scholarly journals VRK2 gene expression in schizophrenia, bipolar disorder and healthy controls

2016 ◽  
Vol 209 (2) ◽  
pp. 114-120 ◽  
Author(s):  
Martin Tesli ◽  
Katrine Verena Wirgenes ◽  
Timothy Hughes ◽  
Francesco Bettella ◽  
Lavinia Athanasiu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bipolar Disorder ◽  
Association Studies ◽  
Mrna Level ◽  
Genome Wide Association Studies ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Nucleotide Polymorphisms ◽  
Schizophrenia Spectrum Disorders ◽  
Underlying Mechanisms

BackgroundCommon variants in the Vaccinia-related kinase 2 (VRK2) gene have been associated with schizophrenia, but the relevance of its encoded protein VRK2 in the disorder remains unclear.AimsTo identify potential differences in VRK2 gene expression levels between schizophrenia, bipolar disorder, psychosis not otherwise specified (PNOS) and healthy controls.MethodVRK2 mRNA level was measured in whole blood in 652 individuals (schizophrenia, n = 201; bipolar disorder, n = 167; PNOS, n = 61; healthy controls, n = 223), and compared across diagnostic categories and subcategories. Additionally, we analysed for association between 1566 VRK2 single nucleotide polymorphisms and mRNA levels.ResultsWe found lower VRK2 mRNA levels in schizophrenia compared with healthy controls (P<10–12), bipolar disorder (P<10–12) and PNOS (P = 0.0011), and lower levels in PNOS than in healthy controls (P = 0.0042) and bipolar disorder (P = 0.00026). Expression quantitative trait loci in close proximity to the transcription start site of the short isoforms of the VRK2 gene were identified.ConclusionsAltered VRK2 gene expression seems specific for schizophrenia and PNOS, which is in accordance with findings from genome-wide association studies. These results suggest that reduced VRK2 mRNA levels are involved in the underlying mechanisms in schizophrenia spectrum disorders.

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.

DDR1 methylation is associated with bipolar disorder and the isoform expression and methylation of myelin genes

Epigenomics ◽  
2021 ◽  
Author(s):  
Beatriz Garcia-Ruiz ◽  
Manuel Castro de Moura ◽  
Gerard Muntané ◽  
Lourdes Martorell ◽  
Elena Bosch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Bipolar Disorder ◽  
Mrna Expression ◽  
Gene Expression Analysis ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Genome Wide ◽  
Isoform Expression

Aim: To investigate DDR1 methylation in the brains of bipolar disorder (BD) patients and its association with DDR1 mRNA levels and comethylation with myelin genes. Materials & methods: Genome-wide profiling of DNA methylation (Infinium MethylationEPIC BeadChip) corrected for glial composition and DDR1 gene expression analysis in the occipital cortices of individuals with BD (n = 15) and healthy controls (n = 15) were conducted. Results: DDR1 5-methylcytosine levels were increased and directly associated with DDR1b mRNA expression in the brains of BD patients. We also observed that DDR1 was comethylated with a group of myelin genes. Conclusion: DDR1 is hypermethylated in BD brain tissue and is associated with isoform expression. Additionally, DDR1 comethylation with myelin genes supports the role of this receptor in myelination.

scholarly journals A selective inference approach for false discovery rate control using multiomics covariates yields insights into disease risk

2020 ◽  
Vol 117 (26) ◽  
pp. 15028-15035 ◽  
Author(s):  
Ronald Yurko ◽  
Max G’Sell ◽  
Kathryn Roeder ◽  
Bernie Devlin
Keyword(s):  
Gene Expression ◽  
Multiple Testing ◽  
Disease Risk ◽  
Association Studies ◽  
Auxiliary Information ◽  
Primary Data ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Hypothesis Tests ◽  
Selective Inference

