scholarly journals Silencing of the tRNA Modification Enzyme Cdkal1 Effects Functional Insulin Synthesis in NIT-1 Cells: tRNALys3 Lacking ms2- (ms2t6A37) is Unable to Establish Sufficient Anticodon:Codon Interactions to Decode the Wobble Codon AAG

2021 ◽  
Vol 7 ◽  
Author(s):  
Amithi Narendran ◽  
Sweta Vangaveti ◽  
Srivathsan V. Ranganathan ◽  
Emily Eruysal ◽  
Miranda Craft ◽  
...  
Keyword(s):  
Cell Line ◽  
Association Studies ◽  
Significant Risk ◽  
Genome Wide Association Studies ◽  
Trna Modification ◽  
Nucleotide Polymorphisms ◽  
Insulin Production ◽  
Case Control Studies ◽  
Knock Out ◽  
Insulin Synthesis

Human Genome Wide Association Studies found a significant risk of Type 2 Diabetes Mellitus (T2DM) in single nucleotide polymorphisms in the cdkal1 gene. The cdkal1 gene is remote from the insulin gene and with the surprising function of a specific tRNA modification. Population studies and case control studies acquired evidences of the connection between Cdkal1 protein and insulin production over the years. To obtain biochemical proofs directly linking potential SNPs to their roles in insulin production and availability is challenging, but the development of Cdkal1 knock out mice and knock out cell lines made it possible to extend our knowledge towards therapeutic field of diabetic research. Supporting the evidences, here we show that knock down of the cdkal1 gene using small interfering and short hairpin RNA in the NIT-1 cell line, a β-cell line inducible for insulin resulted in reduced levels of cdkal1 and mature insulin mRNAs, increased the level of precursor insulin mRNA, decreased Cdkal1 and insulin proteins, and diminished modification of tRNALys3 from t6A37 to ms2t6A37, the specified function of Cdkal1. tRNALys3 lacking ms2- is incapable of establishing sufficient hydrogen bonding energy and hydrophobic stabilization to decode the wobble codon AAG.

scholarly journals Functional Testing of Thousands of Osteoarthritis-Associated Variants for Regulatory Activity

2018 ◽  
Author(s):  
Jason Chesler Klein ◽  
Aidan Keith ◽  
Sarah J. Rice ◽  
Colin Shepherd ◽  
Vikram Agarwal ◽  
...  
Keyword(s):  
Cell Line ◽  
Disease Risk ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Osteosarcoma Cell ◽  
Nucleotide Polymorphisms ◽  
Regulatory Activity ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Massively Parallel Reporter Assay

AbstractTo date, genome-wide association studies have implicated at least 35 loci in osteoarthritis, but due to linkage disequilibrium, we have yet to pinpoint the specific variants that underlie these associations, nor the mechanisms by which they contribute to disease risk. Here we functionally tested 1,605 single nucleotide variants associated with osteoarthritis for regulatory activity using a massively parallel reporter assay. We identified six single nucleotide polymorphisms (SNPs) with differential regulatory activity between the major and minor alleles. We show that our most significant hit, rs4730222, drives increased expression of an alternative isoform of HBP1 in a heterozygote chondrosarcoma cell line, a CRISPR-edited osteosarcoma cell line, and in chondrocytes derived from osteoarthritis patients.

scholarly journals Association between PRDM16, MEF2D, TRPM8, LRP1 gene polymorphisms and migraine susceptibility in the She ethnic population in China

2019 ◽  
Vol 42 (1) ◽  
pp. E21-E30 ◽  
Author(s):  
Xianguo Fu ◽  
Jing Yang ◽  
Xiaoyang Wu ◽  
Qifang Lin ◽  
Yuli Zeng ◽  
...  
Keyword(s):  
Association Studies ◽  
Direct Sequencing ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Han Chinese ◽  
Small Sample ◽  
Genome Wide Association Studies ◽  
Healthy Controls ◽  
Nucleotide Polymorphisms ◽  
Asian Populations

