Cross-Species Integration of Transcriptomic Effects of Tobacco and Nicotine Exposure Helps to Prioritize Genetic Effects on Human Tobacco Consumption

ABSTRACTComputational advances have fostered the development of new methods and tools to integrate gene expression and functional evidence into human-genetic association analyses. Integrative functional genomics analysis for altered response to alcohol in mice provided the first evidence that multi-species analysis tools, such as GeneWeaver, can identify or confirm novel alcohol-related loci. The present study describes an integrative framework to investigate how highly-connected genes linked by their association to tobacco-related behaviors, contribute to individual differences in tobacco consumption. Data from individuals of European ancestry in the UKBiobank (N=139,043) were used to examine the relative contribution of orthologs of a set of genes that are transcriptionally co-regulated by tobacco or nicotine exposure in model organism experiments to human tobacco consumption. Multi-component mixed linear models using genotyped and imputed single nucleotide variants indicated that: (1) variation within human orthologs of these genes accounted for 2-5% of the observed heritability (meta h2SNP-Total=0.08 [95% CI: 0.07, 0.09]) of tobacco/nicotine consumption across three independent folds of unrelated individuals (enrichment ranging from 0.85 - 2.98), and (2) variation around (5, 10, 15, 25, and 50 Kb regions) the set of co-transcriptionally regulated genes accounted for 5-36% of the observed SNP-heritability (enrichment ranging from 1.60 – 31.45). Notably, the effects of variants in co-transcriptionally regulated genes were enriched in tobacco GWAS. These findings highlight the advantages of using multiple species evidence to isolate genetic factors to better understand the etiological complexity of tobacco and other nicotine consumption.

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Multi-omic and multi-species meta-analyses of nicotine consumption

Translational Psychiatry ◽

10.1038/s41398-021-01231-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rohan H. C. Palmer ◽

Chelsie E. Benca-Bachman ◽

Spencer B. Huggett ◽

Jason A. Bubier ◽

John E. McGeary ◽

...

Keyword(s):

Model Organism ◽

Tobacco Consumption ◽

Negative Control ◽

European Ancestry ◽

Model Organisms ◽

Dna Variation ◽

Integrative Framework ◽

Polygenic Scores ◽

Nicotine Consumption ◽

Meta Analyses

AbstractCross-species translational approaches to human genomic analyses are lacking. The present study uses an integrative framework to investigate how genes associated with nicotine use in model organisms contribute to the genetic architecture of human tobacco consumption. First, we created a model organism geneset by collecting results from five animal models of nicotine exposure (RNA expression changes in brain) and then tested the relevance of these genes and flanking genetic variation using genetic data from human cigarettes per day (UK BioBank N = 123,844; all European Ancestry). We tested three hypotheses: (1) DNA variation in, or around, the ‘model organism geneset’ will contribute to the heritability to human tobacco consumption, (2) that the model organism genes will be enriched for genes associated with human tobacco consumption, and (3) that a polygenic score based off our model organism geneset will predict tobacco consumption in the AddHealth sample (N = 1667; all European Ancestry). Our results suggested that: (1) model organism genes accounted for ~5–36% of the observed SNP-heritability in human tobacco consumption (enrichment: 1.60–31.45), (2) model organism genes, but not negative control genes, were enriched for the gene-based associations (MAGMA, H-MAGMA, SMultiXcan) for human cigarettes per day, and (3) polygenic scores based on our model organism geneset predicted cigarettes per day in an independent sample. Altogether, these findings highlight the advantages of using multiple species evidence to isolate genetic factors to better understand the etiological complexity of tobacco and other nicotine consumption.

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The Gut Microbial Architecture of Efficiency Traits in the Domestic Poultry Model Species Japanese Quail (Coturnix japonica) Assessed by Mixed Linear Models

G3 Genes|Genome|Genetics ◽

10.1534/g3.120.401424 ◽

2020 ◽

Vol 10 (7) ◽

pp. 2553-2562 ◽

Cited By ~ 1

Author(s):

Solveig Vollmar ◽

Robin Wellmann ◽

Daniel Borda-Molina ◽

Markus Rodehutscord ◽

Amélia Camarinha-Silva ◽

...