To correct for a large number of hypothesis tests, most researchers rely on simple multiple testing corrections. Yet, new methodologies of selective inference could potentially improve power while retaining statistical guarantees, especially those that enable exploration of test statistics using auxiliary information (covariates) to weight hypothesis tests for association. We explore one such method, adaptiveP-value thresholding (AdaPT), in the framework of genome-wide association studies (GWAS) and gene expression/coexpression studies, with particular emphasis on schizophrenia (SCZ). Selected SCZ GWAS associationPvalues play the role of the primary data for AdaPT; single-nucleotide polymorphisms (SNPs) are selected because they are gene expression quantitative trait loci (eQTLs). This natural pairing of SNPs and genes allow us to map the following covariate values to these pairs: GWAS statistics from genetically correlated bipolar disorder, the effect size of SNP genotypes on gene expression, and gene–gene coexpression, captured by subnetwork (module) membership. In all, 24 covariates per SNP/gene pair were included in the AdaPT analysis using flexible gradient boosted trees. We demonstrate a substantial increase in power to detect SCZ associations using gene expression information from the developing human prefrontal cortex. We interpret these results in light of recent theories about the polygenic nature of SCZ. Importantly, our entire process for identifying enrichment and creating features with independent complementary data sources can be implemented in many different high-throughput settings to ultimately improve power.

Association of functional (GA)n microsatellite polymorphism in the FLI1 gene with susceptibility to human systemic sclerosis

Rheumatology ◽  
2020 ◽  
Vol 59 (11) ◽  
pp. 3553-3562 ◽  
Author(s):  
Keita Yamashita ◽  
Aya Kawasaki ◽  
Takashi Matsushita ◽  
Hiroshi Furukawa ◽  
Yuya Kondo ◽  
...  
Keyword(s):  
Roc Analysis ◽  
Association Studies ◽  
Additive Model ◽  
Skin Thickness ◽  
Genome Wide Association Studies ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Operating Characteristics ◽  
Genome Wide ◽  
Characteristic Features

Abstract Objective Susceptibility genes that can account for characteristic features of SSc such as fibrosis, vasculopathy and autoimmunity remain to be determined. In mice, deficiency of Friend leukaemia integration 1 transcription factor (Fli1) causes SSc-like disease with these features. The human FLI1 gene contains (GA)n microsatellite, which has been shown to be associated with expression level. Because microsatellite polymorphisms are difficult to capture by genome-wide association studies, we directly genotyped FLI1 (GA)n microsatellite and examined its association with SSc. Methods Genomic DNA from 639 Japanese SSc patients and 851 healthy controls was genotyped for (GA)n microsatellite using the fragment assay. The cut-off repeat number for susceptibility to SSc was determined by receiver operating characteristics (ROC) analysis. Association with susceptibility and clinical characteristics was examined using logistic regression analysis. FLI1 mRNA levels were determined using quantitative RT-PCR. Results Based on the ROC analysis, (GA)n alleles with ≥22 repeats were collectively defined as L alleles and alleles with ≤21 repeats as S alleles. (GA)n L alleles were significantly associated with susceptibility to SSc (P = 5.0e-04, odds ratio 1.34, additive model). Significant association was observed both in diffuse cutaneous and limited cutaneous SSc. Among the SSc, (GA)n L alleles were significantly enriched in the patients with a modified Rodnan total skin thickness score ≥10 compared with those with a score &lt;10. FLI1 mRNA levels were significantly decreased in healthy controls carrying (GA)n L alleles as compared with non-carriers. Conclusion Extended repeat alleles of FLI1 (GA)n microsatellite may be associated with lower FLI1 mRNA levels and susceptibility to human SSc.

scholarly journals Identification of Novel Susceptible Genes of Gastric Cancer Based on Integrated Omics Data

2021 ◽  
Vol 9 ◽  
Author(s):  
Huang Yaoxing ◽  
Yu Danchun ◽  
Sun Xiaojuan ◽  
Jiang Shuman ◽  
Yan Qingqing ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Association Studies ◽  
Gene Expression Level ◽  
Expression Level ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Coding Region ◽  
Level Data ◽  
Integrated Omics

