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

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.

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

Frontiers in Neuroscience ◽

10.3389/fnins.2021.738037 ◽

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.

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Genetic risk factors associated with respiratory distress syndrome

Korean Journal of Pediatrics ◽

10.3345/kjp.2014.57.4.157 ◽

2014 ◽

Vol 57 (4) ◽

pp. 157 ◽

Cited By ~ 6

Author(s):

Heui Seung Jo

Keyword(s):

Risk Factors ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Genetic Risk ◽

Distress Syndrome ◽

Genetic Risk Factors ◽

Factors Associated

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Genetic risk factors associated with NAFLD

Hepatoma Research ◽

10.20517/2394-5079.2020.96 ◽

2020 ◽

Vol 2020 ◽

Author(s):

Dong Yun Kim ◽

Jun Yong Park

Keyword(s):

Risk Factors ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Factors Associated

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Clinical and genetic risk factors associated with suicidality in Korean patients with mood disorders

European Neuropsychopharmacology ◽

10.1016/s0924-977x(17)31564-x ◽

2017 ◽

Vol 27 ◽

pp. S873-S874

Author(s):

S.I. Kim ◽

H.Y. Choi ◽

W.J. Lim ◽

E.J. Kim ◽

Y.C. Kim ◽

...

Keyword(s):

Risk Factors ◽

Mood Disorders ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Factors Associated ◽

Korean Patients

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Common Genetic Risk of Major Depression and Nicotine Dependence: The Contribution of Antisocial Traits in a United States Veteran Male Twin Cohort

Twin Research and Human Genetics ◽

10.1375/twin.10.3.470 ◽

2007 ◽

Vol 10 (3) ◽

pp. 470-478 ◽

Cited By ~ 15

Author(s):

Qiang Fu ◽

Andrew C. Heath ◽

Kathleen K. Bucholz ◽

Michael J. Lyons ◽

Ming T. Tsuang ◽

...

Keyword(s):

Risk Factors ◽

Major Depression ◽

Predominantly White ◽

Nicotine Dependence ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Diagnostic Interview ◽

Genetic Influences ◽

Vietnam Era ◽

Shared Genetic

AbstractMany studies that found associations between depression and nicotine dependence have ignored possible shared genetic influences associated with antisocial traits. The present study examined the contribution of genetic and environmental effects associated with conduct disorder (CD) and antisocial personality disorder (ASPD) to the comorbidity of major depression (MD) and nicotine dependence (ND). A telephone diagnostic interview, the Diagnostic Interview Schedule-III-R, was administered to eligible twins from the Vietnam Era Twin (VET) Registry in 1992. Multivariate genetic models were fitted to 3360 middle-aged and predominantly white twin pairs (1868 monozygotic, 1492 dizygotic pairs) of which both members completed the pertinent diagnostic interview sections. Genetic influences on CD accounted for 100%, 68%, and 50% of the total genetic variance in risk for ASPD, MD and ND, respectively. After controlling for genetic influences on CD, the partial genetic correlation between MD and ND was no longer statistically significant. Nonshared environmental contributions to the comorbidity among these disorders were not significant. This study not only demonstrates that the comorbidity between ND and MD is influenced by common genetic risk factors, but also further suggests that the common genetic risk factors overlapped with those for antisocial traits such as CD and ASPD in men.

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Genetics of Keratoconus: Where Do We Stand?

Journal of Ophthalmology ◽

10.1155/2014/641708 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 27

Author(s):

Khaled K. Abu-Amero ◽

Abdulrahman M. Al-Muammar ◽

Altaf A. Kondkar

Keyword(s):

Risk Factors ◽

Candidate Gene ◽

Genetic Risk ◽

Current Knowledge ◽

Genetic Risk Factors ◽

Factors Associated ◽

Genetic Components ◽

Genome Wide ◽

Molecular Etiology

Keratoconus is a progressive thinning and anterior protrusion of the cornea that results in steepening and distortion of the cornea, altered refractive powers, and reduced vision. Keratoconus has a complex multifactorial etiology, with environmental, behavioral, and multiple genetic components contributing to the disease pathophysiology. Using genome-wide and candidate gene approaches several genomic loci and genes have been identified that highlight the complex molecular etiology of this disease. The review focuses on current knowledge of these genetic risk factors associated with keratoconus.

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