scholarly journals Investigating the causal nature of the relationship of subcortical brain volume with smoking and alcohol use

2021 ◽  
pp. 1-9
Author(s):  
Emma Logtenberg ◽  
Martin F. Overbeek ◽  
Joëlle A. Pasman ◽  
Abdel Abdellaoui ◽  
Maartje Luijten ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Genetic Variants ◽  
Brain Volume ◽  
Hippocampal Volume ◽  
Causal Effects ◽  
Mendelian Randomisation ◽  
Brain Volumes ◽  
Subcortical Brain ◽  
Causal Nature ◽  
Relationship Of

Background Structural variation in subcortical brain regions has been linked to substance use, including the most commonly used substances nicotine and alcohol. Pre-existing differences in subcortical brain volume may affect smoking and alcohol use, but there is also evidence that smoking and alcohol use can lead to structural changes. Aims We assess the causal nature of the complex relationship of subcortical brain volume with smoking and alcohol use, using bi-directional Mendelian randomisation. Method Mendelian randomisation uses genetic variants predictive of a certain ‘exposure’ as instrumental variables to test causal effects on an ‘outcome’. Because of random assortment at meiosis, genetic variants should not be associated with confounders, allowing less biased causal inference. We used summary-level data of genome-wide association studies of subcortical brain volumes (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen and thalamus; n = 50 290) and smoking and alcohol use (smoking initiation, n = 848 460; cigarettes per day, n = 216 590; smoking cessation, n = 378 249; alcoholic drinks per week, n = 630 154; alcohol dependence, n = 46 568). The main analysis, inverse-variance weighted regression, was verified by a wide range of sensitivity methods. Results There was strong evidence that liability to alcohol dependence decreased amygdala and hippocampal volume, and smoking more cigarettes per day decreased hippocampal volume. From subcortical brain volumes to substance use, there was no or weak evidence for causal effects. Conclusions Our findings suggest that heavy alcohol use and smoking can causally reduce subcortical brain volume. This adds to accumulating evidence that alcohol and smoking affect the brain, and likely mental health, warranting more recognition in public health efforts.

scholarly journals Investigating the causal nature of the relationship of subcortical brain volume with smoking and alcohol use

2020 ◽  
Author(s):  
Emma Logtenberg ◽  
Martin F Overbeek ◽  
Joelle A Pasman ◽  
Abdel Abdellaoui ◽  
Maartje Luijten ◽  
...  
Keyword(s):  
Substance Use ◽  
Alcohol Use ◽  
Alcohol Dependence ◽  
Genetic Variants ◽  
Brain Volume ◽  
Hippocampal Volume ◽  
Causal Effects ◽  
Subcortical Brain ◽  
Wide Range ◽  
Causal Nature

Background: Structural variation in subcortical brain regions has been linked to substance use, including the most prevalent substances nicotine and alcohol. It may be that pre-existing differences in subcortical brain volume affect smoking and alcohol use, but there is also evidence that smoking and alcohol use can lead to structural changes. We assess the causal nature of this complex relationship with bi-directional Mendelian randomization (MR). Methods: MR uses genetic variants predictive of a certain trait (exposure) as instrumental variables to test causal effects on a certain outcome. Due to random assortment at meiosis, genetic variants shouldnt be associated with confounders, allowing less biased causal inference. We employed summary-level data of the largest available genome-wide association studies of subcortical brain region volumes (nucleus accumbens, amygdala, caudate nucleus, hippocampus, pallidum, putamen, and thalamus; n=50,290) and smoking and alcohol use (smoking initiation, n=848,460; cigarettes per day, n=216,590; smoking cessation, n=378,249; alcohol drinks per week, n=630,154; alcohol dependence, n=46,568). The main analysis, inverse-variance weighted regression, was verified by a wide range of sensitivity methods. Results: There was strong evidence that alcohol dependence decreased amygdala and hippocampal volume and that smoking more cigarettes per day decreased hippocampal volume. From subcortical brain volumes to substance use, there was no or weak evidence for causal effects. Conclusions: Our findings suggest that heavy alcohol use and smoking can causally reduce subcortical brain volume. This adds to accumulating evidence that alcohol and smoking affect the brain, and most likely mental health, warranting more recognition in public health efforts.

scholarly journals Estimation of causal effects of a time-varying exposure at multiple time points through Multivariable Mendelian randomization

2022 ◽  
Author(s):  
Eleanor Sanderson ◽  
Tom G Richardson ◽  
Tim T Morris ◽  
Kate Tilling ◽  
George Davey Smith
Keyword(s):  
Direct Effect ◽  
Genetic Variants ◽  
Causal Effect ◽  
Smoking Behaviour ◽  
Causal Effects ◽  
Mendelian Randomisation ◽  
Multiple Time ◽  
Time Points ◽  
Time Periods ◽  
Multiple Time Points

