The role of glucose-6-phosphatase catalytic domain in glucose homeostasis

Ng, NHJ

Alternative title:: Translating genetic associations in G6PC2 and G6PC for glycemic traits into functional mechanisms

Abstract:: Over the past decade, there has been unprecedented increase in the number of genetic loci associating with type 2 diabetes (T2D) risk and related glycemic traits, thanks to advances in sequencing technologies and access to large sample sizes. Identification of associated genetic variants across the frequency spectrum can provide valuable insight into disease pathophysiology. However, the translation into biological insights has been slow often due to uncertainties over the underlying effec...
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APA Style

Ng, N. H. J. (2016). The role of glucose-6-phosphatase catalytic domain in glucose homeostasis [PhD thesis]. University of Oxford.

MLA Style

Ng, N. HJ. The Role of Glucose-6-Phosphatase Catalytic Domain in Glucose Homeostasis. University of Oxford, 2016.

Chicago Style

Ng, NHJ. 2016. “The Role of Glucose-6-Phosphatase Catalytic Domain in Glucose Homeostasis.” PhD thesis, University of Oxford.
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Files:: Ng_2016_The_role_of.pdf

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Authors

+ Ng, NHJ More by this author

Division:: MSD
Department:: University of Oxford
Role:: Author

Contributors

+ Gloyn, A

Department:: University of Oxford
Role:: Supervisor

+ Rorsman, P

Department:: University of Oxford
Role:: Supervisor

DOI:: 10.5287/ora-bpa7ezrpx
Type of award:: DPhil
Level of award:: Doctoral
Awarding institution:: University of Oxford

Language:: English
Keywords:: G6PC2

variant characterisation

glucose-6-phosphatase

fasting glucose

type 2 diabetes
Subjects:: Metabolism

Endocrinology

Diabetes

Medical Sciences

Genetics
UUID:: uuid:1e5fc469-d474-45e8-9a6b-6b56d1cd3b77
Deposit date:: 2017-05-18

Related item:: Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus
Description:: 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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Copyright holder:: Natasha Hui Jin Ng

Licence:: Terms and Conditions of Use for Oxford University Research Archive

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The role of glucose-6-phosphatase catalytic domain in glucose homeostasis

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The role of glucose-6-phosphatase catalytic domain in glucose homeostasis

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