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 <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.

Novel recessive locus for body mass index in childhood asthma

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2020-215742
Author(s):  
Sanghun Lee ◽  
Jessica Lasky-Su ◽  
Sungho Won ◽  
Cecelia Laurie ◽  
Juan Carlos Celedón ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Body Mass ◽  
Association Studies ◽  
Additive Model ◽  
Recessive Model ◽  
Genome Wide Association Studies ◽  
Association Testing ◽  
Genome Wide ◽  
Children With Asthma ◽  
Recessive Locus

Most genome-wide association studies of obesity and body mass index (BMI) have so far assumed an additive mode of inheritance in their analysis, although association testing supports a recessive effect for some of the established loci, for example, rs1421085 in FTO. In two whole-genome sequencing (WGS) studies of children with asthma and their parents (892 Costa Rican trios and 286 North American trios), we discovered an association between a locus (rs9292139) in LOC102724122 and BMI that reaches genome-wide significance under a recessive model in the combined analysis. As the association does not achieve significance under an additive model, our finding illustrates the benefits of the recessive model in WGS analyses.

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 Systems Genetics of Single Nucleotide Polymorphisms at the Drosophila Obp56h Locus

2021 ◽  
Author(s):  
Sneha S. Mokashi ◽  
Vijay Shankar ◽  
Joel A. Johnstun ◽  
Wen Huang ◽  
Trudy F. C. Mackay ◽  
...  
Keyword(s):  
Quantitative Traits ◽  
Association Studies ◽  
Additive Model ◽  
Sexually Dimorphic ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Environmental Variance ◽  
Genome Wide ◽  
Allele Specific ◽  
Molecular Phenotypes

Variation in quantitative traits arises from naturally segregating alleles with environmentally sensitive effects, but how individual variants in single genes affect the genotype-phenotype map and molecular phenotypes is not understood. We used CRISPR/Cas9 germline gene editing to generate naturally occurring variants with different site classes and allele frequencies in the Drosophila melanogaster Obp56h gene in a common genetic background. Single base pair changes caused large allele-specific and sexually dimorphic effects on the mean and micro-environmental variance for multiple fitness-related traits and in the Obp56h co-regulated transcriptome. However, these alleles were not associated with quantitative traits in the Drosophila Genetic Reference Panel, suggesting that the small allelic effects observed in genome wide association studies may be an artifact of averaging variable context-dependent allelic effects over multiple genetic backgrounds. Thus, the traditional infinitesimal additive model does not reflect the underlying biology of quantitative traits.

Abstract 43: Mice With Cardiac-Specific Inactivation Of Ppap2b (Lipid Phosphate Phosphatase 3) Validates Genome-Wide Association Studies.

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Manikandan Panchatcharam ◽  
Sumitra Miriyala ◽  
Natalie D Hendrix ◽  
Diana Escalante-Alcalde
Keyword(s):  
Heart Rate ◽  
Cell Function ◽  
Association Studies ◽  
Myocardial Infarct ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Mrna Levels ◽  
Bioactive Lipids ◽  
Genome Wide ◽  
Lipid Phosphate