Mendelian Randomisation (MR) is a powerful tool in epidemiology to estimate the causal effect of an exposure on an outcome in the presence of unobserved confounding, by utilising genetic variants as instrumental variables (IVs) for the exposure. The effects obtained from MR studies are often interpreted as the lifetime effect of the exposure in question. However, the causal effects of many exposures are thought to vary throughout an individual's lifetime and there may be periods during which an exposure has more of an effect on a particular outcome. Multivariable MR (MVMR) is an extension of MR that allows for multiple, potentially highly related, exposures to be included in an MR estimation. MVMR estimates the direct effect of each exposure on the outcome conditional on all of the other exposures included in the estimation. We explore the use of MVMR to estimate the direct effect of a single exposure at different time points in an individual's lifetime on an outcome. We use simulations to illustrate the interpretation of the results from such analyses and the key assumptions required. We show that causal effects at different time periods can be estimated through MVMR when the association between the genetic variants used as instruments and the exposure measured at those time periods varies, however this estimation will not necessarily identify exact time periods over which an exposure has the most effect on the outcome. We illustrate the method through estimation of the causal effects of childhood and adult BMI on smoking behaviour.

Genetic correlations between subcortical brain volumes and psychiatric disorders

2020 ◽  
Vol 216 (5) ◽  
pp. 280-283
Author(s):  
Kazutaka Ohi ◽  
Takamitsu Shimada ◽  
Yuzuru Kataoka ◽  
Toshiki Yasuyama ◽  
Yasuhiro Kawasaki ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Genetic Variants ◽  
Large Scale ◽  
Association Studies ◽  
Genetic Correlations ◽  
Intracranial Volume ◽  
Genome Wide Association Studies ◽  
Brain Volumes ◽  
Subcortical Brain ◽  
Genome Wide

SummaryPsychiatric disorders as well as subcortical brain volumes are highly heritable. Large-scale genome-wide association studies (GWASs) for these traits have been performed. We investigated the genetic correlations between five psychiatric disorders and the seven subcortical brain volumes and the intracranial volume from large-scale GWASs by linkage disequilibrium score regression. We revealed weak overlaps between the genetic variants associated with psychiatric disorders and subcortical brain and intracranial volumes, such as in schizophrenia and the hippocampus and bipolar disorder and the accumbens. We confirmed shared aetiology and polygenic architecture across the psychiatric disorders and the specific subcortical brain and intracranial volume.

scholarly journals Causal associations between body mass index and mental health: a Mendelian randomisation study

2018 ◽  
Vol 72 (8) ◽  
pp. 708-710 ◽  
Author(s):  
Nina van den Broek ◽  
Jorien L Treur ◽  
Junilla K Larsen ◽  
Maaike Verhagen ◽  
Karin J H Verweij ◽  
...  
Keyword(s):  
Mental Health ◽  
Body Mass Index ◽  
Depressive Symptoms ◽  
Body Mass ◽  
Genetic Variants ◽  
Well Being ◽  
Causal Effects ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Subjective Well Being

BackgroundBody mass index (BMI) is correlated negatively with subjective well-being and positively with depressive symptoms. Whether these associations reflect causal effects is unclear.MethodsWe examined bidirectional, causal effects between BMI and mental health with Mendelian randomisation using summary-level data from published genome-wide association studies (BMI: n=339 224; subjective well-being: n=204 966; depressive symptoms: n=161 460). Genetic variants robustly related to the exposure variable acted as instrumental variable to estimate causal effects. We combined estimates of individual genetic variants with inverse-variance weighted meta-analysis, weighted median regression and MR-Egger regression.ResultsThere was evidence for a causal, increasing effect of BMI on depressive symptoms and suggestive evidence for a decreasing effect of BMI on subjective well-being. We found no evidence for causality in the other direction.ConclusionThis study provides support for a higher BMI causing poorer mental health. Further research should corroborate these findings and explore mechanisms underlying this potential causality.

scholarly journals Genetic variation within GRIN2B in adolescents with alcohol use disorder may be associated with larger left posterior cingulate cortex volume

2016 ◽  
Vol 29 (4) ◽  
pp. 252-258 ◽  
Author(s):  
Shareefa Dalvie ◽  
Samantha J. Brooks ◽  
Valerie Cardenas ◽  
George Fein ◽  
Raj Ramesar ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Genetic Variants ◽  
Alcohol Use Disorder ◽  
Brain Volume ◽  
Cingulate Cortex ◽  
Posterior Cingulate Cortex ◽  
Magnetic Resonance Images ◽  
Mixed Ancestry ◽  
Posterior Cingulate ◽  
Left Posterior