Background: The prevalence of migraines in the She population, a minority in China, is significantly higher than that in Han Chinese and other Asian populations. Two single nucleotide polymorphisms (SNPs) have been found to be associated with migraine susceptibility in the She population. Purpose: This study investigated four SNPs, identified in genome-wide association studies, within migraine-susceptible loci in Han Chinese for their association with migraine susceptibility in the She population. Methods: Two-hundred unrelated migraine patients and 200 healthy controls were recruited. The SNPs examined included rs2651899 (PRDM16 ), rs2274316 (MEF2D ), rs7577262 (TRPM8) and rs11172113 (LRP1). Genotyping of the SNPs was performed by allele-specific polymerase chain reaction and direct sequencing. Results: No significant differences between the participants with migraines and controls (participants without migraines) were demonstrated in genotypes, alleles and allele carriage frequencies for the four SNPs. A subgroup analysis found that migraine with aura had a lower frequency of C allele positivity in rs2651899 than in healthy controls (59.6% vs. 74.5%, respectively; P < 0.034). Univariate analyses indicated that no genotype of the four SNPs had a significant association with migraines. Males had a lower risk of migraines, and advanced age was a significant risk factor for migraines in females. Conclusion: The SNPs in four migraine susceptible loci in Han Chinese were not risk factors for migraines in a relatively small sample of the She population.

scholarly journals Network Analysis and Human Single Cell Brain Transcriptomics Reveal Novel Aspects of Alpha-Synuclein (SNCA) Biology

2020 ◽  
Author(s):  
Erin Teeple ◽  
Khushboo Jindal ◽  
Beril Kiragasi ◽  
Siddharth Annaldasula ◽  
Ann Byrne ◽  
...  
Keyword(s):  
Association Studies ◽  
Alpha Synuclein ◽  
Anterior Cingulate ◽  
Inhibitory Neurons ◽  
Middle Temporal Gyrus ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Ppi Network ◽  
Knock Out ◽  
Expression Module

ABSTRACTAlpha-synuclein (SNCA) aggregates are pathological hallmarks of synucleinopathies, neurodegenerative disorders including Parkinson’s Disease (PD) and Lewy Body Dementia (LBD). Functional networks are not yet well-characterized for SNCA by CNS cell type. We investigated cell-specific differences in SNCA expression using Allen Brain Database single-nucleus RNA-seq data from human Middle Temporal Gyrus (MTG, 15,928 nuclei) and Anterior Cingulate Cortex (ACC, 7,258 nuclei). Weighted gene co-expression analysis (WGCNA) and hierarchical clustering identified a conserved SNCA co-expression module. Module genes were highly conserved (p < 10−10) and most highly expressed in excitatory neurons versus inhibitory neurons and other glial cells. SNCA co-expression module genes from ACC and MTG regions were then used to construct a protein-protein interaction (PPI) network, with SNCA empirically top hub. Genes in the SNCA PPI network were compared with genes nearest single nucleotide polymorphisms linked with PD risk in genome-wide association studies. 16 genes in our PPI network are nearest genes to PD risk loci (p < 0.0006) and 55 genes map within 100kb. Selected SNCA PPI network genes nearest PD risk loci were disrupted by CRISPR knock out gene editing for validation of network functional significance; disruption of STK39, GBA, and MBNL2 resulted in significantly elevated intracellular SNCA expression.

scholarly journals METU-SNP: An Integrated Software System for SNPComplex Disease Association Analysis

2011 ◽  
Vol 8 (2) ◽  
pp. 204-221 ◽  
Author(s):  
Gürkan Üstünkar ◽  
Yeşim Aydın Son
Keyword(s):  
Association Studies ◽  
Case Control ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Case Control Studies ◽  
Single Nucleotide ◽  
High Dimensional Case ◽  
Genome Wide ◽  
Desktop Application ◽  
Integrated Software

