Transcript Expression Data from Human Islets Links Regulatory Signals from Genome-Wide Association Studies for Type 2 Diabetes and Glycemic Traits to Their Downstream Effectors.
The intersection of genome-wide association analyses with physiological and functional data indicates that variants regulating islet gene transcription influence type 2 diabetes (T2D) predisposition and glucose homeostasis. However, the specific genes through which these regulatory variants act rema...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-12-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1005694 |
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| author | Martijn van de Bunt Jocelyn E Manning Fox Xiaoqing Dai Amy Barrett Caleb Grey Lei Li Amanda J Bennett Paul R Johnson Raymond V Rajotte Kyle J Gaulton Emmanouil T Dermitzakis Patrick E MacDonald Mark I McCarthy Anna L Gloyn |
| author_facet | Martijn van de Bunt Jocelyn E Manning Fox Xiaoqing Dai Amy Barrett Caleb Grey Lei Li Amanda J Bennett Paul R Johnson Raymond V Rajotte Kyle J Gaulton Emmanouil T Dermitzakis Patrick E MacDonald Mark I McCarthy Anna L Gloyn |
| author_sort | Martijn van de Bunt |
| collection | DOAJ |
| description | The intersection of genome-wide association analyses with physiological and functional data indicates that variants regulating islet gene transcription influence type 2 diabetes (T2D) predisposition and glucose homeostasis. However, the specific genes through which these regulatory variants act remain poorly characterized. We generated expression quantitative trait locus (eQTL) data in 118 human islet samples using RNA-sequencing and high-density genotyping. We identified fourteen loci at which cis-exon-eQTL signals overlapped active islet chromatin signatures and were coincident with established T2D and/or glycemic trait associations. At some, these data provide an experimental link between GWAS signals and biological candidates, such as DGKB and ADCY5. At others, the cis-signals implicate genes with no prior connection to islet biology, including WARS and ZMIZ1. At the ZMIZ1 locus, we show that perturbation of ZMIZ1 expression in human islets and beta-cells influences exocytosis and insulin secretion, highlighting a novel role for ZMIZ1 in the maintenance of glucose homeostasis. Together, these findings provide a significant advance in the mechanistic insights of T2D and glycemic trait association loci. |
| format | Article |
| id | doaj-art-91ef871658694086b9a889a097fc114f |
| institution | DOAJ |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2015-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-91ef871658694086b9a889a097fc114f2025-08-20T03:10:08ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042015-12-011112e100569410.1371/journal.pgen.1005694Transcript Expression Data from Human Islets Links Regulatory Signals from Genome-Wide Association Studies for Type 2 Diabetes and Glycemic Traits to Their Downstream Effectors.Martijn van de BuntJocelyn E Manning FoxXiaoqing DaiAmy BarrettCaleb GreyLei LiAmanda J BennettPaul R JohnsonRaymond V RajotteKyle J GaultonEmmanouil T DermitzakisPatrick E MacDonaldMark I McCarthyAnna L GloynThe intersection of genome-wide association analyses with physiological and functional data indicates that variants regulating islet gene transcription influence type 2 diabetes (T2D) predisposition and glucose homeostasis. However, the specific genes through which these regulatory variants act remain poorly characterized. We generated expression quantitative trait locus (eQTL) data in 118 human islet samples using RNA-sequencing and high-density genotyping. We identified fourteen loci at which cis-exon-eQTL signals overlapped active islet chromatin signatures and were coincident with established T2D and/or glycemic trait associations. At some, these data provide an experimental link between GWAS signals and biological candidates, such as DGKB and ADCY5. At others, the cis-signals implicate genes with no prior connection to islet biology, including WARS and ZMIZ1. At the ZMIZ1 locus, we show that perturbation of ZMIZ1 expression in human islets and beta-cells influences exocytosis and insulin secretion, highlighting a novel role for ZMIZ1 in the maintenance of glucose homeostasis. Together, these findings provide a significant advance in the mechanistic insights of T2D and glycemic trait association loci.https://doi.org/10.1371/journal.pgen.1005694 |
| spellingShingle | Martijn van de Bunt Jocelyn E Manning Fox Xiaoqing Dai Amy Barrett Caleb Grey Lei Li Amanda J Bennett Paul R Johnson Raymond V Rajotte Kyle J Gaulton Emmanouil T Dermitzakis Patrick E MacDonald Mark I McCarthy Anna L Gloyn Transcript Expression Data from Human Islets Links Regulatory Signals from Genome-Wide Association Studies for Type 2 Diabetes and Glycemic Traits to Their Downstream Effectors. PLoS Genetics |
| title | Transcript Expression Data from Human Islets Links Regulatory Signals from Genome-Wide Association Studies for Type 2 Diabetes and Glycemic Traits to Their Downstream Effectors. |
| title_full | Transcript Expression Data from Human Islets Links Regulatory Signals from Genome-Wide Association Studies for Type 2 Diabetes and Glycemic Traits to Their Downstream Effectors. |
| title_fullStr | Transcript Expression Data from Human Islets Links Regulatory Signals from Genome-Wide Association Studies for Type 2 Diabetes and Glycemic Traits to Their Downstream Effectors. |
| title_full_unstemmed | Transcript Expression Data from Human Islets Links Regulatory Signals from Genome-Wide Association Studies for Type 2 Diabetes and Glycemic Traits to Their Downstream Effectors. |
| title_short | Transcript Expression Data from Human Islets Links Regulatory Signals from Genome-Wide Association Studies for Type 2 Diabetes and Glycemic Traits to Their Downstream Effectors. |
| title_sort | transcript expression data from human islets links regulatory signals from genome wide association studies for type 2 diabetes and glycemic traits to their downstream effectors |
| url | https://doi.org/10.1371/journal.pgen.1005694 |
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