scholarly journals Genome-wide association study in a Korean population identifies six novel susceptibility loci for rheumatoid arthritis

2020 ◽  
Vol 79 (11) ◽  
pp. 1438-1445
Author(s):  
Young-Chang Kwon ◽  
Jiwoo Lim ◽  
So-Young Bang ◽  
Eunji Ha ◽  
Mi Yeong Hwang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Large Fraction ◽  
Genome Wide Association ◽  
Chromatin Interaction ◽  
Genome Wide Association Studies ◽  
Bioinformatics Analyses ◽  
Specific Expression ◽  
Genome Wide

ObjectiveGenome-wide association studies (GWAS) in rheumatoid arthritis (RA) have discovered over 100 RA loci, explaining patient-relevant RA pathogenesis but showing a large fraction of missing heritability. As a continuous effort, we conducted GWAS in a large Korean RA case–control population.MethodsWe newly generated genome-wide variant data in two independent Korean cohorts comprising 4068 RA cases and 36 487 controls, followed by a whole-genome imputation and a meta-analysis of the disease association results in the two cohorts. By integrating publicly available omics data with the GWAS results, a series of bioinformatic analyses were conducted to prioritise the RA-risk genes in RA loci and to dissect biological mechanisms underlying disease associations.ResultsWe identified six new RA-risk loci (SLAMF6, CXCL13, SWAP70, NFKBIA, ZFP36L1 and LINC00158) with pmeta<5×10−8 and consistent disease effect sizes in the two cohorts. A total of 122 genes were prioritised from the 6 novel and 13 replicated RA loci based on physical distance, regulatory variants and chromatin interaction. Bioinformatics analyses highlighted potentially RA-relevant tissues (including immune tissues, lung and small intestine) with tissue-specific expression of RA-associated genes and suggested the immune-related gene sets (such as CD40 pathway, IL-21-mediated pathway and citrullination) and the risk-allele sharing with other diseases.ConclusionThis study identified six new RA-associated loci that contributed to better understanding of the genetic aetiology and biology in RA.

scholarly journals Genome-wide association study of liver enzyme elevation in rheumatoid arthritis patients starting methotrexate

2021 ◽  
Author(s):  
Johanna Karlsson Sundbaum ◽  
Eva Baecklund ◽  
Niclas Eriksson ◽  
Hugo Kohnke ◽  
Matilda Wallenberg ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Maximum Level ◽  
Janus Kinase ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Enzyme Elevation

Aim: To identify novel genetic variants predisposing to elevation of Alanine aminotransferase (ALT) in rheumatoid arthritis (RA) patients after initiation of methotrexate (MTX) treatment. Patients & methods: We performed genome-wide association studies in 198 RA patients starting MTX. Outcomes were maximum level of ALT and ALT >1.5-times the upper level of normal within the first 6 months of treatment. Results: RAVER2 (rs72675408) was significantly associated with maximum level of ALT (p = 4.36 × 10-8). This variant is in linkage disequilibrium with rs72675451, which is associated with differential expression of JAK1 and RAVER2. Conclusion: We found an association between ALT elevation and genetic variants that may regulate the expression of JAK1 and RAVER2. JAK1 encodes a janus kinase involved in the pathogenesis of RA.

scholarly journals Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Daniel L. McCartney ◽  
Josine L. Min ◽  
Rebecca C. Richmond ◽  
Ake T. Lu ◽  
Maria K. Sobczyk ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Biological Aging ◽  
Genome Wide Association Studies ◽  
Genetic Loci ◽  
Biomarkers Of Aging ◽  
Genome Wide ◽  
Shared Genetic

Abstract Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

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.

scholarly journals Measles Contributes to Rheumatoid Arthritis: Evidence from Pathway and Network Analyses of Genome-Wide Association Studies

PLoS ONE ◽  
2013 ◽  
Vol 8 (10) ◽  
pp. e75951 ◽  
Author(s):  
Guiyou Liu ◽  
Yongshuai Jiang ◽  
Xiaoguang Chen ◽  
Ruijie Zhang ◽  
Guoda Ma ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Network Analyses ◽  
Genome Wide

scholarly journals Heritability and genome-wide association study of diffusing capacity of the lung

2018 ◽  
Author(s):  
Natalie Terzikhan ◽  
Fangui Sun ◽  
Fien M. Verhamme ◽  
Hieab H.H. Adams ◽  
Daan Loth ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Considerable Proportion ◽  
Genome Wide Association Studies ◽  
Diffusing Capacity ◽  
Human Lung Tissue ◽  
Alveolar Volume ◽  
Genome Wide

AbstractBackgroundAlthough several genome wide association studies (GWAS) have investigated the genetics of pulmonary ventilatory function, little is known about the genetic factors that influence gas exchange.AimTo investigate the heritability of, and genetic variants associated with the diffusing capacity of the lung.MethodsGWAS was performed on diffusing capacity, measured by carbon monoxide uptake (DLCO) and per alveolar volume (DLCO/VA) using the single-breath technique, in 8,372 individuals from two population-based cohort studies, the Rotterdam Study and the Framingham Heart Study. Heritability was estimated in related (n=6,246) and unrelated (n=3,286) individuals.ResultsHeritability of DLCO and DLCO/VA ranged between 23% and 28% in unrelated individuals and between 45% and 49% in related individuals. Meta-analysis identified a genetic variant in GPR126 that is significantly associated with DLCO/VA. Gene expression analysis of GPR126 in human lung tissue revealed a decreased expression in patients with COPD and subjects with decreased DLCO/VA.ConclusionDLCO and DLCO/VA are heritable traits, with a considerable proportion of variance explained by genetics. A functional variant in GPR126 gene region was significantly associated with DLCO/VA. Pulmonary GPR126 expression was decreased in patients with COPD.

