scholarly journals Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer

2015 ◽  
Vol 112 (19) ◽  
pp. 6128-6133 ◽  
Author(s):  
Huiling He ◽  
Wei Li ◽  
Sandya Liyanarachchi ◽  
Mukund Srinivas ◽  
Yanqiang Wang ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Long Range ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Linkage Disequilibrium Block ◽  
Thyroid Tissue ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Papillary Thyroid ◽  
Functional Variants

The [A] allele of SNP rs965513 in 9q22 has been consistently shown to be highly associated with increased papillary thyroid cancer (PTC) risk with an odds ratio of ∼1.8 as determined by genome-wide association studies, yet the molecular mechanisms remain poorly understood. Previously, we noted that the expression of two genes in the region, forkhead box E1 (FOXE1) and PTC susceptibility candidate 2 (PTCSC2), is regulated by rs965513 in unaffected thyroid tissue, but the underlying mechanisms were not elucidated. Here, we fine-mapped the 9q22 region in PTC and controls and detected an ∼33-kb linkage disequilibrium block (containing the lead SNP rs965513) that significantly associates with PTC risk. Chromatin characteristics and regulatory element signatures in this block disclosed at least three regulatory elements functioning as enhancers. These enhancers harbor at least four SNPs (rs7864322, rs12352658, rs7847449, and rs10759944) that serve as functional variants. The variant genotypes are associated with differential enhancer activities and/or transcription factor binding activities. Using the chromosome conformation capture methodology, long-range looping interactions of these elements with the promoter region shared by FOXE1 and PTCSC2 in a human papillary thyroid carcinoma cell line (KTC-1) and unaffected thyroid tissue were found. Our results suggest that multiple variants coinherited with the lead SNP and located in long-range enhancers are involved in the transcriptional regulation of FOXE1 and PTCSC2 expression. These results explain the mechanism by which the risk allele of rs965513 predisposes to thyroid cancer.

scholarly journals p63 establishes epithelial enhancers at critical craniofacial development genes

2019 ◽  
Vol 5 (5) ◽  
pp. eaaw0946 ◽  
Author(s):  
Enrique Lin-Shiao ◽  
Yemin Lan ◽  
Julia Welzenbach ◽  
Katherine A. Alexander ◽  
Zhen Zhang ◽  
...  
Keyword(s):  
Cleft Lip ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Point Mutations ◽  
Regulatory Elements ◽  
Craniofacial Development ◽  
Developmental Defect ◽  
Genome Wide Association Studies ◽  
Interaction Domain ◽  
Developmental Defects

The transcription factor p63 is a key mediator of epidermal development. Point mutations in p63 in patients lead to developmental defects, including orofacial clefting. To date, knowledge on how pivotal the role of p63 is in human craniofacial development is limited. Using an inducible transdifferentiation model, combined with epigenomic sequencing and multicohort meta-analysis of genome-wide association studies data, we show that p63 establishes enhancers at craniofacial development genes to modulate their transcription. Disease-specific substitution mutation in the DNA binding domain or sterile alpha motif protein interaction domain of p63, respectively, eliminates or reduces establishment of these enhancers. We show that enhancers established by p63 are highly enriched for single-nucleotide polymorphisms associated with nonsyndromic cleft lip ± cleft palate (CL/P). These orthogonal approaches indicate a strong molecular link between p63 enhancer function and CL/P, illuminating molecular mechanisms underlying this developmental defect and revealing vital regulatory elements and new candidate causative genes.

scholarly journals Fine-mapping cis-regulatory variants in diverse human populations

2018 ◽  
Author(s):  
Ashley K. Tehranchi ◽  
Brian Hie ◽  
Michael Dacre ◽  
Irene M. Kaplow ◽  
Kade P Pettie ◽  
...  
Keyword(s):  
Long Range ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Chromatin Accessibility ◽  
Human Populations ◽  
Genome Wide Association Studies ◽  
Diverse Populations ◽  
Regulatory Variants ◽  
Causal Variants ◽  
In Cis

AbstractGenome-wide association studies (GWAS) are a powerful approach for connecting genotype to phenotype. Most GWAS hits are located in cis-regulatory regions, but the underlying causal variants and their molecular mechanisms remain unknown. To better understand human cis-regulatory variation, we mapped quantitative trait loci for chromatin accessibility (caQTLs)—a key step in cis-regulation—in 1000 individuals from 10 diverse populations. Most caQTLs were shared across populations, allowing us to leverage the genetic diversity to fine-map candidate causal regulatory variants, several thousand of which have been previously implicated in GWAS. In addition, many caQTLs that affect the expression of distal genes also alter the landscape of long-range chromosomal interactions, suggesting a mechanism for long-range expression QTLs. In sum, our results show that molecular QTL mapping integrated across diverse populations provides a high-resolution view of how worldwide human genetic variation affects chromatin accessibility, gene expression, and phenotype.

