scholarly journals Trait-associated noncoding variant regions affect TBX3 regulation and cardiac conduction

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Jan Hendrik van Weerd ◽  
Rajiv A Mohan ◽  
Karel van Duijvenboden ◽  
Ingeborg B Hooijkaas ◽  
Vincent Wakker ◽  
...  
Keyword(s):  
Association Studies ◽  
Cardiac Conduction ◽  
Regulatory Function ◽  
Genome Wide Association Studies ◽  
Gene Desert ◽  
Reporter Mice ◽  
Genome Wide ◽  
Pr Interval ◽  
Dna Elements ◽  
Regulatory Dna

Genome-wide association studies have implicated common genomic variants in the gene desert upstream of TBX3 in cardiac conduction velocity. Whether these noncoding variants affect expression of TBX3 or neighboring genes and how they affect cardiac conduction is not understood. Here, we use high-throughput STARR-seq to test the entire 1.3 Mb human and mouse TBX3 locus, including two cardiac conduction-associated variant regions, for regulatory function. We identified multiple accessible and functional regulatory DNA elements that harbor variants affecting their activity. Both variant regions drove gene expression in the cardiac conduction tissue in transgenic reporter mice. Genomic deletion from the mouse genome of one of the regions caused increased cardiac expression of only Tbx3, PR interval shortening and increased QRS duration. Combined, our findings address the mechanistic link between trait-associated variants in the gene desert, TBX3 regulation and cardiac conduction.

scholarly journals Diverse Functions Associate With Non-Coding Trans-species Polymorphisms in Humans

2021 ◽  
Author(s):  
Keila Velazquez-Arcelay ◽  
Mary Lauren Benton ◽  
John A. Capra
Keyword(s):  
Immune System ◽  
Allelic Variation ◽  
Balancing Selection ◽  
Association Studies ◽  
Regulatory Function ◽  
Genome Wide Association Studies ◽  
Functional Annotations ◽  
Coding Regions ◽  
Genome Wide ◽  
Mhc Locus

Abstract Background: Long-term balancing selection (LTBS) can maintain allelic variation at a locus over millions of years and through speciation events. Variants shared between species, hereafter “trans-species polymorphisms” (TSPs), often result from LTBS due to host-pathogen interactions. For instance, the major histocompatibility complex (MHC) locus contains TSPs present across primates. Several hundred candidate TSPs have been identified in humans and chimpanzees; however, because many are in non-coding regions of the genome, the functions and adaptive roles for most TSPs remain unknown. Results: We integrated diverse genomic annotations, with a focus on non-coding regions, to explore the functions of 125 previously identified regions containing multiple TSPs in humans and chimpanzees. We analyzed genome-wide functional assays, expression quantitative trait loci (eQTL), genome-wide association studies (GWAS), and phenome-wide association studies (PheWAS). We identify functional annotations for 119 TSP regions, including 71 with evidence of gene regulatory function from GTEx or genome-wide functional genomics data and 21 with evidence of trait association from GWAS and PheWAS. TSPs in humans associate with many immune system phenotypes, including response to pathogens, but we also find associations with a range of other phenotypes, including body mass, alcohol intake, urate levels, chronotype, and risk-taking behavior. Conclusions: The diversity of traits associated with non-coding human TSPs further support previous hypotheses that functions beyond the immune system are subject to LTBS. Furthermore, several of these trait associations provide support and candidate genetic loci for previous hypothesis about behavioral diversity in great ape populations, such as the importance of variation in sleep cycles and risk sensitivity.

scholarly journals Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control

2019 ◽  
Author(s):  
James Boocock ◽  
Megan Leask ◽  
Yukinori Okada ◽  
Hirotaka Matsuo ◽  
Yusuke Kawamura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Organic Anion ◽  
Serum Urate ◽  
Regulatory Function ◽  
Eqtl Analysis ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Causal Genes