Gastric cancer (GC) is one of the most common causes of cancer-related deaths in the world. This cancer has been regarded as a biological and genetically heterogeneous disease with a poorly understood carcinogenesis at the molecular level. Thousands of biomarkers and susceptible loci have been explored via experimental and computational methods, but their effects on disease outcome are still unknown. Genome-wide association studies (GWAS) have identified multiple susceptible loci for GC, but due to the linkage disequilibrium (LD), single-nucleotide polymorphisms (SNPs) may fall within the non-coding region and exert their biological function by modulating the gene expression level. In this study, we collected 1,091 cases and 410,350 controls from the GWAS catalog database. Integrating with gene expression level data obtained from stomach tissue, we conducted a machine learning-based method to predict GC-susceptible genes. As a result, we identified 787 novel susceptible genes related to GC, which will provide new insight into the genetic and biological basis for the mechanism and pathology of GC development.

scholarly journals Identification, expression and variation of theGNPDA2gene, and its association with body weight and fatness traits in chicken

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2129 ◽  
Author(s):  
Hongjia Ouyang ◽  
Huan Zhang ◽  
Weimin Li ◽  
Sisi Liang ◽  
Endashaw Jebessa ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
High Glucose ◽  
Association Studies ◽  
Mrna Level ◽  
Subcutaneous Fat ◽  
Basal Diet ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Allosteric Enzyme

Background.TheGNPDA2(glucosamine-6-phosphate deaminase 2) gene is a member ofGlucosamine-6-phosphate (GlcN6P) deaminase subfamily, which encoded an allosteric enzyme of GlcN6P. Genome-wide association studies (GWAS) have shown that variations of humanGNPDA2are associated with body mass index and obesity risk, but its function and metabolic implications remain to be elucidated.The object of this study was to characterize the gene structure, expression, and biological functions ofGNPDA2in chickens.Methods.Variant transcripts of chickenGNPDA2and their expression were investigated using rapid amplification of cDNA ends (RACE) system and real-time quantitative PCR technology. We detected theGNPDA2expression in hypothalamic, adipose, and liver tissue of Xinghua chickens with fasting and high-glucose-fat diet treatments, and performed association analysis of variations ofGNPDA2with productive traits in chicken. The function ofGNPDA2was further studied by overexpression and small interfering RNA (siRNA) methods in chicken preadipocytes.Results.Four chickenGNPDA2transcripts (cGNPDA2-a∼cGNPDA2-d) were identified in this study. The complete transcriptGNPDA2-a was predominantly expressed in adipose tissue (subcutaneous fat and abdominal fat), hypothalamus, and duodenum. In fasting chickens, the mRNA level ofGNPDA2was decreased by 58.8% (P< 0.05) in hypothalamus, and returned to normal level after refeeding. Chicken fed a high-glucose-fat diet increasedGNPDA2gene expression about 2-fold higher in adipose tissue (P< 0.05) than that in the control (fed a basal diet), but decreased its expression in hypothalamus. Two single-nucleotide polymorphisms of theGNPDA2gene were significantly associated with body weight and a number of fatness traits in chicken (P< 0.05).Conclusion.Our findings indicated that theGNPDA2gene has a potential roles in the regulation of body weight, fat and energy metabolism in chickens.

scholarly journals Association ofTNFAIP3Polymorphism with Susceptibility to Systemic Lupus Erythematosus in a Japanese Population

2010 ◽  
Vol 2010 ◽  
pp. 1-5 ◽  
Author(s):  
Aya Kawasaki ◽  
Ikue Ito ◽  
Satoshi Ito ◽  
Taichi Hayashi ◽  
Daisuke Goto ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Japanese Population ◽  
Association Studies ◽  
Susceptibility Gene ◽  
Allelic Association ◽  
Genome Wide Association Studies ◽  
Mrna Levels ◽  
Nucleotide Polymorphisms ◽  
Systemic Lupus

