scholarly journals White Matter Integrity and Nicotine Dependence: Evaluating Vertical and Horizontal Pleiotropy

2021 ◽  
Vol 15 ◽  
Author(s):  
Zhenyao Ye ◽  
Chen Mo ◽  
Song Liu ◽  
Kathryn S. Hatch ◽  
Si Gao ◽  
...  
Keyword(s):  
White Matter ◽  
Nicotine Dependence ◽  
Genetic Factors ◽  
Genome Wide Association Study ◽  
Smoking Status ◽  
Brain Regions ◽  
Future Research ◽  
Cerebral White Matter ◽  
A Genome ◽  
Causal Pathway

Tobacco smoking is an addictive behavior that supports nicotine dependence and is an independent risk factor for cancer and other illnesses. Its neurogenetic mechanisms are not fully understood but may act through alterations in the cerebral white matter (WM). We hypothesized that the vertical pleiotropic pathways, where genetic variants influence a trait that in turn influences another trait, link genetic factors, integrity of cerebral WM, and nicotine addiction. We tested this hypothesis using individual genetic factors, WM integrity measured by fractional anisotropy (FA), and nicotine dependence-related smoking phenotypes, including smoking status (SS) and cigarettes per day (CPDs), in a large epidemiological sample collected by the UK Biobank. We performed a genome-wide association study (GWAS) to identify previously reported loci associated with smoking behavior. Smoking was found to be associated with reduced WM integrity in multiple brain regions. We then evaluated two competing vertical pathways: Genes → WM integrity → Smoking versus Genes → Smoking → WM integrity and a horizontal pleiotropy pathway where genetic factors independently affect both smoking and WM integrity. The causal pathway analysis identified 272 pleiotropic single-nucleotide polymorphisms (SNPs) whose effects on SS were mediated by FA, as well as 22 pleiotropic SNPs whose effects on FA were mediated by CPD. These SNPs were mainly located in important susceptibility genes for smoking-induced diseases NCAM1 and IREB2. Our findings revealed the role of cerebral WM in the maintenance of the complex addiction and provided potential genetic targets for future research in examining how changes in WM integrity contribute to the nicotine effects on the brain.

scholarly journals White matter integrity and nicotine dependence in smokers: evaluating vertical and horizontal pleiotropy

2020 ◽  
Author(s):  
Zhenyao Ye ◽  
Chen Mo ◽  
Kathryn Hatch ◽  
Song Liu ◽  
Si Gao ◽  
...  
Keyword(s):  
Risk Factors ◽  
White Matter ◽  
Nicotine Dependence ◽  
Genetic Risk ◽  
Smoking Status ◽  
Susceptibility Gene ◽  
Genetic Risk Factors ◽  
Cerebral White Matter ◽  
Factors Associated ◽  
Causal Pathway

AbstractSmoking is a heritable behavior and nicotine dependency is complex mechanism supported by both positive and negative reinforcements. We hypothesized that cerebral white matter (WM) may mediate the individual dependency on nicotine integrity because its integrity is altered in smokers and shows dose-related response to nicotine administration. Two vertical and one horizontal pleiotropy pathways that combined individual genetic variations, measure of WM integrity by fractional anisotropy (FA), and nicotine dependence were evaluated in a large epidemiological sample (N=12,264 and 4,654 participants that have genetic, FA measure and nicotine dependence data available for smoking status and cigarettes per day (CPD), respectively) collected UK Biobank. We started by selecting the candidate genetic regions including genetic risk factors associated with smoking from genome-wide association study (GWAS) for causal pathway analysis. Then we identified pleiotropic loci that influence both nicotine dependence and WM integrity from these regions. We tested a horizontal pleiotropy pathway: (A) genetic risk factors associated with smoking were independently affecting both nicotine dependence and WM integrity. We also evaluated two vertical pleiotropy that assumed that individual genetic factors associated with nicotine dependence impacted B) impacted WM integrity which in turn led to higher nicotine dependence vs. C) led to nicotine dependence and resulting white matter alterations. There were 10 and 23 candidate pleiotropic variants identified for smoking status and CPD traits. All these variants exhibited vertical pleiotropy. For smoking status, the genetic effect on smoking status was mediated by FA measures over multiple brain regions. The variants were located in a gene SARDH, which catalyzes the oxidative demethylation of sarcosine that plays a role in reducing tolerance effect on nicotine. Conversely, CPD was a significant mediator in the vertical pleiotropy pathway to FA. The identified variants were located in gene IREB2, that was reported as a susceptibility gene for both neurodegeneration and smoking-induced diseases.