scholarly journals Genotypic and Phenotypic Characterization of Lettuce Bacterial Pathogen Xanthomonas hortorum pv. vitians Populations Collected in Quebec, Canada

Agronomy ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 2386
Author(s):  
Pierre-Olivier Hébert ◽  
Martin Laforest ◽  
Dong Xu ◽  
Marie Ciotola ◽  
Mélanie Cadieux ◽  
...  
Keyword(s):  
Leaf Spot ◽  
Genome Wide Association Study ◽  
De Novo ◽  
Association Studies ◽  
Genome Wide Association ◽  
Phenotypic Characterization ◽  
Genome Wide Association Studies ◽  
Bacterial Leaf Spot ◽  
Eastern Canada ◽  
Genome Wide

Bacterial leaf spot of lettuce, caused by Xanthomonas hortorum pv. vitians, is an economically important disease worldwide. For instance, it caused around 4 million CAD in losses in only a few months during the winter of 1992 in Florida. Because only one pesticide is registered to control this disease in Canada, the development of lettuce cultivars tolerant to bacterial leaf spot remains the most promising approach to reduce the incidence and severity of the disease in lettuce fields. The lack of information about the genetic diversity of the pathogen, however, impairs breeding programs, especially when disease resistance is tested on newly developed lettuce germplasm lines. To evaluate the diversity of X. hortorum pv. vitians, a multilocus sequence analysis was performed on 694 isolates collected in Eastern Canada through the summers of 2014 to 2017 and two isolates in 1996 and 2007. All isolates tested were clustered into five phylogroups. Six pathotypes were identified following pathogenicity tests conducted in greenhouses, but when phylogroups were compared with pathotypes, no correlation could be drawn. However, in vitro production of xanthan and xanthomonadins was investigated, and isolates with higher production of xanthomonadins were generally causing less severe symptoms on the tolerant cultivar Little Gem. Whole-genome sequencing was undertaken for 95 isolates belonging to the pathotypes identified, and de novo assembly made with reads unmapped to the reference strain’s genome sequence resulted in 694 contigs ranging from 128 to 120,795 bp. Variant calling was performed prior to genome-wide association studies computed with single-nucleotide polymorphisms (SNPs), copy-number variants and gaps. Polymorphisms with significant p-values were only found on the cultivar Little Gem. Our results allowed molecular identification of isolates likely to cause bacterial leaf spot of lettuce, using two SNPs identified through genome-wide association study.

scholarly journals Prioritization of genes associated with the pathogenesis of leukosis in cattle

2019 ◽  
Vol 22 (8) ◽  
pp. 1063-1069 ◽  
Author(s):  
N. S. Yudin ◽  
N. L. Podkolodnyy ◽  
T. A. Agarkova ◽  
E. V. Ignatieva
Keyword(s):  
Protein Interactions ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Mammalian Species ◽  
Genome Wide Association ◽  
Farm Animals ◽  
Genome Wide Association Studies ◽  
Protein Protein Interactions ◽  
Genome Wide ◽  
A Genome

Selection by means of genetic markers is a promising approach to the eradication of infectious diseases in farm animals, especially in the absence of effective methods of treatment and prevention. Bovine leukemia virus (BLV) is spread throughout the world and represents one of the biggest problems for the livestock production and food security in Russia. However, recent genome-wide association studies have shown that sensitivity/resistance to BLV is polygenic. The aim of this study was to create a catalog of cattle genes and genes of other mammalian species involved in the pathogenesis of BLV-induced infection and to perform gene prioritization using bioinformatics methods. Based on manually collected information from a range of open sources, a total of 446 genes were included in the catalog of cattle genes and genes of other mammals involved in the pathogenesis of BLV-induced infection. The following criteria were used to prioritize 446 genes from the catalog: (1) the gene is associated with leukemia according to a genome-wide association study; (2) the gene is associated with leukemia according to a case-control study; (3) the role of the gene in leukemia development has been studied using knockout mice; (4) protein-protein interactions exist between the gene-encoded protein and either viral particles or individual viral proteins; (5) the gene is annotated with Gene Ontology terms that are overrepresented for a given list of genes; (6) the gene participates in biological pathways from the KEGG or REACTOME databases, which are over-represented for a given list of genes; (7) the protein encoded by the gene has a high number of protein-protein interactions with proteins encoded by other genes from the catalog. Based on each criterion, a rank was assigned to each gene. Then the ranks were summarized and an overall rank was determined. Prioritization of 446 candidate genes allowed us to identify 5 genes of interest (TNF,LTB,BOLA-DQA1,BOLA-DRB3,ATF2), which can affect the sensitivity/resistance of cattle to leukemia.

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