A recent meta-analysis of Genome-Wide Association Studies (GWAS) of coronary artery disease (CAD) involving over 86,000 individuals identified PPAP2B (encodes lipid phosphate phosphatase-3; LPP3) as a new loci (SNP rs17114036; P= 3.81 X 10 −19 ) that independently predicts CAD. LPP3 is an integral membrane enzyme that dephosphorylates lysophosphatidic acid, sphingosine-1-phosphate and related bioactive lipids. Strikingly, we found that targeted inactivation of LPP3 in endothelial cells results in early embryonic lethality, in part to due to vascular patterning defects. In addition, we found that constitutive inactivation of LPP3 in the myocardium results in cardiac dysfunction, indicating that dysregulation of LPP3-dependent cardiomyocyte cell function. Heart rate was significantly higher in conditional Ppap2b Δ mice (P<0.001), which may indicate a role for LPP3 in regulating heart rate and/or function. Further, we found that myocardial LPP3 levels are altered following myocardial infarction in mice and these results are in accord with our myocardial infarct data from patient that had down-regulated myocardial LPP3 levels. The major rs17114036A allele was associated with a 1.17 odds ratio for CAD. This SNP is located in the final intron of the six exon PPAP2B gene. At least seven SNPs are in robust linkage disequilbrium (r2>0.9) with rs17114036. The sequence surrounding the SNP rs17114036 matches a U1 spliceosome recognition sequence, and the variant base is located at the final position of a sequence with high homology to a U1 spliceosome 5’ spice site recognition motif. Binding of the U1 spliceosome may alter mRNA stability or processing, perhaps by masking cryptic splice sites, thus enabling efficient splicing or promoting polyadenylation of the mature message. To address the polymorphism, we transfected MDA MB 453 cells, which are homozygous for the “T’ allele of rs17114036 SNP, with a short synthetic 2’-O-methyl phosphorothioate RNA. We found a dramatic decrease in both LPP3 protein expression and LPP3 mRNA levels. These results imply that the region containing the rs17114036 SNP may be important for proper processing and/or stability of the LPP3 transcript thereby functionally validating the GWAS study.

scholarly journals Genetic predictors of gene expression associated with risk of bipolar disorder

2016 ◽  
Author(s):  
Kaanan Shah ◽  
Heather E Wheeler ◽  
Eric R Gamazon ◽  
Dan L Nicolae ◽  
Nancy J Cox ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Prediction Models ◽  
Association Studies ◽  
Anterior Cingulate ◽  
Health Concern ◽  
Ras Signaling ◽  
Genome Wide Association Studies ◽  
Mrna Levels ◽  
Genome Wide ◽  
Increased Risk

Bipolar disorder (BD) affects the quality of life of approximately 1% of the population and represents a major public health concern. It is known to be highly heritable but large-scale genome-wide association studies (GWAS) have discovered only a handful of markers associated with the disease. Furthermore, the biological mechanisms underlying these markers need to be elucidated. We recently published a gene-level association test, PrediXcan that integrates transcriptome regulation data to characterize the function of these markers in a tissue specific manner. In this study, we developed prediction models for mRNA levels in 10 brain regions using data from the GTEx project and performed PrediXcan analysis in WTCCC as well as in an independent cohort, GAIN. We replicate the association between predicted expression of PTPRE and BD risk in whole blood and recapitulate the association in brain tissues. PTPRE encodes the protein tyrosine phosphatase, receptor type E, that is known to be involved in RAS signaling and activation of voltage-gated K+ channels. We also found a new genome-wide significant association between lower predicted expression of BBX (bobby sox homolog) in the anterior cingulate cortex region of the brain and increased risk of BD (pWTCCC = 7.02 x 10e-6, pGAIN = 4.68 x 10e-3, pmeta = 1.11 x 10e-7). In sum, we used our mechanistically informed approach, PrediXcan, to identify and replicate two novel genome-wide significant genes using existing GWAS studies.

scholarly journals Operating Characteristics of the Rank-Based Inverse Normal Transformation for Quantitative Trait Analysis in Genome-Wide Association Studies

2019 ◽  
Author(s):  
Zachary R. McCaw ◽  
Jacqueline M. Lane ◽  
Richa Saxena ◽  
Susan Redline ◽  
Xihong Lin
Keyword(s):  
Type I Error ◽  
Association Studies ◽  
Genome Wide Association ◽  
Type I ◽  
Genome Wide Association Studies ◽  
Operating Characteristics ◽  
Association Tests ◽  
Genome Wide ◽  
Normal Transformation ◽  
Normally Distributed