ObjectiveBrain structure differences and adolescent alcohol dependence both show substantial heritability. However, exactly which genes are responsible for brain volume variation in adolescents with substance abuse disorders are currently unknown. The aim of this investigation was to determine whether genetic variants previously implicated in psychiatric disorders are associated with variation in brain volume in adolescents with alcohol use disorder (AUD).MethodsThe cohort consisted of 58 adolescents with DSM-IV AUD and 58 age and gender-matched controls of mixed ancestry ethnicity. An Illumina Infinium iSelect custom 6000 bead chip was used to genotype 5348 single nucleotide polymorphisms (SNPs) in 378 candidate genes. Magnetic resonance images were acquired and volumes of global and regional structures were estimated using voxel-based morphometry. To determine whether any of the genetic variants were associated with brain volume, association analysis was conducted using linear regression in Plink.ResultsFrom the exploratory analysis, the GRIN2B SNP rs219927 was associated with brain volume in the left posterior cingulate cortex (p<0.05), whereby having a G-allele was associated with a bigger volume.ConclusionThe GRIN2B gene is involved in glutamatergic signalling and may be associated with developmental differences in AUD in brain regions such as the posterior cingulate cortex. Such differences may play a role in risk for AUD, and deserve more detailed investigation.

scholarly journals Cortical and Subcortical Brain Volumes Partially Mediate the Association between Dietary Composition and Behavioral Disinhibition: A UK Biobank Study

Nutrients ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 3542
Author(s):  
Daan van Rooij ◽  
Lizanne Schweren ◽  
Huiqing Shi ◽  
Catharina A Hartman ◽  
Jan K Buitelaar
Keyword(s):  
Brain Volume ◽  
Adult Population ◽  
Dietary Quality ◽  
Outcome Variable ◽  
Behavioral Disinhibition ◽  
Dietary Composition ◽  
Uk Biobank ◽  
Brain Volumes ◽  
Subcortical Brain ◽  
Dietary Components

Behavioral disinhibition is observed to be an important characteristic of many neurodevelopmental and psychiatric disorders. Recent studies have linked dietary quality to levels of behavioral inhibition. However, it is currently unclear whether brain factors might mediate this. The current study investigates whether cortical and subcortical brain volumes mediate part of the association between dietary composition and behavioral disinhibition. A total of 15,258 subjects from the UK Biobank project were included in the current study. Dietary composition and behavioral disinhibition were based on Principle Component Analyses of self-reported dietary composition). As a further data reduction step, cortical and subcortical volume segmentations were input into an Independent Component Analysis. The resulting four components were used as mediator variables in the main mediation analyses, where behavioral disinhibition served as the outcome variable and dietary components as predictors. Our results show: (1) significant associations between all dietary components and brain volume components; (2) brain volumes are associated with behavioral disinhibition; (3) the mediation models show that part of the variance in behavioral disinhibition explained by dietary components (for healthy diet, restricted diet, and high-fat dairy diet) is mediated through the frontal-temporal/parietal brain volume component. These results are in part confirming our hypotheses and offer a first insight into the underlying mechanisms linking dietary composition, frontal-parietal brain volume, and behavioral disinhibition in the general adult population.

scholarly journals Investigating causal pathways between liability to ADHD and substance use, and liability to substance use and ADHD risk, using Mendelian randomization

2019 ◽  
Author(s):  
Jorien L Treur ◽  
Ditte Demontis ◽  
George Davey Smith ◽  
Hannah Sallis ◽  
Tom G Richardson ◽  
...  
Keyword(s):  
Substance Use ◽  
Alcohol Use ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Smoking Initiation ◽  
Cannabis Use ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Causal Pathways

ABSTRACTBackgroundAttention-deficit hyperactivity disorder (ADHD) has consistently been associated with substance (ab)use, but the nature of this association is not fully understood. In view of preventive efforts, a vital question is whether there are causal effects, from ADHD to substance use and/or from substance use to ADHD.MethodsWe applied bidirectional Mendelian randomization using summary-level data from the largest available genome-wide association studies (GWASs) on ADHD, smoking (initiation, cigarettes/day, cessation, and a compound measure of lifetime smoking), alcohol use (drinks/week and alcohol use disorder), cannabis use (initiation and cannabis use disorder (CUD)) and coffee consumption (cups/day). Genetic variants robustly associated with the ‘exposure’ were selected as instruments and then identified in the ‘outcome’ GWAS. Effect estimates from individual genetic variants were combined with inverse-variance weighted regression and five sensitivity analyses were applied (weighted median, weighted mode, MR-Egger, generalized summary-data-based MR, and Steiger filtering).ResultsWe found strong evidence that liability to ADHD increases likelihood of smoking initiation and also cigarettes per day among smokers, decreases likelihood of smoking cessation, and increases likelihood of cannabis initiation and CUD. In the other direction, there was evidence that liability to smoking initiation and CUD increase ADHD risk. There was no clear evidence of causal effects between liability to ADHD and alcohol or caffeine consumption.ConclusionsWe find evidence for causal effects of liability to ADHD on smoking and cannabis use, and of liability to smoking and cannabis use on ADHD risk, indicating bidirectional pathways. Further work is needed to explore causal mechanisms.