Non-coding genome functions in diabetes

2015 ◽  
Vol 56 (1) ◽  
pp. R1-R20 ◽  
Author(s):  
Inês Cebola ◽  
Lorenzo Pasquali
Keyword(s):  
Gene Regulation ◽  
Sequence Variation ◽  
High Throughput Sequencing ◽  
Association Studies ◽  
Cell Types ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Coding Regions ◽  
Pancreatic Progenitors ◽  
Functional Variants

Most of the genetic variation associated with diabetes, through genome-wide association studies, does not reside in protein-coding regions, making the identification of functional variants and their eventual translation to the clinic challenging. In recent years, high-throughput sequencing-based methods have enabled genome-scale high-resolution epigenomic profiling in a variety of human tissues, allowing the exploration of the human genome outside of the well-studied coding regions. These experiments unmasked tens of thousands of regulatory elements across several cell types, including diabetes-relevant tissues, providing new insights into their mechanisms of gene regulation. Regulatory landscapes are highly dynamic and cell-type specific and, being sensitive to DNA sequence variation, can vary with individual genomes. The scientific community is now in place to exploit the regulatory maps of tissues central to diabetes etiology, such as pancreatic progenitors and adult islets. This giant leap forward in the understanding of pancreatic gene regulation is revolutionizing our capacity to discriminate between functional and non-functional non-coding variants, opening opportunities to uncover regulatory links between sequence variation and diabetes susceptibility. In this review, we focus on the non-coding regulatory landscape of the pancreatic endocrine cells and provide an overview of the recent developments in this field.

scholarly journals Rare variants in non-coding regulatory regions of the genome that affect gene expression in systemic lupus erythematosus

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Sarah A. Jones ◽  
Stuart Cantsilieris ◽  
Huapeng Fan ◽  
Qiang Cheng ◽  
Brendan E. Russ ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Association Studies ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Systemic Lupus ◽  
High Resolution Melt ◽  
Functional Variants ◽  
Reporter Assays

Abstract Personalized medicine approaches are increasingly sought for diseases with a heritable component. Systemic lupus erythematosus (SLE) is the prototypic autoimmune disease resulting from loss of immunologic tolerance, but the genetic basis of SLE remains incompletely understood. Genome wide association studies (GWAS) identify regions associated with disease, based on common single nucleotide polymorphisms (SNPs) within them, but these SNPs may simply be markers in linkage disequilibrium with other, causative mutations. Here we use an hierarchical screening approach for prediction and testing of true functional variants within regions identified in GWAS; this involved bioinformatic identification of putative regulatory elements within close proximity to SLE SNPs, screening those regions for potentially causative mutations by high resolution melt analysis, and functional validation using reporter assays. Using this approach, we screened 15 SLE associated loci in 143 SLE patients, identifying 7 new variants including 5 SNPs and 2 insertions. Reporter assays revealed that the 5 SNPs were functional, altering enhancer activity. One novel variant was linked to the relatively well characterized rs9888739 SNP at the ITGAM locus, and may explain some of the SLE heritability at this site. Our study demonstrates that non-coding regulatory elements can contain private sequence variants affecting gene expression, which may explain part of the heritability of SLE.

scholarly journals Functional Annotation of Putative Regulatory Elements at Cancer Susceptibility Loci

2014 ◽  
Vol 13s2 ◽  
pp. CIN.S13789
Author(s):  
Stephanie A. Rosse ◽  
Paul L. Auer ◽  
Christopher S. Carlson
Keyword(s):  
Cancer Susceptibility ◽  
Association Studies ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Functional Polymorphisms ◽  
Functional Variants ◽  
Genome Wide ◽  
Regulatory Variant ◽  
Causal Variants

Most cancer-associated genetic variants identified from genome-wide association studies (GWAS) do not obviously change protein structure, leading to the hypothesis that the associations are attributable to regulatory polymorphisms. Translating genetic associations into mechanistic insights can be facilitated by knowledge of the causal regulatory variant (or variants) responsible for the statistical signal. Experimental validation of candidate functional variants is onerous, making bioinformatic approaches necessary to prioritize candidates for laboratory analysis. Thus, a systematic approach for recognizing functional (and, therefore, likely causal) variants in noncoding regions is an important step toward interpreting cancer risk loci. This review provides a detailed introduction to current regulatory variant annotations, followed by an overview of how to leverage these resources to prioritize candidate functional polymorphisms in regulatory regions.