SummaryQuantitative traits analyzed in Genome-Wide Association Studies (GWAS) are often non-normally distributed. For such traits, association tests based on standard linear regression are subject to reduced power and inflated type I error in finite samples. Applying the rank-based Inverse Normal Transformation (INT) to non-normally distributed traits has become common practice in GWAS. However, the different variations on INT-based association testing have not been formally defined, and guidance is lacking on when to use which approach. In this paper, we formally define and systematically compare the direct (D-INT) and indirect (I-INT) INT-based association tests. We discuss their assumptions, underlying generative models, and connections. We demonstrate that the relative powers of D-INT and I-INT depend on the underlying data generating process. Since neither approach is uniformly most powerful, we combine them into an adaptive omnibus test (O-INT). O-INT is robust to model misspecification, protects the type I error, and is well powered against a wide range of non-normally distributed traits. Extensive simulations were conducted to examine the finite sample operating characteristics of these tests. Our results demonstrate that, for non-normally distributed traits, INT-based tests outperform the standard untransformed association test (UAT), both in terms of power and type I error rate control. We apply the proposed methods to GWAS of spirometry traits in the UK Biobank. O-INT has been implemented in the R package RNOmni, which is available on CRAN.

scholarly journals Polymorphism in the GATM Locus Associated with Dialysis-Independent Chronic Kidney Disease but Not Dialysis-Dependent Kidney Failure

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 834
Author(s):  
Špela Šalamon ◽  
Sebastjan Bevc ◽  
Robert Ekart ◽  
Radovan Hojs ◽  
Uroš Potočnik
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Kidney Failure ◽  
Association Studies ◽  
Genetic Difference ◽  
Genome Wide Association Studies ◽  
Healthy Controls ◽  
Genome Wide ◽  
Stage Renal Disease ◽  
End Stage

The ten most statistically significant estimated glomerular filtration rate (eGFRcrea)-associated loci from genome-wide association studies (GWAs) are tested for associations with chronic kidney disease (CKD) in 208 patients, including dialysis-independent CKD and dialysis-dependent end-stage renal disease (kidney failure). The allele A of intergenic SNP rs2453533 (near GATM) is more frequent in dialysis-independent CKD patients (n = 135, adjusted p = 0.020) but not dialysis-dependent kidney failure patients (n = 73) compared to healthy controls (n = 309). The allele C of intronic SNP rs4293393 (UMOD) is more frequent in healthy controls (adjusted p = 0.042) than in CKD patients. The Allele T of intronic SNP rs9895661 (BCAS3) is associated with decreased eGFRcys (adjusted p = 0.001) and eGFRcrea (adjusted p = 0.017). Our results provide further evidence of a genetic difference between dialysis-dialysis-independent CKD and dialysis-dependent kidney failure, and add the GATM gene locus to the list of loci associated only with dialysis-independent CKD. GATM risk allele carriers in the dialysis-independent group may have a genetic susceptibility to higher creatinine production rather than increased serum creatinine due to kidney malfunction, and therefore, do not progress to dialysis-dependent kidney failure. When using eGFRcrea for CKD diagnosis, physicians might benefit from information about creatinine-increasing loci.

scholarly journals mGWAS identification of six novel single nucleotide polymorphism loci with strong correlation to gastric cancer

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Shuangfeng Yang ◽  
Yuan-Liang Wang ◽  
Yanping Lyu ◽  
Yu Jiang ◽  
Jianjun Xiang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Association Studies ◽  
Genetic Regulation ◽  
Population Data ◽  
Cell Receptor ◽  
Genome Wide Association Studies ◽  
Healthy Controls ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genome Wide

Abstract Background Metabolite genome-wide association studies (mGWAS) are key for understanding the genetic regulation of metabolites in complex diseases including cancers. Although mGWAS has revealed hundreds of metabolomics quantitative trait loci (mQTLs) in the general population, data relating to gastric cancer (GC) are still incomplete. Methods We identified mQTLs associated with GC by analyzing genome-wide and metabolome-wide datasets generated from 233 GC patients and 233 healthy controls. Results Twenty-two metabolites were statistically different between GC cases and healthy controls, and all of them were associated with the risk of gastric cancer. mGWAS analyses further revealed that 9 single nucleotide polymorphisms (SNPs) were significantly associated with 3 metabolites. Of these 9 SNPs, 6 loci were never reported in the previous mGWAS studies. Surprisingly, 4 of 9 SNPs were significantly enriched in genes involved in the T cell receptor signaling pathway. Conclusions Our study unveiled several novel GC metabolite and genetic biomarkers, which may be implicated in the prevention and diagnosis of gastric cancer.

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