scholarly journals Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection

2022 ◽  
Author(s):  
Richard J Packer ◽  
Nick Shrine ◽  
Robert Hall ◽  
Carl Melbourne ◽  
Rebecca Thompson ◽  
...  
Keyword(s):  
Association Study ◽  
Respiratory Disease ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Chromosome 11 ◽  
Genome Wide ◽  
Sputum Production ◽  
A Genome ◽  
Wide Range

Background Chronic sputum production impacts on quality of life and is a feature of many respiratory diseases. Identification of the genetic variants associated with chronic sputum production in a disease agnostic sample could improve understanding of its causes and identify new molecular targets for treatment. Methods We conducted a genome-wide association study (GWAS) of chronic sputum production in UK Biobank. Signals meeting genome-wide significance (P<5x10-8) were fine-mapped and putative causal genes identified by gene expression analysis. GWAS of respiratory traits were interrogated to identify whether the signals were driven by existing respiratory disease amongst the cases and variants were further investigated for wider pleiotropic effects using phenome-wide association studies (PheWAS). Findings From a GWAS of 9,714 cases and 48,471 controls, we identified six novel genome-wide significant signals for chronic sputum production including the Human Leukocyte Antigen (HLA) locus, chromosome 11 mucin locus (containing MUC2, MUC5AC and MUC5B) and the FUT2 locus. The mucin locus signal had previously been reported for association with moderate-to-severe asthma. The HLA signal was fine-mapped to an amino-acid change of threonine to arginine (frequency 36.8%) in HLA-DRB1 (HLA-DRB1*03:147). The signal near FUT2 was associated with expression of several genes including FUT2, for which the direction of effect was tissue dependent. Our PheWAS identified a wide range of associations. Interpretation Novel signals at the FUT2 and mucin loci highlight mucin flucosylation as a driver of chronic sputum production even in the absence of diagnosed respiratory disease and provide genetic support for this pathway as a target for therapeutic intervention.

scholarly journals The maternal environment interacts with genetic variation in regulating seed dormancy in Arabidopsis thaliana

2017 ◽  
Author(s):  
Envel Kerdaffrec ◽  
Magnus Nordborg
Keyword(s):  
Arabidopsis Thaliana ◽  
Association Study ◽  
Seed Dormancy ◽  
Genome Wide Association Study ◽  
Seed Maturation ◽  
Genome Wide Association ◽  
Maternal Environment ◽  
Genome Wide ◽  
A Genome ◽  
Wide Range

AbstractSeed dormancy is a complex adaptive trait that controls the timing of seed germination, one of the major fitness components in many plant species. Despite being highly heritable, seed dormancy is extremely plastic and influenced by a wide range of environmental cues. Here, using a set of 92 Arabidopsis thaliana lines from Sweden, we investigate the effect of seed maturation temperature on dormancy variation at the population level. The response to temperature differs dramatically between lines, demonstrating that genotype and the maternal environment interact in controlling the trait. By performing a genome-wide association study (GWAS), we identified several candidate genes that could account for this plasticity, two of which are involved in the photoinduction of germination. Altogether, our results provide insight into both the molecular mechanisms and the evolution of dormancy plasticity, and can serve to improve our understanding of environmentally dependent life-history transitions.HighlightThe effect of low seed-maturation temperatures on seed dormancy is highly variable in Arabidopsis thaliana accessions from Sweden, denoting strong genotype-environment interactions, and a genome-wide association study identified compelling candidates that could account for this plasticity.

scholarly journals Genome-wide Association Study of Anxiety and Stress-related Disorders in the iPSYCH Cohort

2018 ◽  
Author(s):  
Sandra M. Meier ◽  
Kalevi Trontti ◽  
Thomas Damm Als ◽  
Mikaela Laine ◽  
Marianne Giørtz Pedersen ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Common Mental Disorders ◽  
Twin Studies ◽  
Genome Wide Association ◽  
Sensitivity Analyses ◽  
Association Analyses ◽  
Genome Wide ◽  
A Genome ◽  
Wide Range