scholarly journals Integration of Alzheimer’s disease genetics and myeloid genomics reveals novel disease risk mechanisms

2019 ◽  
Author(s):  
Gloriia Novikova ◽  
Manav Kapoor ◽  
Julia TCW ◽  
Edsel M. Abud ◽  
Anastasia G. Efthymiou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gene Expression Regulation ◽  
Disease Risk ◽  
Association Studies ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Functional Variants ◽  
Analytical Approaches

AbstractGenome-wide association studies (GWAS) have identified more than thirty loci associated with Alzheimer’s disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown thus impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS signals with myeloid epigenomic and transcriptomic datasets using novel analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We nominate candidate AD risk enhancers and identify their target causal genes (including AP4E1, AP4M1, APBB3, BIN1, CD2AP, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, SPPL2A, TP53INP1, ZKSCAN1, and ZYX) in sixteen loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify disease susceptibility by regulating causal gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it experimentally in human induced pluripotent stem cell (hiPSC)-derived microglia. Combined, these results strongly implicate dysfunction of the myeloid endolysosomal system in the etiology of AD.

scholarly journals Pig genome functional annotation enhances the biological interpretation of complex traits and human disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhangyuan Pan ◽  
Yuelin Yao ◽  
Hongwei Yin ◽  
Zexi Cai ◽  
Ying Wang ◽  
...  
Keyword(s):  
Adaptive Evolution ◽  
Complex Traits ◽  
Functional Annotation ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Regulatory Elements ◽  
Neutral Evolution ◽  
Genome Wide Association Studies ◽  
Tissue Specific ◽  
Slow Evolution

AbstractThe functional annotation of livestock genomes is crucial for understanding the molecular mechanisms that underpin complex traits of economic importance, adaptive evolution and comparative genomics. Here, we provide the most comprehensive catalogue to date of regulatory elements in the pig (Sus scrofa) by integrating 223 epigenomic and transcriptomic data sets, representing 14 biologically important tissues. We systematically describe the dynamic epigenetic landscape across tissues by functionally annotating 15 different chromatin states and defining their tissue-specific regulatory activities. We demonstrate that genomic variants associated with complex traits and adaptive evolution in pig are significantly enriched in active promoters and enhancers. Furthermore, we reveal distinct tissue-specific regulatory selection between Asian and European pig domestication processes. Compared with human and mouse epigenomes, we show that porcine regulatory elements are more conserved in DNA sequence, under both rapid and slow evolution, than those under neutral evolution across pig, mouse, and human. Finally, we provide biological insights on tissue-specific regulatory conservation, and by integrating 47 human genome-wide association studies, we demonstrate that, depending on the traits, mouse or pig might be more appropriate biomedical models for different complex traits and diseases.

scholarly journals Functional characterization of T2D-associated SNP effects on baseline and ER stress-responsive β cell transcriptional activation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shubham Khetan ◽  
Susan Kales ◽  
Romy Kursawe ◽  
Alexandria Jillette ◽  
Jacob C. Ulirsch ◽  
...  
Keyword(s):  
Steady State ◽  
Er Stress ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Functional Characterization ◽  
Genome Wide Association Studies ◽  
Β Cell ◽  
Functional Variants

AbstractGenome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) at >250 loci in the human genome to type 2 diabetes (T2D) risk. For each locus, identifying the functional variant(s) among multiple SNPs in high linkage disequilibrium is critical to understand molecular mechanisms underlying T2D genetic risk. Using massively parallel reporter assays (MPRA), we test the cis-regulatory effects of SNPs associated with T2D and altered in vivo islet chromatin accessibility in MIN6 β cells under steady state and pathophysiologic endoplasmic reticulum (ER) stress conditions. We identify 1,982/6,621 (29.9%) SNP-containing elements that activate transcription in MIN6 and 879 SNP alleles that modulate MPRA activity. Multiple T2D-associated SNPs alter the activity of short interspersed nuclear element (SINE)-containing elements that are strongly induced by ER stress. We identify 220 functional variants at 104 T2D association signals, narrowing 54 signals to a single candidate SNP. Together, this study identifies elements driving β cell steady state and ER stress-responsive transcriptional activation, nominates causal T2D SNPs, and uncovers potential roles for repetitive elements in β cell transcriptional stress response and T2D genetics.

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