Summary Recently, there has been increasing research to discover genomic biomarkers, haplotypes, and potentially other variables that together contribute to the development of diseases. Single Nucleotide Polymorphisms (SNPs) are the most common form of genomic variations and they can represent an individual’s genetic variability in greatest detail. Genome-wide association studies (GWAS) of SNPs, high-dimensional case-control studies, are among the most promising approaches for identifying disease causing variants. METU-SNP software is a Java based integrated desktop application specifically designed for the prioritization of SNP biomarkers and the discovery of genes and pathways related to diseases via analysis of the GWAS case-control data. Outputs of METU-SNP can easily be utilized for the downstream biomarkers research to allow the prediction and the diagnosis of diseases and other personalized medical approaches. Here, we introduce and describe the system functionality and architecture of the METU-SNP. We believe that the METU-SNP will help researchers with the reliable identification of SNPs that are involved in the etiology of complex diseases, ultimately supporting the development of personalized medicine approaches and targeted drug discoveries

Association of the ZC3H11B, ZFHX1B and SNTB1 genes with myopia of different severities

2019 ◽  
Vol 104 (10) ◽  
pp. 1472-1476 ◽  
Author(s):  
Shu Min Tang ◽  
Fen Fen Li ◽  
Shi Yao Lu ◽  
Ka Wai Kam ◽  
Pancy O S Tam ◽  
...  
Keyword(s):  
High Myopia ◽  
Association Studies ◽  
Susceptibility Gene ◽  
Significant Risk ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Chinese Populations ◽  
Genome Wide ◽  
Chinese Cohort

ObjectiveTo investigate the associations of single-nucleotide polymorphisms (SNPs) in the ZC3H11B, ZFHX1B, VIPR2, SNTB1 and MIPEP genes with severities of myopia in Chinese populations.MethodsBased on previous myopia genome-wide association studies, five SNPs (ZC3H11B rs4373767, ZFHX1B rs13382811, VIPR2 rs2730260, SNTB1 rs7839488 and MIPEP rs9318086) were selected for genotyping in a Chinese cohort of 2079 subjects: 252 extreme myopia, 277 high myopia, 393 moderate myopia, 366 mild myopia and 791 non-myopic controls. Genotyping was performed by TaqMan assays. Allelic frequencies of the SNPs were compared with myopia severities and ophthalmic biometric measurements.ResultsThe risk allele T of ZC3H11B SNP rs4373767 was significantly associated with high myopia (OR=1.39, p=0.007) and extreme myopia (OR=1.34, p=0.013) when compared with controls, whereas ZFHX1B rs13382811 (allele T, OR=1.33, p=0.018) and SNTB1 rs7839488 (allele G, OR=1.71, p=8.44E-05) were significantly associated with extreme myopia only. In contrast, there was no significant association of these SNPs with moderate or mild myopia. When compared with mild myopia, subjects carrying T allele of rs4373767 had a risk of progressing to high myopia (spherical equivalent ≤−6 dioptres) (OR=1.29, p=0.017). Similarly, the T allele of rs13382811 also imposed a significant risk to high myopia (OR=1.36, p=0.007). In quantitative traits analysis, SNPs rs4373767, rs13382811 and rs7839488 were correlated with axial length and refractive errors.ConclusionsWe confirmed ZC3H11B as a susceptibility gene for high and extreme myopia, and ZFHX1B and SNTB for extreme myopia in Chinese populations. Instead of myopia onset, these three genes were more likely to impose risks of progressing to high and extreme myopia.

scholarly journals Association between 20q12 rs13041247 polymorphism and risk of nonsyndromic cleft lip with or without cleft palate: a meta-analysis

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Liheng Huang ◽  
Xinglong Liang ◽  
Yangzhan Ou ◽  
Shijie Tang ◽  
Yunpu He
Keyword(s):  
Cleft Palate ◽  
Cleft Lip ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Case Control Studies ◽  
Chromosomal Locus ◽  
Asian Ethnicity ◽  
Study Population