AbstractAnxiety and stress-related disorders (ASRD) are among the most common mental disorders with the majority of patients suffering from additional disorders. Family and twin studies indicate that genetic and environmental factors are underlying their etiology. As ASRD are likely to configure various expressions of abnormalities in the basic stress-response system, we conducted a genome-wide association study including 12,655 cases with various anxiety and stress-related diagnoses and 19,225 controls. Standard association analyses were performed supplemented by a framework of sensitivity analyses. Variants in PDE4B showed consistent association with ASRD across a wide range of our analyses. In mice models, alternations in PDE4B expression were observed in those mice displaying anxious behavior after exposure to chronic stress. We also showed that 28% of the variance in ASRD was accounted for by common variants and that the genetic signature of ASRD overlapped with psychiatric traits, educational outcomes, obesity-related phenotypes, smoking, and reproductive success.

scholarly journals Panton-Valentine leucocidin is the key determinant of Staphylococcus aureus pyomyositis in a bacterial genome-wide association study

2018 ◽  
Author(s):  
Bernadette C Young ◽  
Sarah G Earle ◽  
Sona Soeng ◽  
Poda Sar ◽  
Varun Kumar ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Bacterial Genome ◽  
Strong Relationship ◽  
Genome Wide Association ◽  
Tropical Regions ◽  
Genome Wide ◽  
A Genome

AbstractPyomyositis is a severe bacterial infection of skeletal muscle, commonly affecting children in tropical regions and predominantly caused by Staphylococcus aureus. To understand the contribution of bacterial genomic factors to pyomyositis, we conducted a genome-wide association study of S. aureus cultured from 101 children with pyomyositis and 417 children with asymptomatic nasal carriage attending the Angkor Hospital for Children in Cambodia. We found a strong relationship between bacterial genetic variation and pyomyositis, with estimated heritability 63.8% (95% CI 49.2-78.4%). The presence of the Panton-Valentine leucocidin (PVL) locus increased the odds of pyomyositis 130-fold (p =10-17.9). The signal of association mapped both to the PVL-coding sequence and the sequence immediately upstream. Together these regions explained > 99.9% of heritability. Our results establish staphylococcal pyomyositis, like tetanus and diphtheria, as critically dependent on expression of a single toxin and demonstrate the potential for association studies to identify specific bacterial genes promoting severe human disease.

scholarly journals A Genome-Wide Association Study for Melatonin Secretion

2021 ◽  
Author(s):  
Pi-Hua Liu ◽  
Gwo-Tsann Chuang ◽  
Chia-Ni Hsiung ◽  
Wei-Shun Yang ◽  
Hsiao-Chia Ku ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
P Value ◽  
Melatonin Level ◽  
Nucleotide Polymorphisms ◽  
Melatonin Secretion ◽  
Genome Wide ◽  
A Genome ◽  
Wide Range

Abstract SummaryPurpose: Melatonin exerts a wide range of effects among various tissues and organs. However, there is currently no study to investigate the genetic determinants of melatonin secretion. Here, we conducted a genome-wide association study (GWAS) for melatonin secretion using morning urine 6-hydroxymelatonin sulfate-to-creatinine ratio (UMCR). Methods: We initially enrolled 5,000 participants from Taiwan Biobank in this study. After excluding individuals that did not have their urine collected in the morning and those who failed to pass quality control, association of single nucleotide polymorphisms with log-transformed UMCR adjusted for age, sex and principal components of ancestry were analyzed. A second model additionally adjusted for estimated glomerular filtration rate (eGFR). Results: A total of 2,504 participants underwent the genome-wide analysis. Six candidate loci associated with log UMCR (P value ranging from 7.54 x 10-7 to 4.65 x 10-6) encompassing GALNT15, ZFHX3, NKAIN2, MME and NBPF22P were identified. Similar results were yielded with further adjustment for eGFR. Interestingly, the identified genes are associated with central nervous system function and clinical condition such as Alzheimer's disease or sleep disorders.Conclusions: We conducted the first GWAS for melatonin secretion and identified six candidate genetic loci associated with melatonin level. Replication and functional studies are needed in the future.

scholarly journals Genome-wide association study identifies two new loci associated with anti-NMDAR encephalitis

2021 ◽  
Author(s):  
Anja K Tietz ◽  
Klemens Angstwurm ◽  
Tobias Baumgartner ◽  
Kathrin Doppler ◽  
Katharina Eisenhut ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Immune Cell ◽  
Genome Wide Association ◽  
Chromosome 11 ◽  
Genetic Determinants ◽  
Nmdar Encephalitis ◽  
Genome Wide ◽  
A Genome ◽  
Causal Genes

