title: Genetic regulatory signatures underlying islet gene expression and type 2 diabetes.
abstract: Genome-wide association studies (GWAS) have identified >100 independent SNPs that modulate the risk of type 2 diabetes (T2D) and related traits. However, the pathogenic mechanisms of most of these SNPs remain elusive. Here, we examined genomic, epigenomic, and transcriptomic profiles in human pancreatic islets to understand the links between genetic variation, chromatin landscape, and gene expression in the context of T2D. We first integrated genome and transcriptome variation across 112 islet samples to produce densecis-expression quantitative trait loci (cis-eQTL) maps. Additional integration with chromatin-state maps for islets and other diverse tissue types revealed thatcis-eQTLs for islet-specific genes are specifically and significantly enriched in islet stretch enhancers. High-resolution chromatin accessibility profiling using assay for transposase-accessible chromatin sequencing (ATAC-seq) in two islet samples enabled us to identify specific transcription factor (TF) footprints embedded in active regulatory elements, which are highly enriched for isletcis-eQTL. Aggregate allelic bias signatures in TF footprints enabled us de novo to reconstruct TF binding affinities genetically, which support the high-quality nature of the TF footprint predictions. Interestingly, we found that T2D GWAS loci were strikingly and specifically enriched in islet Regulatory Factor X (RFX) footprints. Remarkably, within and across independent loci, T2D risk alleles that overlap with RFX footprints uniformly disrupt the RFX motifs at high-information content positions. Together, these results suggest that common regulatory variations have shaped islet TF footprints and the transcriptome and that a confluent RFX regulatory grammar plays a significant role in the genetic component of T2D predisposition.
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Arushi
authors.initials: A
authors.lastname: Varshney
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Scott
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Welch
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Erdos
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Chines
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892.
authors.forename: Narisu
authors.initials: N
authors.lastname: Narisu
authors.affiliation: Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Ricardo D'O
authors.initials: RD
authors.lastname: Albanus
authors.affiliation: Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Peter
authors.initials: P
authors.lastname: Orchard
authors.affiliation: Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Brooke N
authors.initials: BN
authors.lastname: Wolford
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032.
authors.forename: Romy
authors.initials: R
authors.lastname: Kursawe
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599.
authors.forename: Swarooparani
authors.initials: S
authors.lastname: Vadlamudi
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599.
authors.forename: Maren E
authors.initials: ME
authors.lastname: Cannon
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892.
authors.forename: John P
authors.initials: JP
authors.lastname: Didion
authors.affiliation: Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109.
authors.forename: John
authors.initials: J
authors.lastname: Hensley
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892.
authors.forename: Anthony
authors.initials: A
authors.lastname: Kirilusha
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892.
authors.forename: Lori L
authors.initials: LL
authors.lastname: Bonnycastle
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892.|European Molecular Biology Laboratory, Wellcome Trust Genome Campus, European Bioinformatics Institute, Hinxton, Cambridgeshire CB10 1SD, United Kingdom.
authors.forename: D Leland
authors.initials: DL
authors.lastname: Taylor
authors.affiliation: Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA 90089.|Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles, CA 90089.
authors.forename: Richard
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mohlke
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892; collinsf@od.nih.gov scjp@umich.edu.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109; collinsf@od.nih.gov scjp@umich.edu.|Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Stephen C J
authors.initials: SC
authors.lastname: Parker
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Stitzel
mesh_terms: D000483:Alleles; D001483:Base Sequence; D001665:Binding Sites; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D018392:Genomic Imprinting; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D040641:Quantitative Trait Loci; D000071701:Regulatory Factor X Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D002843:Chromatin; D020033:Protein Isoforms; D000071701:Regulatory Factor X Transcription Factors
keywords: chromatin; diabetes; eQTL; epigenome; footprint