Abstract Background Previous genome-wide association studies have identified a link between the rs13041247 single nucleotide polymorphisms (SNPs) in the chromosome 20q12 locus and the development of the congenital malformation known as nonsyndromic cleft lip with or without cleft palate (NSCL/P). The present meta-analysis was therefore designed to formally assess the relationship between rs13041247 and NSCL/P. Methods We searched Embase, Web of Science, PubMed, the China National Knowledge Internet (CNKI), and the China Wanfang database in order to identify relevant published through 25 June 2019. This allowed us to identify 13 studies incorporating 4914 patients and 5981 controls for whom rs13041247 genotyping had been conducted, with STATA 12.0 then being used to conduct a meta-analysis of these pooled results. The I2 statistic was used to compare heterogeneity among studies. Results In total this analysis incorporated 13 case-control studies. No association between the rs13041247 polymorphism and NSCL/P risk was detected in individuals of Asian ethnicity (C vs T: OR = 0.847, 95% CI = 0.702–1.021; CC vs TT: OR = 0.725, 95% CI = 0.494–1.063; CC vs CT: OR = 0.837, 95% CI = 0.657–1.067; CT + TT vs CC: OR = 1.265, 95% CI = 0.951–1.684; CC + CT vs TT: OR = 0.805, 95% CI = 0.630–1.029) or Caucasian ethnicity (C vs T: OR = 0.936, 95% CI = 0.786–1.114; CC vs TT: OR = 0.988, 95% CI = 0.674–1.446; CC vs CT: OR = 1.197, 95% CI = 0.816–1.757; CT + TT vs CC: OR = 0.918, 95% CI = 0.639–1.318; CC + CT vs TT: OR = 0.855, 95% CI = 0.677–1.081). However, an overall analysis of all participants in these studies revealed the rs13041247 C allele, the CT genotype, and the CC + CT model to be linked to a reduced NSCL/P risk (C vs T: OR = 0.897, 95% CI: 0.723–1.114, P = 0.048; CT vs TT: OR = 0.839, 95% CI: 0.734–0.959, P = 0.01; CC + CT vs TT: OR = 0.824, 95% CI: 0.701–0.968, P = 0.019). Conclusion These results suggest that the rs13041247 SNP located at the 20q12 chromosomal locus is associated with NSCL/P risk in an overall pooled study population, although this association was not significant in East Asian or Caucasian populations.

scholarly journals Causal Association between Periodontitis and Parkinson’s Disease: A Bidirectional Mendelian Randomization Study

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 772
Author(s):  
João Botelho ◽  
Vanessa Machado ◽  
José João Mendes ◽  
Paulo Mascarenhas
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Instrumental Variables ◽  
Mendelian Randomization ◽  
Association Studies ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genetic Liability ◽  
Bidirectional Association

The latest evidence revealed a possible association between periodontitis and Parkinson’s disease (PD). We explored the causal relationship of this bidirectional association through two-sample Mendelian randomization (MR) in European ancestry populations. To this end, we used openly accessible data of genome-wide association studies (GWAS) on periodontitis and PD. As instrumental variables for periodontitis, seventeen single-nucleotide polymorphisms (SNPs) from a GWAS of periodontitis (1817 periodontitis cases vs. 2215 controls) and eight non-overlapping SNPs of periodontitis from an additional GWAS for validation purposes. Instrumental variables to explore for the reverse causation included forty-five SNPs from a GWAS of PD (20,184 cases and 397,324 controls). Multiple approaches of MR were carried-out. There was no evidence of genetic liability of periodontitis being associated with a higher risk of PD (B = −0.0003, Standard Error [SE] 0.0003, p = 0.26). The eight independent SNPs (B = −0.0000, SE 0.0001, p = 0.99) validated this outcome. We also found no association of genetically primed PD towards periodontitis (B = −0.0001, SE 0.0001, p = 0.19). These MR study findings do not support a bidirectional causal genetic liability between periodontitis and PD. Further GWAS studies are needed to confirm the consistency of these results.

