scholarly journals Transethnic meta-analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis

2017 ◽  
Vol 76 (6) ◽  
pp. 1150-1158 ◽  
Author(s):  
Chikashi Terao ◽  
Takahisa Kawaguchi ◽  
Philippe Dieude ◽  
John Varga ◽  
Masataka Kuwana ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
T Cell ◽  
Autoimmune Diseases ◽  
Association Studies ◽  
Meta Analysis ◽  
Enrichment Analysis ◽  
Susceptibility Genes ◽  
Genome Wide Association Studies ◽  
Hla Association ◽  
Genome Wide

ObjectivesSystemic sclerosis (SSc) is an autoimmune disease characterised by skin and systemic fibrosis culminating in organ damage. Previous genetic studies including genome-wide association studies (GWAS) have identified 12 susceptibility loci satisfying genome-wide significance. Transethnic meta-analyses have successfully expanded the list of susceptibility genes and deepened biological insights for other autoimmune diseases.MethodsWe performed transethnic meta-analysis of GWAS in the Japanese and European populations, followed by a two-staged replication study comprising a total of 4436 cases and 14 751 controls. Associations between significant single nuclear polymorphisms (SNPs) and neighbouring genes were evaluated. Enrichment analysis of H3K4Me3, a representative histone mark for active promoter was conducted with an expanded list of SSc susceptibility genes.ResultsWe identified two significant SNP in two loci, GSDMA and PRDM1, both of which are related to immune functions and associated with other autoimmune diseases (p=1.4×10−10 and 6.6×10−10, respectively). GSDMA also showed a significant association with limited cutaneous SSc. We also replicated the associations of previously reported loci including a non-GWAS locus, TNFAIP3. PRDM1 encodes BLIMP1, a transcription factor regulating T-cell proliferation and plasma cell differentiation. The top SNP in GSDMA was a missense variant and correlated with gene expression of neighbouring genes, and this could explain the association in this locus. We found different human leukocyte antigen (HLA) association patterns between the two populations. Enrichment analysis suggested the importance of CD4-naïve primary T cell.ConclusionsGSDMA and PRDM1 are associated with SSc. These findings provide enhanced insight into the genetic and biological basis of SSc.

scholarly journals Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

2018 ◽  
Author(s):  
David M. Howard ◽  
Mark J. Adams ◽  
Toni-Kim Clarke ◽  
Jonathan D. Hafferty ◽  
Jude Gibson ◽  
...  
Keyword(s):  
Multiple Testing ◽  
Drug Repositioning ◽  
Association Studies ◽  
Meta Analysis ◽  
Enrichment Analysis ◽  
Brain Regions ◽  
Genome Wide Association Studies ◽  
Multiple Testing Correction ◽  
Synaptic Structure ◽  
Genome Wide

AbstractMajor depression is a debilitating psychiatric illness that is typically associated with low mood, anhedonia and a range of comorbidities. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximise sample size, we meta-analysed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 gene-sets associated with depression, including both genes and gene-pathways associated with synaptic structure and neurotransmission. Further evidence of the importance of prefrontal brain regions in depression was provided by an enrichment analysis. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant following multiple testing correction. Based on the putative genes associated with depression this work also highlights several potential drug repositioning opportunities. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding aetiology and developing new treatment approaches.

Identification of Critical Core Genes of Sarcoma Based on Centrality Analysis of Networks Nodes

2020 ◽  
Vol 10 (7) ◽  
pp. 1776-1784
Author(s):  
Shudong Wang ◽  
Jixiao Wang ◽  
Xinzeng Wang ◽  
Yuanyuan Zhang ◽  
Tao Yi
Keyword(s):  
Association Studies ◽  
Meta Analysis ◽  
Complex Diseases ◽  
Enrichment Analysis ◽  
Gene Interaction ◽  
Core Gene ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Gene Set ◽  
Genome Wide