scholarly journals Genome-wide analysis identifies a novel LINC-PINT splice variant associated with vascular amyloid pathology in Alzheimer’s disease

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Joseph S. Reddy ◽  
Mariet Allen ◽  
Charlotte C. G. Ho ◽  
Stephanie R. Oatman ◽  
Özkan İş ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genome Wide Association Study ◽  
Transcriptome Profiling ◽  
Brain Regions ◽  
Common Finding ◽  
Amyloid Angiopathy ◽  
Genome Wide ◽  
A Genome ◽  
Male Sex

AbstractCerebral amyloid angiopathy (CAA) contributes to accelerated cognitive decline in Alzheimer’s disease (AD) dementia and is a common finding at autopsy. The APOEε4 allele and male sex have previously been reported to associate with increased CAA in AD. To inform biomarker and therapeutic target discovery, we aimed to identify additional genetic risk factors and biological pathways involved in this vascular component of AD etiology. We present a genome-wide association study of CAA pathology in AD cases and report sex- and APOE-stratified assessment of this phenotype. Genome-wide genotypes were collected from 853 neuropathology-confirmed AD cases scored for CAA across five brain regions, and imputed to the Haplotype Reference Consortium panel. Key variables and genome-wide genotypes were tested for association with CAA in all individuals and in sex and APOEε4 stratified subsets. Pathway enrichment was run for each of the genetic analyses. Implicated loci were further investigated for functional consequences using brain transcriptome data from 1,186 samples representing seven brain regions profiled as part of the AMP-AD consortium. We confirmed association of male sex, AD neuropathology and APOEε4 with increased CAA, and identified a novel locus, LINC-PINT, associated with lower CAA amongst APOEε4-negative individuals (rs10234094-C, beta = −3.70 [95% CI −0.49—−0.24]; p = 1.63E-08). Transcriptome profiling revealed higher LINC-PINT expression levels in AD cases, and association of rs10234094-C with altered LINC-PINT splicing. Pathway analysis indicates variation in genes involved in neuronal health and function are linked to CAA in AD patients. Further studies in additional and diverse cohorts are needed to assess broader translation of our findings.

scholarly journals Systematic biological prioritization after a genome-wide association study: an application to nicotine dependence

2008 ◽  
Vol 24 (16) ◽  
pp. 1805-1811 ◽  
Author(s):  
Scott F. Saccone ◽  
Nancy L. Saccone ◽  
Gary E. Swan ◽  
Pamela A. F. Madden ◽  
Alison M. Goate ◽  
...  
Keyword(s):  
Association Study ◽  
Nicotine Dependence ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

scholarly journals White Matter Hyperintensities Predict Cognitive Decline: A Community-Based Study

2019 ◽  
Vol 46 (04) ◽  
pp. 383-388 ◽  
Author(s):  
Xuemei Qi ◽  
Huidong Tang ◽  
Qi Luo ◽  
Bei Ding ◽  
Jie Chen ◽  
...  
Keyword(s):  
White Matter ◽  
Cognitive Decline ◽  
White Matter Hyperintensities ◽  
Smoking Status ◽  
Brain Magnetic Resonance Imaging ◽  
The Elderly ◽  
Brain Regions ◽  
Cholinergic Pathways ◽  
Mri Scans ◽  
Magnetic Resonance Imaging Mri

ABSTRACT:Introduction: White matter hyperintensities (WMHs) were commonly seen in brain magnetic resonance imaging (MRI) of the elderly. Many studies found that WMHs were associated with cognitive decline and dementia. However, the association between WMHs in different brain regions and cognitive decline remains debated. Methods: We explored the association of the severity of WMHs and cognitive decline in 115 non-demented elderly (≥50 years old) sampled from the Wuliqiao Community located in urban area of Shanghai. MRI scans were done during 2009–2011 at the beginning of the study. Severity of WMHs in different brain regions was scored by Improved Scheltens Scale and Cholinergic Pathways Hyperintensities Scale (CHIPS). Cognitive function was evaluated by Mini-Mental State Examination (MMSE) every 2 to 4 years during 2009–2018. Results: After adjusting for confounding factors including age, gender, education level, smoking status, alcohol consumption, depression, hypertension, diabetes, hyperlipidemia, brain infarcts, brain atrophy, apoE4 status, and baseline MMSE score, periventricular and subcortical WMH lesions as well as WMHs in cholinergic pathways were significantly associated with annual MMSE decline ( p < 0.05), in which the severity of periventricular WMHs predicted a faster MMSE decline (–0.187 points/year, 95% confidence interval: –0.349, –0.026, p = 0.024). Conclusions: The severity of WMHs at baseline was associated with cognitive decline in the non-demented elderly over time. Interventions on WMH lesions may offer some benefits for cognitive deterioration.