AbstractObjectiveTo investigate the genetic determinants of the most common type of antibody-mediated autoimmune encephalitis, anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis.MethodsWe performed a genome-wide association study in 178 patients with anti-NMDAR encephalitis and 590 healthy controls followed by a colocalization analysis to identify putatively causal genes.ResultsWe identified two independent risk loci harboring genome-wide significant variants (P < 5 × 10−8, OR ≤ 2.2), one on chromosome 15, harboring only the LRRK1 gene, and one on chromosome 11 centered on the ACP2 and NR1H3 genes in a larger region of high linkage-disequilibrium. Colocalization signals with expression quantitative trait loci (eQTL) for different brain regions and immune cell types suggested ACP2, NR1H3, MADD, DDB2, and C11orf49 as putatively causal genes. The best candidate genes in each region are LRRK1, encoding Leucine-Rich Repeat Kinase 1, a protein involved in B-cell development, and NR1H3 liver x receptor alpha, a transcription factor whose activation inhibits inflammatory processes.ConclusionThis study provides evidence for relevant genetic determinants of antibody-mediated autoimmune encephalitides outside the HLA-region. The results suggest that future studies with larger sample sizes will successfully identify additional genetic determinants and contribute to the elucidation of the pathomechanism.

scholarly journals Genome-wide Association Study Identifies 2 New Loci Associated With Anti-NMDAR Encephalitis

2021 ◽  
Vol 8 (6) ◽  
pp. e1085
Author(s):  
Anja K. Tietz ◽  
Klemens Angstwurm ◽  
Tobias Baumgartner ◽  
Kathrin Doppler ◽  
Katharina Eisenhut ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Immune Cell ◽  
Genome Wide Association ◽  
Chromosome 11 ◽  
Genetic Determinants ◽  
Nmdar Encephalitis ◽  
Genome Wide ◽  
A Genome ◽  
Causal Genes

Background and ObjectivesTo investigate the genetic determinants of the most common type of antibody-mediated autoimmune encephalitis, anti-NMDA receptor (anti-NMDAR) encephalitis.MethodsWe performed a genome-wide association study in 178 patients with anti-NMDAR encephalitis and 590 healthy controls, followed by a colocalization analysis to identify putatively causal genes.ResultsWe identified 2 independent risk loci harboring genome-wide significant variants (p < 5 × 10−8, OR ≥ 2.2), 1 on chromosome 15, harboring only the LRRK1 gene, and 1 on chromosome 11 centered on the ACP2 and NR1H3 genes in a larger region of high linkage disequilibrium. Colocalization signals with expression quantitative trait loci for different brain regions and immune cell types suggested ACP2, NR1H3, MADD, DDB2, and C11orf49 as putatively causal genes. The best candidate genes in each region are LRRK1, encoding leucine-rich repeat kinase 1, a protein involved in B-cell development, and NR1H3 liver X receptor alpha, a transcription factor whose activation inhibits inflammatory processes.DiscussionThis study provides evidence for relevant genetic determinants of antibody-mediated autoimmune encephalitides outside the human leukocyte antigen (HLA) region. The results suggest that future studies with larger sample sizes will successfully identify additional genetic determinants and contribute to the elucidation of the pathomechanism.

scholarly journals GENOME-WIDE ASSOCIATION STUDY OF EXTREME HUMAN LONGEVITY DISCOVERS UNCOMMON LONGEVITY VARIANTS

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S209-S209
Author(s):  
Anastasia Gurinovich ◽  
Anastasia Gurinovich ◽  
Zeyuan Song ◽  
Stacy L Andersen ◽  
Thomas T Perls ◽  
...  
Keyword(s):  
Association Study ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Human Longevity ◽  
Mixed Effect ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome

Abstract The strong heritability of extreme human longevity supports the hypothesis that this is a genetically-regulated trait. However, association studies focused on common genetic variants have discovered a limited number of longevity-associated genes. We conducted a genome-wide association study of 4,216 individuals including 1317 centenarians from the New England Centenarian Study (median age = 104 years) using &gt;9M genetic variants imputed to the HRC panel of ~65,000 haplotypes. The set included approximately 5M uncommon variants. The associations were tested using a mixed effect logistic regression model with genotype-based kinship covariance of the random effects to adjust for cryptic relations using the package GENESIS. The analysis discovered 45 genome-wide significant SNPs (p&lt; 5E-08) including 8 new loci in chromosomes 3, 6, 7, 9, 10, 14 and 15 in addition to the APOE locus. The list includes new pQTLs in serum that suggest a new biological mechanism involved in extreme human longevity.

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