scholarly journals Pharmacogenomics of Lithium Response in Bipolar Disorder

2021 ◽  
Vol 14 (4) ◽  
pp. 287
Author(s):  
Courtney M. Vecera ◽  
Gabriel R. Fries ◽  
Lokesh R. Shahani ◽  
Jair C. Soares ◽  
Rodrigo Machado-Vieira
Keyword(s):  
Bipolar Disorder ◽  
Association Studies ◽  
Mood Stabilizer ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Non Coding Rna ◽  
Genome Wide ◽  
Lithium Response ◽  
Genetic Loading ◽  
Long Non Coding Rna

Despite being the most widely studied mood stabilizer, researchers have not confirmed a mechanism for lithium’s therapeutic efficacy in Bipolar Disorder (BD). Pharmacogenomic applications may be clinically useful in the future for identifying lithium-responsive patients and facilitating personalized treatment. Six genome-wide association studies (GWAS) reviewed here present evidence of genetic variations related to lithium responsivity and side effect expression. Variants were found on genes regulating the glutamate system, including GAD-like gene 1 (GADL1) and GRIA2 gene, a mutually-regulated target of lithium. In addition, single nucleotide polymorphisms (SNPs) discovered on SESTD1 may account for lithium’s exceptional ability to permeate cell membranes and mediate autoimmune and renal effects. Studies also corroborated the importance of epigenetics and stress regulation on lithium response, finding variants on long, non-coding RNA genes and associations between response and genetic loading for psychiatric comorbidities. Overall, the precision medicine model of stratifying patients based on phenotype seems to derive genotypic support of a separate clinical subtype of lithium-responsive BD. Results have yet to be expounded upon and should therefore be interpreted with caution.

scholarly journals Investigation of gene–environment interactions in relation to tic severity

2021 ◽  
Author(s):  
Mohamed Abdulkadir ◽  
Dongmei Yu ◽  
Lisa Osiecki ◽  
Robert A. King ◽  
Thomas V. Fernandez ◽  
...  
Keyword(s):  
Tourette Syndrome ◽  
Association Studies ◽  
Autism Spectrum ◽  
Environment Interaction ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Linear Regression Models ◽  
Compulsive Disorder ◽  
Gene Environment ◽  
Tic Severity

AbstractTourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive–compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene–environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene–environment studies.

scholarly journals Transcriptional Regulation of RUNX1: An Informatics Analysis

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1175
Author(s):  
Amarni L. Thomas ◽  
Judith Marsman ◽  
Jisha Antony ◽  
William Schierding ◽  
Justin M. O’Sullivan ◽  
...  
Keyword(s):  
Association Studies ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Runx1 Gene ◽  
Gene Regulatory Elements ◽  
Important Regulator ◽  
Aml1 Gene ◽  
Regulatory Landscape

The RUNX1/AML1 gene encodes a developmental transcription factor that is an important regulator of haematopoiesis in vertebrates. Genetic disruptions to the RUNX1 gene are frequently associated with acute myeloid leukaemia. Gene regulatory elements (REs), such as enhancers located in non-coding DNA, are likely to be important for Runx1 transcription. Non-coding elements that modulate Runx1 expression have been investigated over several decades, but how and when these REs function remains poorly understood. Here we used bioinformatic methods and functional data to characterise the regulatory landscape of vertebrate Runx1. We identified REs that are conserved between human and mouse, many of which produce enhancer RNAs in diverse tissues. Genome-wide association studies detected single nucleotide polymorphisms in REs, some of which correlate with gene expression quantitative trait loci in tissues in which the RE is active. Our analyses also suggest that REs can be variant in haematological malignancies. In summary, our analysis identifies features of the RUNX1 regulatory landscape that are likely to be important for the regulation of this gene in normal and malignant haematopoiesis.

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