Diffusion Tensor Imaging and Fiber Tractography

2009 ◽  
pp. 229-246
Author(s):  
Evanthia E. Tripoliti ◽  
Dimitrios I. Fotiadis ◽  
Konstantia Veliou
Keyword(s):  
Diffusion Tensor Imaging ◽  
White Matter ◽  
Diffusion Tensor ◽  
Brain Regions ◽  
Cerebral White Matter ◽  
Tissue Microstructure ◽  
Diffusion Weighted Images ◽  
Fiber Tracts ◽  
Diffusion Weighted ◽  
Magnetic Resonance Imaging Mri

Diffusion Tensor Imaging (DTI) is a magnetic resonance imaging (MRI) modality which can significantly improve our understanding of the brain structures and neural connectivity. DTI measures are thought to be representative of brain tissue microstructure and are particularly useful for examining organized brain regions, such as white matter tract areas. DTI measures the water diffusion tensor using diffusion weighted pulse sequences which are sensitive to microscopic random water motion. The resulting diffusion weighted images (DWI) display and allow quantification of how water diffuses along axes or diffusion encoding directions. This can help to measure and quantify the tissue’s orientation and structure, making it an ideal tool for examining cerebral white matter and neural fiber tracts. In this chapter the authors discuss the theoretical aspects of DTI, the information that can be extracted from DTI data, and the use of the extracted information for the reconstruction of fiber tracts and the diagnosis of a disease. In addition, a review of known fiber tracking algorithms is presented.

scholarly journals European landrace diversity for common bean biofortification: a genome-wide association study

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Leonardo Caproni ◽  
Lorenzo Raggi ◽  
Elise F. Talsma ◽  
Peter Wenzl ◽  
Valeria Negri
Keyword(s):  
Common Bean ◽  
Genome Wide Association Study ◽  
Preliminary Evidence ◽  
Snp Markers ◽  
Genome Wide Association ◽  
Future Research ◽  
Balanced Diet ◽  
Genome Wide ◽  
Seed Content ◽  
A Genome

AbstractMineral deficiencies represent a global challenge that needs to be urgently addressed. An adequate intake of iron and zinc results in a balanced diet that reduces chances of impairment of many metabolic processes that can lead to clinical consequences. In plants, bioavailability of such nutrients is reduced by presence of compounds such as phytic acid, that can chelate minerals and reduce their absorption. Biofortification of common bean (Phaseolus vulgaris L.) represents an important strategy to reduce mineral deficiencies, especially in areas of the world where this crop plays a key role in the diet. In this study, a panel of diversity encompassing 192 homozygous genotypes, was screened for iron, zinc and phytate seed content. Results indicate a broad variation of these traits and allowed the identification of accessions reasonably carrying favourable trait combinations. A significant association between zinc seed content and some molecular SNP markers co-located on the common bean Pv01 chromosome was detected by means of genome-wide association analysis. The gene Phvul001G233500, encoding for an E3 ubiquitin-protein ligase, is proposed to explain detected associations. This result represents a preliminary evidence that can foster future research aiming at understanding the genetic mechanisms behind zinc accumulation in beans.

scholarly journals A genome-wide association study unravels cytokinin as a major component in the root defense responses against Ralstonia solanacearum

2021 ◽  
Author(s):  
Alejandro Alonso-Díaz ◽  
Santosh B Satbhai ◽  
Roger de Pedro-Jové ◽  
Hannah M Berry ◽  
Christian Göschl ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Allelic Variation ◽  
Defense Responses ◽  
Genome Wide Association ◽  
Root Growth Inhibition ◽  
Future Research ◽  
Cytokinin Signaling ◽  
Genome Wide ◽  
A Genome