Genome-wide association studies (GWAS) are powerful tools for identifying pathogenic genes of complex diseases and revealing genetic structure of diseases. However, due to gene-to-gene interactions, only a part of the hereditary factors can be revealed. The meta-analysis based on GWAS can integrate gene expression data at multiple levels and reveal the complex relationship between genes. Therefore, we used meta-analysis to integrate GWAS data of sarcoma to establish complex networks and discuss their significant genes. Firstly, we established gene interaction networks based on the data of different subtypes of sarcoma to analyze the node centralities of genes. Secondly, we calculated the significant score of each gene according to the Staged Significant Gene Network Algorithm (SSGNA). Then, we obtained the critical gene set HYC of sarcoma by ranking the scores, and then combined Gene Ontology enrichment analysis and protein network analysis to further screen it. Finally, the critical core gene set Hcore containing 47 genes was obtained and validated by GEPIA analysis. Our method has certain generalization performance to the study of complex diseases with prior knowledge and it is a useful supplement to genome-wide association studies.

scholarly journals Transethnic meta-analysis of genome-wide association studies identifies three new loci and characterizes population-specific differences for coronary artery disease

2019 ◽  
Author(s):  
Hiroshi Matsunaga ◽  
Kaoru Ito ◽  
Masato Akiyama ◽  
Atsushi Takahashi ◽  
Satoshi Koyama ◽  
...  
Keyword(s):  
Adrenal Glands ◽  
Association Studies ◽  
Meta Analysis ◽  
Enrichment Analysis ◽  
Tissue Cell ◽  
Genome Wide Association Studies ◽  
Diverse Populations ◽  
Cell Type ◽  
Genome Wide ◽  
Artery Disease

AbstractBackgroundGenome-wide association studies (GWAS) provided many biological insights into coronary artery disease (CAD), but these studies were mainly performed in Europeans. GWAS in diverse populations have the potential to advance our understanding of CAD.Methods and ResultsWe conducted two GWAS for CAD in the Japanese population, which included 12,494 cases and 28,879 controls, and 2,808 cases and 7,261 controls, respectively. Then, we performed transethnic meta-analysis using the results of the CARDIoGRAMplusC4D 1000 Genomes meta-analysis with UK Biobank. We identified 3 new loci on chromosome 1q21 (CTSS), 10q26 (WDR11-FGFR2), and 11q22 (RDX-FDX1). Quantitative trait locus analyses suggested the association of CTSS and RDX-FDX1 with atherosclerotic immune cells. Tissue/cell type enrichment analysis showed the involvement of arteries, adrenal glands and fat tissues in the development of CAD. Finally, we performed tissue/cell type enrichment analysis using East Asian-frequent and European-frequent variants according to the risk allele frequencies, and identified significant enrichment of adrenal glands in the East Asian-frequent group while the enrichment of arteries and fat tissues was found in the European-frequent group. These findings indicate biological differences in CAD susceptibility between Japanese and Europeans.ConclusionsWe identified 3 new loci for CAD and highlighted the genetic differences between the Japanese and European populations. Moreover, our transethnic analyses showed both shared and unique genetic architectures between the Japanese and Europeans. While most of the underlying genetic bases for CAD are shared, further analyses in diverse populations will be needed to elucidate variations fully.

scholarly journals Identifying insomnia-related chemicals through integrative analysis of genome-wide association studies and chemical–genes interaction information

SLEEP ◽  
2020 ◽  
Vol 43 (9) ◽  
Author(s):  
Om Prakash Kafle ◽  
Shiqiang Cheng ◽  
Mei Ma ◽  
Ping Li ◽  
Bolun Cheng ◽  
...  
Keyword(s):  
Association Studies ◽  
Meta Analysis ◽  
Enrichment Analysis ◽  
Modern Society ◽  
Environmental Chemicals ◽  
Gene Set Enrichment Analysis ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Study Results

