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 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.

[1]  G. Kempermann.  Faculty Opinions recommendation of Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. , 2015 .

[2]  Jun S. Liu,et al.  The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans , 2015, Science.

[3]  M. McCarthy,et al.  Human islet function following 20 years of cryogenic biobanking , 2015, Diabetologia.

[4]  M. Weedon,et al.  Targeted Allelic Expression Profiling in Human Islets Identifies cis-Regulatory Effects for Multiple Variants Identified by Type 2 Diabetes Genome-Wide Association Studies , 2014, Diabetes.

[5]  L. Groop,et al.  Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism , 2014, Proceedings of the National Academy of Sciences.

[6]  Kyle J. Gaulton,et al.  Identification of a Regulatory Variant That Binds FOXA1 and FOXA2 at the CDC123/CAMK1D Type 2 Diabetes GWAS Locus , 2014, PLoS genetics.

[7]  G. Rutter,et al.  ADCY5 Couples Glucose to Insulin Secretion in Human Islets , 2014, Diabetes.

[8]  Inês Barroso,et al.  Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity , 2014, Diabetes.

[9]  John P. Overington,et al.  An atlas of genetic influences on human blood metabolites , 2014, Nature Genetics.

[10]  J. Dennis,et al.  N-Glycan Remodeling on Glucagon Receptor Is an Effector of Nutrient Sensing by the Hexosamine Biosynthesis Pathway* , 2014, The Journal of Biological Chemistry.

[11]  Qian Wang,et al.  IG20/MADD Plays a Critical Role in Glucose-Induced Insulin Secretion , 2014, Diabetes.

[12]  Mark I. McCarthy,et al.  A Central Role for GRB10 in Regulation of Islet Function in Man , 2014, PLoS genetics.

[13]  N. Schork,et al.  Gain‐of‐function ADCY5 mutations in familial dyskinesia with facial myokymia , 2014, Annals of neurology.

[14]  Tanya M. Teslovich,et al.  Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility , 2014 .

[15]  R. Andrews,et al.  Innate Immune Activity Conditions the Effect of Regulatory Variants upon Monocyte Gene Expression , 2014, Science.

[16]  Thomas Meitinger,et al.  Loss-of-function mutations in SLC30A8 protect against type 2 diabetes , 2014, Nature Genetics.

[17]  Christian Fuchsberger,et al.  A common functional regulatory variant at a type 2 diabetes locus upregulates ARAP1 expression in the pancreatic beta cell. , 2014, American journal of human genetics.

[18]  M. Gobbi,et al.  Analysis of hundreds of cis-regulatory landscapes at high resolution in a single, high-throughput experiment , 2014, Nature Genetics.

[19]  Mark I. McCarthy,et al.  Pancreatic islet enhancer clusters enriched in type 2 diabetes risk–associated variants , 2013, Nature Genetics.

[20]  Paolo Piazza,et al.  Improved workflows for high throughput library preparation using the transposome-based nextera system , 2013, BMC Biotechnology.

[21]  Stephen C. J. Parker,et al.  Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants , 2013, Proceedings of the National Academy of Sciences.

[22]  Halit Ongen,et al.  Cell-type, allelic, and genetic signatures in the human pancreatic beta cell transcriptome , 2013, Genome research.

[23]  Cole Trapnell,et al.  TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions , 2013, Genome Biology.

[24]  Hiroshi Suzuki,et al.  Disruption of Stard10 gene alters the PPARα-mediated bile acid homeostasis. , 2013, Biochimica et biophysica acta.

[25]  Rork Kuick,et al.  Convergence of the ZMIZ1 and NOTCH1 pathways at C-MYC in acute T lymphoblastic leukemias. , 2013, Cancer research.

[26]  Christian Fuchsberger,et al.  Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion , 2012, Nature Genetics.

[27]  Olli Simell,et al.  New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism , 2012, Nature Genetics.

[28]  S. Cross,et al.  Collagenase does Not Persist in Human Islets following Isolation , 2012, Cell transplantation.

[29]  Kenny Q. Ye,et al.  An integrated map of genetic variation from 1,092 human genomes , 2012, Nature.

[30]  Simon C. Potter,et al.  Mapping cis- and trans-regulatory effects across multiple tissues in twins , 2012, Nature Genetics.

[31]  Bronwen L. Aken,et al.  GENCODE: The reference human genome annotation for The ENCODE Project , 2012, Genome research.

[32]  Tanya M. Teslovich,et al.  Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways , 2012, Nature Genetics.

[33]  Tanya M. Teslovich,et al.  Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes , 2012, Nature Genetics.

[34]  Raymond K. Auerbach,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[35]  Christian Gieger,et al.  Impact of common regulatory single-nucleotide variants on gene expression profiles in whole blood , 2012, European Journal of Human Genetics.

[36]  Claude Bouchard,et al.  A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance , 2012, Nature Genetics.

[37]  C. Mcintosh,et al.  Regulation of GIP and GLP1 Receptor Cell Surface Expression by N-Glycosylation and Receptor Heteromerization , 2012, PloS one.