Abstract Bacterial wilt caused by the soil-borne pathogen Ralstonia solancearum is economically devastating, with no effective methods to fight the disease. This pathogen invades plants through their roots and colonizes their xylem, clogging the vasculature and causing rapid wilting. Key to preventing colonization are the early defense responses triggered in the host’s root upon infection, which remain mostly unknown. Here, we have taken advantage of a high-throughput in vitro infection system to screen natural variability associated to the root growth inhibition phenotype caused by R. solanacearum in Arabidopsis during the first hours of infection. To analyze the genetic determinants of this trait, we have performed a Genome-Wide Association Study, identifying allelic variation at several loci related to cytokinin metabolism, including genes responsible for biosynthesis and degradation of cytokinin. Further, our data clearly demonstrate that cytokinin signaling is induced early during the infection process and cytokinin contributes to immunity against R. solanacearum. This study highlights a new role of cytokinin in root immunity, paving the way for future research that will help understanding the mechanisms underpinning root defenses.

scholarly journals Cerebral White Matter Sex Dimorphism in Alcoholism: A Diffusion Tensor Imaging Study

2017 ◽  
Author(s):  
Kayle S. Sawyer ◽  
Nasim Maleki ◽  
George Papadimitriou ◽  
Nikos Makris ◽  
Marlene Oscar-Berman ◽  
...  
Keyword(s):  
Sex Differences ◽  
White Matter ◽  
Corpus Callosum ◽  
Diffusion Tensor ◽  
Imaging Study ◽  
Brain Regions ◽  
Cerebral White Matter ◽  
Excessive Alcohol Consumption ◽  
White Matter Microstructure ◽  
White Matter Connectivity

AbstractBackgroundExcessive alcohol consumption is associated with widespread brain damage, including abnormalities in frontal and limbic brain regions. In a prior study of neuronal circuitry connecting the frontal lobes and limbic system structures in abstinent alcoholic men, we demonstrated decreases in white matter fractional anisotropy (FA) on diffusion tensor magnetic resonance imaging (dMRI). In the present study, we examined sex differences in alcoholism-related abnormalities of white matter connectivity.MethodsdMRI scans were acquired from 49 abstinent alcoholic individuals (26 women) and 41 nonalcoholic controls (22 women). Tract-based spatial statistical tools were used to estimate regional FA of white matter tracts and to determine sex differences and their relation to measures of alcoholism history.ResultsSex-related differences in white matter connectivity were observed in association with alcoholism: Compared to nonalcoholic men, alcoholic men had diminished FA in portions of the corpus callosum, the superior longitudinal fasciculi II and III, and the arcuate fasciculus and extreme capsule. In contrast, alcoholic women had higher FA in these regions. Sex differences also were observed for correlations between corpus callosum FA and length of sobriety.ConclusionsSexual dimorphism in white matter microstructure in abstinent alcoholics may implicate underlying differences in the neurobehavioral liabilities for developing alcohol abuse disorders, or for sequelae following abuse.

scholarly journals Expanding the Genetic Architecture of Nicotine Dependence and its Shared Genetics with Multiple Traits: Findings from the Nicotine Dependence GenOmics (iNDiGO) Consortium

2020 ◽  
Author(s):  
Bryan C. Quach ◽  
Michael J. Bray ◽  
Nathan C. Gaddis ◽  
Mengzhen Liu ◽  
Teemu Palviainen ◽  
...  
Keyword(s):  
Nicotine Dependence ◽  
Genetic Architecture ◽  
Genome Wide Association Study ◽  
African Ancestry ◽  
Multiple Traits ◽  
Expression Of Genes ◽  
Genome Wide ◽  
A Genome ◽  
The Uk ◽  
Smoking Index

AbstractCigarette smoking is the leading cause of preventable morbidity and mortality. Knowledge is evolving on genetics underlying initiation, regular smoking, nicotine dependence (ND), and cessation. We performed a genome-wide association study using the Fagerström Test for ND (FTND) in 58,000 smokers of European or African ancestry. Five genome-wide significant loci, including two novel loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416) were identified, and loci reported for other smoking traits were extended to ND. Using the heaviness of smoking index (HSI) in the UK Biobank (N=33,791), rs2714700 was consistently associated, but rs1862416 was not associated, likely reflecting ND features not captured by the HSI. Both variants were cis-eQTLs (rs2714700 for MAGI2-AS3 in hippocampus, rs1862416 for TENM2 in lung), and expression of genes spanning ND-associated variants was enriched in cerebellum. SNP-based heritability of ND was 8.6%, and ND was genetically correlated with 17 other smoking traits (rg=0.40–0.95) and co-morbidities. Our results emphasize the FTND as a composite phenotype that expands genetic knowledge of smoking, including loci specific to ND.

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