TY - JOUR

T1 - Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus

AU - Mahajan, Anubha

AU - Sim, Xueling

AU - Ng, Hui Jin

AU - Manning, Alisa

AU - Rivas, Manuel A

AU - Highland, Heather M

AU - Locke, Adam E

AU - Grarup, Niels

AU - Im, Hae Kyung

AU - Cingolani, Pablo

AU - Flannick, Jason

AU - Fontanillas, Pierre

AU - Fuchsberger, Christian

AU - Gaulton, Kyle J

AU - Teslovich, Tanya M

AU - Rayner, N William

AU - Robertson, Neil R

AU - Beer, Nicola L

AU - Rundle, Jana K

AU - Bork-Jensen, Jette

AU - Ladenvall, Claes

AU - Blancher, Christine

AU - Buck, David

AU - Buck, Gemma

AU - Burtt, Noël P

AU - Gabriel, Stacey

AU - Gjesing, Anette Marianne Prior

AU - Groves, Christopher J

AU - Hollensted, Mette

AU - Huyghe, Jeroen R

AU - Jackson, Anne U

AU - Jun, Goo

AU - Justesen, Johanne Marie

AU - Mangino, Massimo

AU - Murphy, Jacquelyn

AU - Neville, Matt

AU - Onofrio, Robert

AU - Small, Kerrin S

AU - Stringham, Heather M

AU - Syvänen, Ann-Christine

AU - Trakalo, Joseph

AU - Abecasis, Goncalo

AU - Bell, Graeme I

AU - Blangero, John

AU - Cox, Nancy J

AU - Duggirala, Ravindranath

AU - Linneberg, Allan

AU - Jørgensen, Torben

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - T2D-GENES consortium and GoT2D consortium

PY - 2015/1

Y1 - 2015/1

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pgen.1004876

DO - 10.1371/journal.pgen.1004876

M3 - Journal article

C2 - 25625282

VL - 11

SP - 1

EP - 25

JO - P L o S Genetics

JF - P L o S Genetics

SN - 1553-7390

IS - 1

M1 - e1004876

ER -