AbstractSerum urate is the end-product of purine metabolism. Elevated serum urate is causal of gout and a predictor of renal disease, cardiovascular disease and other metabolic conditions. Genome-wide association studies (GWAS) have reported dozens of loci associated with serum urate control, however there has been little progress in understanding the molecular basis of the associated loci. Here we employed trans-ancestral meta-analysis using data from European and East Asian populations to identify ten new loci for serum urate levels. Genome-wide colocalization with cis-expression quantitative trait loci (eQTL) identified a further five new loci. By cis- and trans-eQTL colocalization analysis we identified 24 and 20 genes respectively where the causal eQTL variant has a high likelihood that it is shared with the serum urate-associated locus. One new locus identified was SLC22A9 that encodes organic anion transporter 7 (OAT7). We demonstrate that OAT7 is a very weak urate-butyrate exchanger. Newly implicated genes identified in the eQTL analysis include those encoding proteins that make up the dystrophin complex, a scaffold for signaling proteins and transporters at the cell membrane; MLXIP that, with the previously identified MLXIPL, is a transcription factor that may regulate serum urate via the pentose-phosphate pathway; and MRPS7 and IDH2 that encode proteins necessary for mitochondrial function. Trans-ancestral functional fine-mapping identified six loci (RREB1, INHBC, HLF, UBE2Q2, SFMBT1, HNF4G) with colocalized eQTL that contained putative causal SNPs (posterior probability of causality > 0.8). This systematic analysis of serum urate GWAS loci has identified candidate causal genes at 19 loci and a network of previously unidentified genes likely involved in control of serum urate levels, further illuminating the molecular mechanisms of urate control.Author SummaryHigh serum urate is a prerequisite for gout and a risk factor for metabolic disease. Previous GWAS have identified numerous loci that are associated with serum urate control, however, only a small handful of these loci have known molecular consequences. The majority of loci are within the non-coding regions of the genome and therefore it is difficult to ascertain how these variants might influence serum urate levels without tangible links to gene expression and / or protein function. We have applied a novel bioinformatic pipeline where we combined population-specific GWAS data with gene expression and genome connectivity information to identify putative causal genes for serum urate associated loci. Overall, we identified 15 novel serum urate loci and show that these loci along with previously identified loci are linked to the expression of 44 genes. We show that some of the variants within these loci have strong predicted regulatory function which can be further tested in functional analyses. This study expands on previous GWAS by identifying further loci implicated in serum urate control and new causal mechanisms supported by gene expression changes.

scholarly journals Genome-Wide Association Studies of the PR Interval in African Americans

PLoS Genetics ◽  
2011 ◽  
Vol 7 (2) ◽  
pp. e1001304 ◽  
Author(s):  
J. Gustav Smith ◽  
Jared W. Magnani ◽  
Cameron Palmer ◽  
Yan A. Meng ◽  
Elsayed Z. Soliman ◽  
...  
Keyword(s):  
African Americans ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Pr Interval

scholarly journals Trans-ethnic meta-analysis identifies new loci associated with longitudinal blood pressure traits

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mateus H. Gouveia ◽  
Amy R. Bentley ◽  
Hampton Leonard ◽  
Karlijn A. C. Meeks ◽  
Kenneth Ekoru ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Association Studies ◽  
Meta Analysis ◽  
Regulatory Function ◽  
Genome Wide Association Studies ◽  
The Novel ◽  
Cross Sectional ◽  
Age Related ◽  
Genome Wide ◽  
The Us

AbstractGenome-wide association studies (GWAS) have identified thousands of genetic loci associated with cross-sectional blood pressure (BP) traits; however, GWAS based on longitudinal BP have been underexplored. We performed ethnic-specific and trans-ethnic GWAS meta-analysis using longitudinal and cross-sectional BP data of 33,720 individuals from five cohorts in the US and one in Brazil. In addition to identifying several known loci, we identified thirteen novel loci with nine based on longitudinal and four on cross-sectional BP traits. Most of the novel loci were ethnic- or study-specific, with the majority identified in African Americans (AA). Four of these discoveries showed additional evidence of association in independent datasets, including an intergenic variant (rs4060030, p = 7.3 × 10–9) with reported regulatory function. We observed a high correlation between the meta-analysis results for baseline and longitudinal average BP (rho = 0.48). BP trajectory results were more correlated with those of average BP (rho = 0.35) than baseline BP(rho = 0.18). Heritability estimates trended higher for longitudinal traits than for cross-sectional traits, providing evidence for different genetic architectures. Furthermore, the longitudinal data identified up to 20% more BP known associations than did cross-sectional data. Our analyses of longitudinal BP data in diverse ethnic groups identified novel BP loci associated with BP trajectory, indicating a need for further longitudinal GWAS on BP and other age-related traits.