Keyword(s):

Japanese Quail ◽

Linear Models ◽

Microbiota Composition ◽

Mixed Linear Models ◽

Model Species ◽

Narrow Sense Heritability ◽

Association Analyses ◽

Domestic Poultry ◽

Calcium Utilization ◽

The Impact

It is well known that mammals and avian gut microbiota compositions are shaped by the host genomes and affect quantitative traits. The microbial architecture describes the impact of the microbiota composition on quantitative trait variation and the number and effect distribution of microbiota features. In the present study the gut microbial architecture of feed-related traits phosphorus and calcium utilization, daily gain, feed intake and feed per gain ratio in the domestic poultry model species Japanese quail were assessed by mixed linear models. The ileum microbiota composition was characterized by 16S rRNA amplicon sequencing techniques of growing individuals. The microbiability of the traits was on a similar level as the narrow sense heritability and was highly significant except for calcium utilization. The animal microbial correlation of the traits was substantial. Microbiome-wide association analyses revealed several traits associated and highly significant microbiota features, both on the bacteria genera as well as on the operational taxonomic unit level. Most features were significant for more than one trait, which explained the high microbial correlations. It can be concluded that the traits are polymicrobial determined with some microbiota features with larger effects and many with small effects. The results are important for the development of hologenomic selection schemes for feed-related traits in avian breeding programs that are targeting the host genome and the metagenome simultaneously.

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Tobacco-related risk behaviors among amateur rugby players, coaches and referees: targets for prevention

European Heart Journal ◽

10.1093/eurheartj/ehab724.2597 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

F Chague ◽

J Israel ◽

J P Guinoiseau ◽

G Garet ◽

E Reboursiere ◽

...

Keyword(s):

Tobacco Consumption ◽

Nicotine Exposure ◽

Funding Sources ◽

Educational Role ◽

Related Risk ◽

High Prevalence ◽

Nicotine Consumption ◽

Public Grant ◽

Rugby Players ◽

Chronic Risk

Abstract Background High prevalence of smoking has been documented in France and new patterns of tobacco and nicotine consumption are emerging, especially in some sports. In amateur rugby population, such attitudes could be harmful, but data are scarce as well as their knowledge of the risk. Purpose We analyzed tobacco consumption in French amateur players, coaches and referees. Methods Each amateur players [>12-y/o], coaches and referees licensed in the French Rugby Federation and participating in the Burgundy amateur championship was invited to answer to an electronic anonymous questionnaire during the 2017–2018 sport season. Results 683 [sex ratio M/F = 0.9] answers were obtained and fit for analysis. Among them, 559 (81.8%) were players, 167 (24,5%) were coaches and 74 (10.8%) were referees. 176 subjects (25.8%) were current smokers, 126 (18.4%) daily smokers, 54 (37% of usual smokers) smoked more than 10 cigarettes a day and 97 (14.2%) were ex-smokers. Moreover, 24 referees (32.4%) and 47 coaches (28.2%) were current smokers. Most smoked 2 hours before or after a rugby session (86.4% of smokers), including coaches (89.4%) and referees (89%). Although 109 smokers (61.9%) considered quitting, only 27 (24.8%) considered vaping to aid them. Only 28 subjects (4.1%) usually vaped, of whom 15 daily (1.9%); 21 of them (75%) vaped in the 2 hours before or after a rugby session. Number of cigarettes in the 19 dual users was not different compared with non-vaping smokers. Among the 28 vapers, motivation to vape included lower risk than smoking (13), consider to quit (12), cheaper than smoking (8), festive and socializing (6), avoid to smoke (3), respect the performance (2). Other tobacco or nicotine products were infrequent: waterpipe (7), dry snuff (1) and none used snus. The knowledge about risk was incomplete: 35 (5.1%) subjects do not know that smoking is dangerous for their health and 12 (1.8%) think it is not. 246 (36%) and 195 (28.6%) do not know if smoking is more dangerous in the 2 hours before or after sport; 45 (6.6%) and 18 (2.6%) think it is not. Moreover, 27.5% of coaches were unaware on the risk of smoking before a sport session and 19.2% on the risk after. 244 subjects (35.7%) do not know if vaping is less dangerous than smoking; 272 (39.8%) are not informed of the potential risk of nicotine when vaping. Conclusion Despite information, prevalence of smoking remains high in the French amateur rugby players, coaches and referees. Smokers usually smoke in the 2 hours before or after the sport session. This is dangerous for them and for their peers. The low knowledge about the CV risk is of great concern, especially when considering the coaches and referees considering both their symbolic position and their educational role. Vaping and other patterns of nicotine exposure are infrequent; none of them use snus. Targeted education programs are urgently needed to reduce acute and chronic risk of tobacco consumption in this population. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): CHU Dijon Bourgogne ARS Bourgogne Franche Comté

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Inheritance and Correlation Analysis of Main Agronomic Traits in Mungbean (Vigna radiata L.) by Mixed Linear Models

ACTA AGRONOMICA SINICA ◽

10.3724/sp.j.1006.2012.00624 ◽

2013 ◽

Vol 38 (4) ◽

pp. 624-631

Author(s):

Chang-You LIU ◽

Bao-Jie FAN ◽

Zhi-Min CAO ◽

Yan WANG ◽

Zhi-Xiao ZHANG ◽

...