Abstract Study Objectives Insomnia is a common sleep disorder and constitutes a major issue in modern society. We provide new clues for revealing the association between environmental chemicals and insomnia. Methods Three genome-wide association studies (GWAS) summary datasets of insomnia (n = 113,006, n = 1,331,010, and n = 453,379, respectively) were driven from the UK Biobank, 23andMe, and deCODE. The chemical–gene interaction dataset was downloaded from the Comparative Toxicogenomics Database. First, we conducted a meta-analysis of the three datasets of insomnia using the METAL software. Using the result of meta-analysis, transcriptome-wide association studies were performed to calculate the expression association testing statistics of insomnia. Then chemical-related gene set enrichment analysis (GSEA) was used to explore the association between chemicals and insomnia. Results For GWAS meta-analysis dataset of insomnia, we identified 42 chemicals associated with insomnia in brain tissue (p < 0.05) by GSEA. We detected five important chemicals such as pinosylvin (p = 0.0128), bromobenzene (p = 0.0134), clonidine (p = 0.0372), gabapentin (p = 0.0372), and melatonin (p = 0.0404) which are directly associated with insomnia. Conclusion Our study results provide new clues for revealing the roles of environmental chemicals in the development of insomnia.

Meta-analysis of genome-wide association studies and functional assays decipher susceptibility genes for gastric cancer in Chinese populations

Gut ◽  
2019 ◽  
Vol 69 (4) ◽  
pp. 641-651 ◽  
Author(s):  
Caiwang Yan ◽  
Meng Zhu ◽  
Yanbing Ding ◽  
Ming Yang ◽  
Mengyun Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Association Studies ◽  
Meta Analysis ◽  
Susceptibility Genes ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Enhancer Activity ◽  
Chinese Populations ◽  
Genome Wide

ObjectiveAlthough a subset of genetic loci have been associated with gastric cancer (GC) risk, the underlying mechanisms are largely unknown. We aimed to identify new susceptibility genes and elucidate their mechanisms in GC development.DesignWe conducted a meta-analysis of four genome-wide association studies (GWASs) encompassing 3771 cases and 5426 controls. After targeted sequencing and functional annotation, we performed in vitro and in vivo experiments to confirm the functions of genetic variants and candidate genes. Moreover, we selected 33 promising variants for two-stage replication in 7035 cases and 8323 controls from other five studies.ResultsThe meta-analysis of GWASs identified three loci at 1q22, 5p13.1 and 10q23.33 associated with GC risk at p<5×10−8 and replicated seven known loci at p<0.05. At 5p13.1, the risk rs59133000[C] allele enhanced the binding affinity of NF-κB1 (nuclear factor kappa B subunit 1) to the promoter of PRKAA1, resulting in a reduced promoter activity and lower expression. The knockout of PRKAA1 promoted both GC cell proliferation and xenograft tumour growth in nude mice. At 10q23.33, the rs3781266[C] and rs3740365[T] risk alleles in complete linkage disequilibrium disrupted and created, respectively, the binding motifs of POU2F1 and PAX3, resulting in an increased enhancer activity and expression of NOC3L, while the NOC3L knockdown suppressed GC cell growth. Moreover, two new loci at 3q11.2 (OR=1.21, p=4.56×10−9) and 4q28.1 (OR=1.14, p=3.33×10−11) were associated with GC risk.ConclusionWe identified 12 loci to be associated with GC risk in Chinese populations and deciphered the mechanisms of PRKAA1 at 5p13.1 and NOC3L at 10q23.33 in gastric tumourigenesis.

Genome-Wide Association Studies Identify Two Novel Loci Conferring Susceptibility to Diabetic Retinopathy in Japanese Patients with Type 2 Diabetes

2021 ◽  
Author(s):  
Minako Imamura ◽  
Atsushi Takahashi ◽  
Masatoshi Matsunami ◽  
Momoko Horikoshi ◽  
Minoru Iwata ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Association Studies ◽  
Meta Analysis ◽  
Japanese Patients ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Stage 1