[38]  R. Durbin,et al.  Using probabilistic estimation of expression residuals (PEER) to obtain increased power and interpretability of gene expression analyses , 2012, Nature Protocols.

[39]  Inês Barroso,et al.  Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes , 2012, Nature Genetics.

[40]  Simon C. Potter,et al.  Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis , 2011, Nature.

[41]  Andrey A. Shabalin,et al.  Matrix eQTL: ultra fast eQTL analysis via large matrix operations , 2011, Bioinform..

[42]  Mark I. McCarthy,et al.  Identification of an imprinted master trans-regulator at the KLF14 locus related to multiple metabolic phenotypes , 2011, Nature Genetics.

[43]  Ayellet V. Segrè,et al.  Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis , 2010, Nature Genetics.

[44]  Silke Szymczak,et al.  Genetics and Beyond – The Transcriptome of Human Monocytes and Disease Susceptibility , 2010, PloS one.

[45]  Simon C. Potter,et al.  New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk , 2010, Nature Genetics.

[46]  J. Shapiro,et al.  Partial dorsal agenesis accompanied with circumportal pancreas in a donor for islet transplantation , 2010, Islets.

[47]  R. Guigó,et al.  Transcriptome genetics using second generation sequencing in a Caucasian population , 2010, Nature.

[48]  T. Assimes,et al.  Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans , 2010, Diabetes.

[49]  P. Donnelly,et al.  A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies , 2009, PLoS genetics.

[50]  J. Todd,et al.  Rare Variants of IFIH1, a Gene Implicated in Antiviral Responses, Protect Against Type 1 Diabetes , 2009, Science.

[51]  D. Rowitch,et al.  Expression and function of Nkx6.3 in vertebrate hindbrain , 2008, Brain Research.

[52]  R. Shivdasani,et al.  Requirement of the Tissue-Restricted Homeodomain Transcription Factor Nkx6.3 in Differentiation of Gastrin-Producing G Cells in the Stomach Antrum , 2008, Molecular and Cellular Biology.

[53]  Jane Lee,et al.  The novel PIAS-like protein hZimp10 is a transcriptional co-activator of the p53 tumor suppressor , 2007, Nucleic acids research.

[54]  J. Beliakoff,et al.  The Novel PIAS-like Protein hZimp10 Enhances Smad Transcriptional Activity* , 2006, Journal of Biological Chemistry.

[55]  G. Lewis,et al.  Differential effects of monounsaturated, polyunsaturated and saturated fat ingestion on glucose-stimulated insulin secretion, sensitivity and clearance in overweight and obese, non-diabetic humans , 2006, Diabetologia.

[56]  J. Marth,et al.  Dietary and Genetic Control of Glucose Transporter 2 Glycosylation Promotes Insulin Secretion in Suppressing Diabetes , 2005, Cell.

[57]  M. Sander,et al.  NKX6 transcription factor activity is required for α- andβ -cell development in the pancreas , 2005 .

[58]  W. Engel,et al.  Mutation in the gene encoding lysosomal acid phosphatase (Acp2) causes cerebellum and skin malformation in mouse , 2004, Neurogenetics.

[59]  Yuzhuo Wang,et al.  hZimp10 is an androgen receptor co‐activator and forms a complex with SUMO‐1 at replication foci , 2003, The EMBO journal.

[60]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[61]  John D. Storey.  A direct approach to false discovery rates , 2002 .

[62]  P. Schimmel,et al.  A human aminoacyl-tRNA synthetase as a regulator of angiogenesis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[63]  F. Tinahones,et al.  Unsaturated fatty acids alter the insulin secretion response of the islets of Langerhans in vitro. , 1997, Diabetes research and clinical practice.

[64]  G. Reaven,et al.  Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus , 1995, Nature.

[65]  P. Halban.  Structural domains and molecular lifestyles of insulin and its precursors in the pancreatic Beta cell , 1991, Diabetologia.

[66]  Ann Smith,et al.  The Pancreas. , 1991, Monographs in pathology.

[67]  C. Wollheim,et al.  Glucose and carbachol generate 1,2-diacylglycerols by different mechanisms in pancreatic islets. , 1988, The Journal of clinical investigation.

[68]  张静,et al.  Banana Ovate family protein MaOFP1 and MADS-box protein MuMADS1 antagonistically regulated banana fruit ripening , 2015 .

[69]  Tanya M. Teslovich,et al.  Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility , 2014 .

[70]  David C. Wilson,et al.  Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease , 2012, Nature.

[71]  O. Delaneau,et al.  Supplementary Information for ‘ Improved whole chromosome phasing for disease and population genetic studies ’ , 2012 .

[72]  E. Oetjen,et al.  Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes , 2011, Diabetes.

[73]  D. Altshuler,et al.  Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion , 2009, Nature Genetics.

[74]  M. Sander,et al.  NKX6 transcription factor activity is required for alpha- and beta-cell development in the pancreas. , 2005, Development.