Keyword(s):

Correlation Analysis ◽

Vigna Radiata ◽

Linear Models ◽

Agronomic Traits ◽

Mixed Linear Models

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Rare Germline Variants in Chordoma-Related Genes and Chordoma Susceptibility

Cancers ◽

10.3390/cancers13112704 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2704

Author(s):

Sally Yepes ◽

Nirav N. Shah ◽

Jiwei Bai ◽

Hela Koka ◽

Chuzhong Li ◽

...

Keyword(s):

Internal Control ◽

Susceptibility Gene ◽

Copy Number Variants ◽

Bone Cancer ◽

Chinese Patients ◽

European Ancestry ◽

Unknown Etiology ◽

Loss Of Function ◽

Single Nucleotide Variants ◽

Pathogenic Variants

Background: Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains largely unknown. In this study, we investigated rare germline genetic variants in genes involved in TBXT/chordoma-related signaling pathways and other biological processes in chordoma patients from North America and China. Methods: We identified variants that were very rare in general population and internal control datasets and showed evidence for pathogenicity in 265 genes in a whole exome sequencing (WES) dataset of 138 chordoma patients of European ancestry and in a whole genome sequencing (WGS) dataset of 80 Chinese patients with skull base chordoma. Results: Rare and likely pathogenic variants were identified in 32 of 138 European ancestry patients (23%), including genes that are part of notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex and mesoderm development pathways. Rare pathogenic variants in COL2A1, EXT1, PDK1, LRP2, TBXT and TSC2, among others, were also observed in Chinese patients. Conclusion: We identified several rare loss-of-function and predicted deleterious missense variants in germline DNA from patients with chordoma, which may influence chordoma predisposition and reflect a complex susceptibility, warranting further investigation in large studies.

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HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry

Translational Psychiatry ◽

10.1038/s41398-021-01322-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Bettina Konte ◽

James T. R. Walters ◽

Dan Rujescu ◽

Sophie E. Legge ◽

Antonio F. Pardiñas ◽

...

Keyword(s):

Genetic Factors ◽

Risk Allele ◽

Effect Sizes ◽

European Ancestry ◽

Treatment Resistant ◽

Allele Distribution ◽

Association Analyses ◽

Local Ancestry ◽

Risk Variants ◽

Effective Medication

AbstractThe atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm3 and 1500/mm3 were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E−06) and agranulocytosis (OR = 10.49, P = 1.83E−06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E−08; agranulocytosis: OR = 16.31, P = 1.39E−06), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects.

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Involvement of RpoN in Regulating Bacterial Arsenite Oxidation

Applied and Environmental Microbiology ◽

10.1128/aem.00238-12 ◽

2012 ◽

Vol 78 (16) ◽

pp. 5638-5645 ◽

Cited By ~ 23

Author(s):

Yoon-Suk Kang ◽

Brian Bothner ◽

Christopher Rensing ◽

Timothy R. McDermott

Keyword(s):

Binding Site ◽

Sigma Factor ◽

Model Organism ◽

Coding Region ◽

Rt Pcr ◽

Obvious Effect ◽

Content Type ◽

Definitive Evidence ◽

Relative Contribution ◽

Insertional Inactivation

ABSTRACTIn this study with the model organismAgrobacterium tumefaciens, we used a combination oflacZgene fusions, reverse transcriptase PCR (RT-PCR), and deletion and insertional inactivation mutations to show unambiguously that the alternative sigma factor RpoN participates in the regulation of AsIIIoxidation. A deletion mutation that removed the RpoN binding site from theaioBApromoter and anaacC3(gentamicin resistance) cassette insertional inactivation of therpoNcoding region eliminatedaioBAexpression and AsIIIoxidation, althoughrpoNexpression was not related to cell exposure to AsIII. Putative RpoN binding sites were identified throughout the genome and, as examples, included promoters foraioB,phoB1,pstS1,dctA,glnA,glnB, andflgBthat were examined by using qualitative RT-PCR andlacZreporter fusions to assess the relative contribution of RpoN to their transcription. The expressions ofaioBanddctAin the wild-type strain were considerably enhanced in cells exposed to AsIII, and both genes were silent in therpoN::aacC3mutant regardless of AsIII. The expression level ofglnAwas not influenced by AsIIIbut was reduced (but not silent) in therpoN::aacC3mutant and further reduced in the mutant under N starvation conditions. TherpoN::aacC3mutation had no obvious effect on the expression ofglnB,pstS1,phoB1, orflgB. These experiments provide definitive evidence to document the requirement of RpoN for AsIIIoxidation but also illustrate that the presence of a consensus RpoN binding site does not necessarily link the associated gene with regulation by AsIIIor by this sigma factor.

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