Abstract Several reports have suggested that genetic susceptibility contributes to the development and progression of diabetic retinopathy. We aimed to identify genetic loci that confer susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes. We analysed 5 790 508 single nucleotide polymorphisms (SNPs) in 8880 Japanese patients with type 2 diabetes, 4839 retinopathy cases and 4041 controls, as well as 2217 independent Japanese patients with type 2 diabetes, 693 retinopathy cases, and 1524 controls. The results of these two genome-wide association studies (GWAS) were combined with an inverse variance meta-analysis (Stage-1), followed by de novo genotyping for the candidate SNP loci (p &lt; 1.0 × 10−4) in an independent case–control study (Stage-2, 2260 cases and 723 controls). After combining the association data (Stage-1 and -2) using meta-analysis, the associations of two loci reached a genome-wide significance level: rs12630354 near STT3B on chromosome 3, p = 1.62 × 10−9, odds ratio (OR) = 1.17, 95% confidence interval (CI) 1.11–1.23, and rs140508424 within PALM2 on chromosome 9, p = 4.19 × 10−8, OR = 1.61, 95% CI 1.36–1.91. However, the association of these two loci were not replicated in Korean, European, or African American populations. Gene-based analysis using Stage-1 GWAS data identified a gene-level association of EHD3 with susceptibility to diabetic retinopathy (p = 2.17 × 10−6). In conclusion, we identified two novel SNP loci, STT3B and PALM2, and a novel gene, EHD3, that confers susceptibility to diabetic retinopathy; however, further replication studies are required to validate these associations.

scholarly journals Association analysis of juvenile idiopathic arthritis genetic susceptibility factors in Estonian patients

2021 ◽  
Author(s):  
Tiit Nikopensius ◽  
Priit Niibo ◽  
Toomas Haller ◽  
Triin Jagomägi ◽  
Ülle Voog-Oras ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Juvenile Idiopathic Arthritis ◽  
Autoimmune Diseases ◽  
Genetic Risk ◽  
Association Studies ◽  
Control Sample ◽  
Case Control ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

Abstract Background Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition of childhood. Genetic association studies have revealed several JIA susceptibility loci with the strongest effect size observed in the human leukocyte antigen (HLA) region. Genome-wide association studies have augmented the number of JIA-associated loci, particularly for non-HLA genes. The aim of this study was to identify new associations at non-HLA loci predisposing to the risk of JIA development in Estonian patients. Methods We performed genome-wide association analyses in an entire JIA case–control sample (All-JIA) and in a case–control sample for oligoarticular JIA, the most prevalent JIA subtype. The entire cohort was genotyped using the Illumina HumanOmniExpress BeadChip arrays. After imputation, 16,583,468 variants were analyzed in 263 cases and 6956 controls. Results We demonstrated nominal evidence of association for 12 novel non-HLA loci not previously implicated in JIA predisposition. We replicated known JIA associations in CLEC16A and VCTN1 regions in the oligoarticular JIA sample. The strongest associations in the All-JIA analysis were identified at PRKG1 (P = 2,54 × 10−6), LTBP1 (P = 9,45 × 10−6), and ELMO1 (P = 1,05 × 10−5). In the oligoarticular JIA analysis, the strongest associations were identified at NFIA (P = 5,05 × 10−6), LTBP1 (P = 9,95 × 10−6), MX1 (P = 1,65 × 10−5), and CD200R1 (P = 2,59 × 10−5). Conclusion This study increases the number of known JIA risk loci and provides additional evidence for the existence of overlapping genetic risk loci between JIA and other autoimmune diseases, particularly rheumatoid arthritis. The reported loci are involved in molecular pathways of immunological relevance and likely represent genomic regions that confer susceptibility to JIA in Estonian patients. Key Points• Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease with heterogeneous presentation and genetic predisposition.• Present genome-wide association study for Estonian JIA patients is first of its kind in Northern and Northeastern Europe.• The results of the present study increase the knowledge about JIA risk loci replicating some previously described associations, so adding weight to their relevance and describing novel loci.• The study provides additional evidence for the existence of overlapping genetic risk loci between JIA and other autoimmune diseases, particularly rheumatoid arthritis.

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