scholarly journals Parkinson’s Disease Genetic Risk Evaluation in Microglia Highlights Autophagy and Lysosomal Genes

2020 ◽  
Author(s):  
Alix Booms ◽  
Steven E. Pierce ◽  
Gerhard A. Coetzee
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Cell Type ◽  
Genome Wide ◽  
Risk Snps ◽  
A Cell ◽  
Regulatory Dna

AbstractGenome-wide association studies (GWAS) have uncovered thousands of single nucleotide polymorphisms (SNPs) that are associated with Parkinson’s disease (PD) risk. The functions of most of these SNPs, including the cell type they influence, and how they affect PD etiology remain largely unknown. To identify functional SNPs, we aligned PD risk SNPs within active regulatory regions of DNA in microglia, a cell type implicated in PD development. Out of 6,749 ‘SNPs of interest’ from the most recent PD GWAS metanalysis, 73 were located in open regulatory chromatin as determined by both ATAC-seq and H3K27ac ChIP-seq. We highlight a subset of SNPs that are favorable candidates for further mechanistic studies. These SNPs are located in regulatory DNA at the SLC50A1, SNCA, BAG3, FBXL19, SETD1A, and NUCKS1 loci. A network analysis of the genes with risk SNPs in their promoters, implicated substance transport, involving autophagy and lysosomal genes. Our study provides a more focused set of risk SNPs and their associated risk genes as candidates for further follow-up studies, which will help identify mechanisms in microglia that increase the risk for PD.

scholarly journals T-box transcription factor 3 governs a transcriptional program for the function of the mouse atrioventricular conduction system

2020 ◽  
Vol 117 (31) ◽  
pp. 18617-18626
Author(s):  
Rajiv A. Mohan ◽  
Fernanda M. Bosada ◽  
Jan H. van Weerd ◽  
Karel van Duijvenboden ◽  
Jianan Wang ◽  
...  
Keyword(s):  
Conduction System ◽  
Atrioventricular Conduction ◽  
Cardiac Conduction ◽  
Specific Gene ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
A Genome ◽  
Pr Interval ◽  
Qrs Duration ◽  
Atrioventricular Nodes

Genome-wide association studies have identified noncoding variants nearTBX3that are associated with PR interval and QRS duration, suggesting that subtle changes inTBX3expression affect atrioventricular conduction system function. To explore whether and to what extent the atrioventricular conduction system is affected by Tbx3 dose reduction, we first characterized electrophysiological properties and morphology of heterozygousTbx3mutant (Tbx3+/−) mouse hearts. We found PR interval shortening and prolonged QRS duration, as well as atrioventricular bundle hypoplasia after birth in heterozygous mice. The atrioventricular node size was unaffected. Transcriptomic analysis of atrioventricular nodes isolated by laser capture microdissection revealed hundreds of deregulated genes inTbx3+/−mutants. Notably,Tbx3+/−atrioventricular nodes showed increased expression of working myocardial gene programs (mitochondrial and metabolic processes, muscle contractility) and reduced expression of pacemaker gene programs (neuronal, Wnt signaling, calcium/ion channel activity). By integrating chromatin accessibility profiles (ATAC sequencing) of atrioventricular tissue and other epigenetic data, we identified Tbx3-dependent atrioventricular regulatory DNA elements (REs) on a genome-wide scale. We used transgenic reporter assays to determine the functionality of candidate REs nearRyr2,an up-regulated chamber-enriched gene, and inCacna1g,a down-regulated conduction system-specific gene. Using genome editing to delete candidate REs, we showed that a strong intronic bipartite RE selectively governsCacna1gexpression in the conduction system in vivo. Our data provide insights into the multifactorial Tbx3-dependent transcriptional network that regulates the structure and function of the cardiac conduction system, which may underlie the differences in PR duration and QRS interval between individuals carrying variants in theTBX3locus.

scholarly journals Multi-species, multi-transcription factor binding highlights conserved control of tissue-specific biological pathways