Recent genome-wide association studies demonstrated association of single nucleotide polymorphisms (SNPs) in theTNFAIP3region at 6q23 with systemic lupus erythematosus (SLE) in European-American populations. In this study, we investigated whether SNPs in theTNFAIP3region are associated with SLE also in a Japanese population. A case-control association study was performed on the SNPs rs13192841, rs2230926, and rs6922466 in 318 Japanese SLE patients and 444 healthy controls. Association of rs2230926 G allele with SLE was replicated in Japanese (allelic associationP=.033, odds ratio [OR] 1.47, recessive modelP=.023, OR 8.52). The association was preferentially observed in the SLE patients with nephritis. When theTNFAIP3mRNA levels of the HapMap samples were examined using GENEVAR database, the presence ofTNFAIP3rs2230926 G allele was associated with lower mRNA expression ofTNFAIP3(P=.013). These results indicated thatTNFAIP3is a susceptibility gene to SLE both in the Caucasian and Asian populations.

scholarly journals Identifying Liver Cancer-Related Enhancer SNPs by Integrating GWAS and Histone Modification ChIP-seq Data

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Tianjiao Zhang ◽  
Yang Hu ◽  
Xiaoliang Wu ◽  
Rui Ma ◽  
Qinghua Jiang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Liver Cancer ◽  
Histone Modification ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Protein Coding ◽  
Noncoding Regions ◽  
Coding Regions ◽  
Genome Wide

Many disease-related single nucleotide polymorphisms (SNPs) have been inferred from genome-wide association studies (GWAS) in recent years. Numerous studies have shown that some SNPs located in protein-coding regions are associated with numerous diseases by affecting gene expression. However, in noncoding regions, the mechanism of how SNPs contribute to disease susceptibility remains unclear. Enhancer elements are functional segments of DNA located in noncoding regions that play an important role in regulating gene expression. The SNPs located in enhancer elements may affect gene expression and lead to disease. We presented a method for identifying liver cancer-related enhancer SNPs through integrating GWAS and histone modification ChIP-seq data. We identified 22 liver cancer-related enhancer SNPs, 9 of which were regulatory SNPs involved in distal transcriptional regulation. The results highlight that these enhancer SNPs may play important roles in liver cancer.

scholarly journals Chromatin Conformation Links Distal Target Genes to CKD Loci

2017 ◽  
Vol 29 (2) ◽  
pp. 462-476 ◽  
Author(s):  
Maarten M. Brandt ◽  
Claartje A. Meddens ◽  
Laura Louzao-Martinez ◽  
Noortje A.M. van den Dungen ◽  
Nico R. Lansu ◽  
...  
Keyword(s):  
Target Genes ◽  
Association Studies ◽  
Regulatory Region ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Mrna Levels ◽  
Nucleotide Polymorphisms ◽  
Common Variants ◽  
Circular Chromosome ◽  
Single Nucleotide

Genome-wide association studies (GWASs) have identified many genetic risk factors for CKD. However, linking common variants to genes that are causal for CKD etiology remains challenging. By adapting self-transcribing active regulatory region sequencing, we evaluated the effect of genetic variation on DNA regulatory elements (DREs). Variants in linkage with the CKD-associated single-nucleotide polymorphism rs11959928 were shown to affect DRE function, illustrating that genes regulated by DREs colocalizing with CKD-associated variation can be dysregulated and therefore, considered as CKD candidate genes. To identify target genes of these DREs, we used circular chromosome conformation capture (4C) sequencing on glomerular endothelial cells and renal tubular epithelial cells. Our 4C analyses revealed interactions of CKD-associated susceptibility regions with the transcriptional start sites of 304 target genes. Overlap with multiple databases confirmed that many of these target genes are involved in kidney homeostasis. Expression quantitative trait loci analysis revealed that mRNA levels of many target genes are genotype dependent. Pathway analyses showed that target genes were enriched in processes crucial for renal function, identifying dysregulated geranylgeranyl diphosphate biosynthesis as a potential disease mechanism. Overall, our data annotated multiple genes to previously reported CKD-associated single-nucleotide polymorphisms and provided evidence for interaction between these loci and target genes. This pipeline provides a novel technique for hypothesis generation and complements classic GWAS interpretation. Future studies are required to specify the implications of our dataset and further reveal the complex roles that common variants have in complex diseases, such as CKD.

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