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 Marianne Prior 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; Allan Linneberg; Torben Jørgensen; Torben Hansen; Oluf Pedersen; T2D-GENES consortium and GoT2D consortium

doi:10.1371/journal.pgen.1004876

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-JensenClaes Ladenvall, Christine Blancher, David Buck, Gemma Buck, Noël P Burtt, Stacey Gabriel, Anette Marianne Prior 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, Allan Linneberg, Torben Jørgensen, Torben Hansen, Oluf Pedersen, T2D-GENES consortium and GoT2D consortium

64 Citations (Scopus)

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.

Original language	English
Article number	e1004876
Journal	P L o S Genetics
Volume	11
Issue number	1
Pages (from-to)	1-25
Number of pages	25
ISSN	1553-7390
DOIs	https://doi.org/10.1371/journal.pgen.1004876
Publication status	Published - 27 Jan 2015

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10.1371/journal.pgen.1004876

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Mahajan, A., Sim, X., Ng, H. J., Manning, A., Rivas, M. A., Highland, H. M., Locke, A. E., Grarup, N., Im, H. K., Cingolani, P., Flannick, J., Fontanillas, P., Fuchsberger, C., Gaulton, K. J., Teslovich, T. M., Rayner, N. W., Robertson, N. R., Beer, N. L., Rundle, J. K., ... T2D-GENES consortium and GoT2D consortium (2015). Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus. P L o S Genetics, 11(1), 1-25. [e1004876]. https://doi.org/10.1371/journal.pgen.1004876

Mahajan, A, Sim, X, Ng, HJ, Manning, A, Rivas, MA, Highland, HM, Locke, AE, Grarup, N, Im, HK, Cingolani, P, Flannick, J, Fontanillas, P, Fuchsberger, C, Gaulton, KJ, Teslovich, TM, Rayner, NW, Robertson, NR, Beer, NL, Rundle, JK, Bork-Jensen, J, Ladenvall, C, Blancher, C, Buck, D, Buck, G, Burtt, NP, Gabriel, S, Gjesing, AMP, Groves, CJ, Hollensted, M, Huyghe, JR, Jackson, AU, Jun, G, Justesen, JM, Mangino, M, Murphy, J, Neville, M, Onofrio, R, Small, KS, Stringham, HM, Syvänen, A-C, Trakalo, J, Abecasis, G, Bell, GI, Blangero, J, Cox, NJ, Duggirala, R, Linneberg, A, Jørgensen, T, Hansen, T , Pedersen, O & T2D-GENES consortium and GoT2D consortium 2015, 'Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus', P L o S Genetics, vol. 11, no. 1, e1004876, pp. 1-25. https://doi.org/10.1371/journal.pgen.1004876

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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",

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.",

author = "Anubha Mahajan and Xueling Sim and Ng, {Hui Jin} and Alisa Manning and Rivas, {Manuel A} and Highland, {Heather M} and Locke, {Adam E} and Niels Grarup and Im, {Hae Kyung} and Pablo Cingolani and Jason Flannick and Pierre Fontanillas and Christian Fuchsberger and Gaulton, {Kyle J} and Teslovich, {Tanya M} and Rayner, {N William} and Robertson, {Neil R} and Beer, {Nicola L} and Rundle, {Jana K} and Jette Bork-Jensen and Claes Ladenvall and Christine Blancher and David Buck and Gemma Buck and Burtt, {No{\"e}l P} and Stacey Gabriel and Gjesing, {Anette Marianne Prior} and Groves, {Christopher J} and Mette Hollensted and Huyghe, {Jeroen R} and Jackson, {Anne U} and Goo Jun and Justesen, {Johanne Marie} and Massimo Mangino and Jacquelyn Murphy and Matt Neville and Robert Onofrio and Small, {Kerrin S} and Stringham, {Heather M} and Ann-Christine Syv{\"a}nen and Joseph Trakalo and Goncalo Abecasis and Bell, {Graeme I} and John Blangero and Cox, {Nancy J} and Ravindranath Duggirala and Allan Linneberg and Torben J{\o}rgensen and Torben Hansen and Oluf Pedersen and {T2D-GENES consortium and GoT2D consortium}",

year = "2015",

month = jan,

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doi = "10.1371/journal.pgen.1004876",

language = "English",

volume = "11",

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journal = "P L o S Genetics",

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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 - 2015/1/27

Y1 - 2015/1/27

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

SN - 1553-7390

VL - 11

SP - 1

EP - 25

JO - P L o S Genetics

JF - P L o S Genetics

IS - 1

M1 - e1004876

ER -

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

Abstract

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