like Peptide-1 Receptor

Glucose-6-Phosphatase - genetics

Glycemic Index - genetics

Humans

Insulin - blood

Insulin - genetics

Polymorphism, Single Nucleotide

Receptors, Glucagon - genetics

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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Title: Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus
Creators: Anubha Mahajan - University of Oxford
Xueling Sim - Michigan United
Hui Jin Ng - University of Oxford
Alisa Manning - Broad Institute
Manuel A Rivas - University of Oxford
Heather M Highland - The University of Texas Health Science Center at Houston
Adam E Locke - Michigan United
Niels Grarup - University of Copenhagen
Hae Kyung Im - University of Chicago
Pablo Cingolani - McGill University
Jason Flannick - Broad Institute
Pierre Fontanillas - Broad Institute
Christian Fuchsberger - Michigan United
Kyle J Gaulton - Wellcome Centre for Human Genetics
Tanya M Teslovich - Michigan United
N William Rayner - Oxford Centre for Diabetes, Endocrinology and Metabolism
Neil R Robertson - University of Oxford
Nicola L Beer - Oxford Centre for Diabetes, Endocrinology and Metabolism
Jana K Rundle - Oxford Centre for Diabetes, Endocrinology and Metabolism
Jette Bork-Jensen - University of Copenhagen
Claes Ladenvall - Lund University
Christine Blancher - Genomics
David Buck - University of Oxford
Gemma Buck - Genomics
Noël P Burtt - Broad Institute
Stacey Gabriel - Broad Institute
Anette P Gjesing - University of Copenhagen
Christopher J Groves - Oxford Centre for Diabetes, Endocrinology and Metabolism
Mette Hollensted - University of Copenhagen
Jeroen R Huyghe - University of Michigan–Ann Arbor
Anne U Jackson - University of Michigan–Ann Arbor
Goo Jun - University of Michigan–Ann Arbor
Johanne Marie Justesen - Novo Nordisk Foundation
Massimo Mangino - King's College London
Jacquelyn Murphy - Broad Institute
Matt Neville - University of Oxford
Robert Onofrio - Broad Institute
Kerrin S Small - King's College London
Heather M Stringham - University of Michigan–Ann Arbor
Ann-Christine Syvänen - Uppsala University
Joseph Trakalo - Wellcome Centre for Human Genetics
Goncalo Abecasis - University of Michigan–Ann Arbor
Graeme I Bell - University of Chicago
John Blangero - Texas Biomedical Research Institute
Nancy J Cox - University of Chicago
Ravindranath Duggirala - Texas Biomedical Research Institute
Craig L Hanis - The University of Texas Health Science Center at Houston
Mark Seielstad - University of California, San Francisco
James G Wilson - University of Mississippi Medical Center
Cramer Christensen - Vejle Sygehus
Ivan Brandslund - Vejle Sygehus
Rainer Rauramaa - Foundation for Research in Health, Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland
Gabriela L Surdulescu - King's College London
Alex S F Doney - Ninewells Hospital
Lars Lannfelt - Uppsala University
Allan Linneberg - University of Copenhagen
Bo Isomaa - Folkhälsans Forskningscentrum
Tiinamaija Tuomi
Marit E Jørgensen - Steno Diabetes Center
Torben Jørgensen - Aalborg University
Johanna Kuusisto - Kuopio University Hospital
Matti Uusitupa - University of Eastern Finland
Veikko Salomaa - Finnish Institute for Health and Welfare
Timothy D Spector - King's College London
Andrew D Morris - Ninewells Hospital
Colin N A Palmer - Ninewells Hospital
Francis S Collins - National Human Genome Research Institute
Karen L Mohlke - University of North Carolina at Chapel Hill
Richard N Bergman - Cedars-Sinai Medical Center
Erik Ingelsson - Science for Life Laboratory
Lars Lind - Uppsala University
Jaakko Tuomilehto - King Abdulaziz University
Torben Hansen - Novo Nordisk Foundation
Richard M Watanabe - University of Southern California
Inga Prokopenko - Oxford Centre for Diabetes, Endocrinology and Metabolism
Josee Dupuis - Boston University
Fredrik Karpe - Oxford Centre for Diabetes, Endocrinology and Metabolism
Leif Groop - Lund University
Markku Laakso - University of Eastern Finland
Oluf Pedersen - University of Copenhagen
Jose C Florez - Massachusetts General Hospital
Andrew P Morris - University of Liverpool
David Altshuler - Broad Institute
James B Meigs - Massachusetts General Hospital
Michael Boehnke - University of Michigan–Ann Arbor
Mark I McCarthy - Wellcome Centre for Human Genetics
Cecilia M Lindgren - University of Oxford
Anna L Gloyn - University of Oxford
T2D-GENES consortium and GoT2D consortium
Publication Details: PLoS genetics, Vol.11(1), pp.e1004876-e1004876
Date published: 01/01/2015
Grant note: R01 DK062370 / NIDDK NIH HHS Wellcome Trust U01 DK085524 / NIDDK NIH HHS U01 DK078616 / NIDDK NIH HHS RC2 DK088389 / NIDDK NIH HHS R01 DK072193 / NIDDK NIH HHS U01 DK085545 / NIDDK NIH HHS DK085526 / NIDDK NIH HHS 090532 / Wellcome Trust R01 DK098032 / NIDDK NIH HHS
Identifiers: 99928737302346
Academic Unit: School of Biosciences
Language: English
Resource Type: Journal article

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

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