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Benoit Ballester ◽  
Alejandra Medina-Rivera ◽  
Dominic Schmidt ◽  
Mar Gonzàlez-Porta ◽  
Matthew Carlucci ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Association Studies ◽  
Specific Gene ◽  
Genome Wide Association Studies ◽  
Tissue Specific ◽  
Genome Wide ◽  
Multiple Species ◽  
Lipid Metabolism Genes ◽  
Genomic Regions ◽  
Regulatory Dna

As exome sequencing gives way to genome sequencing, the need to interpret the function of regulatory DNA becomes increasingly important. To test whether evolutionary conservation of cis-regulatory modules (CRMs) gives insight into human gene regulation, we determined transcription factor (TF) binding locations of four liver-essential TFs in liver tissue from human, macaque, mouse, rat, and dog. Approximately, two thirds of the TF-bound regions fell into CRMs. Less than half of the human CRMs were found as a CRM in the orthologous region of a second species. Shared CRMs were associated with liver pathways and disease loci identified by genome-wide association studies. Recurrent rare human disease causing mutations at the promoters of several blood coagulation and lipid metabolism genes were also identified within CRMs shared in multiple species. This suggests that multi-species analyses of experimentally determined combinatorial TF binding will help identify genomic regions critical for tissue-specific gene control.

Abstract P357: Genome-Wide Association Study of the PR Interval in Hispanic Populations

Circulation ◽  
2015 ◽  
Vol 131 (suppl_1) ◽  
Author(s):  
Amanda A Seyerle ◽  
Henry J Lin ◽  
Stephanie M Gogarten ◽  
Elsayed Z Soliman ◽  
Susan R Heckbert ◽  
...  
Keyword(s):  
Asian American ◽  
Fixed Effects ◽  
Association Studies ◽  
Pacemaker Implantation ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
1000 Genomes ◽  
Genome Wide ◽  
Cardiovascular Morbidity And Mortality ◽  
Pr Interval

BACKGROUND: The PR interval (PR) is an electrocardiographic measure of atrial and atrioventricular nodal conduction. PR prolongation has been associated with atrial fibrillation, pacemaker implantation, heart failure, and all-cause mortality. Although Hispanic/Latino (HL) populations have high burdens of cardiovascular morbidity and mortality, they remain a chronically understudied population, with previous genome-wide association studies of PR limited to European (EU), African (AA), and Asian (AS) descent populations. METHODS: We included 13,507 participants of HL ancestry from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and Women’s Health Initiative clinical trials (WHI). PR was automatically measured from digital electrocardiogram tracings recorded using standardized methods in all participants. Genotype data were imputed to the 1000 Genomes Phase 1 reference panel, and associations were examined using linear regression assuming an additive genetic model and adjusting for global ancestry, study center or region, clinical covariates (age, sex, heart rate, height, body mass index, systolic blood pressure, beta blocker use), and study weights (HCHS/SOL only). Study-specific results were combined using a fixed-effects, inverse variance weighted meta-analysis. Linkage disequilibrium (LD) patterns were examined using LocusZoom, and r2 values were calculated using 1000 Genomes reference populations. RESULTS: We identified six loci associated with PR in HL populations at genome-wide significant levels: SLC8A1, SCN5A, SCN10A, ARHGAP24, CAV1/CAV2, and SOX5. At these loci, index SNPs had important effects (β range: 2-4 ms) and common minor allele frequencies (MAF range: 13-40%). Of note, five of the six identified loci were previously associated with PR in EU populations, and four in AA populations; however, the association with SLC8A1 has been found only in AS populations. Whereas the SLC8A1 index SNP, rs17026148, is common in AS (MAF = 50%), AA (MAF = 15%), and HL populations (MAF = 17%), it is rare in EU populations (MAF < 5%). Interestingly, SLC8A1 LD patterns are similar across AS, EU, and HL populations in this region. CONCLUSIONS: Our results suggest that genetic determinants of PR are consistent across race/ethnicity but that previous studies in EU populations were either underpowered to detect the SLC8A1 locus or that it resides on an Asian/American Indian haplotype, thus underscoring the importance of conducting genetic studies in diverse populations.

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