scholarly journals MAPK14 and CNR1 gene variant interactions: effects on brain volume deficits in schizophrenia patients with marijuana misuse

2012 ◽  
Vol 43 (3) ◽  
pp. 619-631 ◽  
Author(s):  
O. E. Onwuameze ◽  
K. W. Nam ◽  
E. A. Epping ◽  
T. H. Wassink ◽  
S. Ziebell ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Brain Volume ◽  
Marijuana Use ◽  
Mitogen Activated Protein Kinase ◽  
Gene Interactions ◽  
Nucleotide Polymorphisms ◽  
Brain Volumes ◽  
Marijuana Abuse ◽  
Increased Risk ◽  
Induced Apoptosis

BackgroundAdolescent marijuana use is associated with increased risk for schizophrenia. We previously reported that marijuana misuse in conjunction with specific cannabinoid receptor 1 (CNR1) genetic variants (rs12720071-G-allele carriers) contributed to white-matter (WM) brain volume deficits in schizophrenia patients. In this study, we assessed the influence of another cannabinoid-related gene, mitogen-activated protein kinase 14 (MAPK14), and potential MAPK14–CNR1 gene–gene interactions in conferring brain volume abnormalities among schizophrenia patients with marijuana abuse/dependence. MAPK14 encodes a member of the MAPK family involved in diverse cellular processes, including CNR1-induced apoptosis.MethodWe genotyped 235 schizophrenia patients on nine MAPK14 tag single nucleotide polymorphisms (tSNPs). Approximately one quarter of the sample had marijuana abuse or dependence. Differential effects of MAPK14 tSNPs on brain volumes across patients with versus without marijuana abuse/dependence were examined using ANCOVA.ResultsOf the MAPK14 tSNPs, only rs12199654 had significant genotype effects and genotype × marijuana misuse interaction effects on WM volumes. rs12199654-A homozygotes with marijuana abuse/dependence had significantly smaller total cerebral and lobar WM volumes. The effects of MAPK14 rs12199654 on WM volume deficits remained significant even after controlling for the CNR1 rs12720071 genotype. There were significant main effects of the MAPK14 CNR1 diplotype and diplotype × marijuana interaction on WM brain volumes, with both genetic variants having additive contributions to WM volume deficits only in patients with marijuana misuse.ConclusionsGiven that CNR1-induced apoptosis is preceded by increased MAPK phosphorylation, our study suggests that potential MAPK14–CNR1 gene–gene interactions may mediate brain morphometric features in schizophrenia patients with heavy marijuana use.

scholarly journals Stereological Investigation of Regional Brain Volumes after Acute and Chronic Cuprizone-Induced Demyelination

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1024 ◽  
Author(s):  
Tanja Hochstrasser ◽  
Sebastian Rühling ◽  
Kerstin Hecher ◽  
Kai H. Fabisch ◽  
Uta Chrzanowski ◽  
...  
Keyword(s):  
Brain Atrophy ◽  
Brain Volume ◽  
Internal Capsule ◽  
Brain Regions ◽  
Therapeutic Interventions ◽  
Male Mice ◽  
Neuroprotective Effects ◽  
Brain Volumes ◽  
Subcortical Brain ◽  
Underlying Mechanisms

Brain volume measurement is one of the most frequently used biomarkers to establish neuroprotective effects during pre-clinical multiple sclerosis (MS) studies. Furthermore, whole-brain atrophy estimates in MS correlate more robustly with clinical disability than traditional, lesion-based metrics. However, the underlying mechanisms leading to brain atrophy are poorly understood, partly due to the lack of appropriate animal models to study this aspect of the disease. The purpose of this study was to assess brain volumes and neuro-axonal degeneration after acute and chronic cuprizone-induced demyelination. C57BL/6 male mice were intoxicated with cuprizone for up to 12 weeks. Brain volume, as well as total numbers and densities of neurons, were determined using design-based stereology. After five weeks of cuprizone intoxication, despite severe demyelination, brain volumes were not altered at this time point. After 12 weeks of cuprizone intoxication, a significant volume reduction was found in the corpus callosum and diverse subcortical areas, particularly the internal capsule and the thalamus. Thalamic volume loss was accompanied by glucose hypermetabolism, analyzed by [18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron-emission tomography. This study demonstrates region-specific brain atrophy of different subcortical brain regions after chronic cuprizone-induced demyelination. The chronic cuprizone demyelination model in male mice is, thus, a useful tool to study the underlying mechanisms of subcortical brain atrophy and to investigate the effectiveness of therapeutic interventions.

scholarly journals Relationship of Cigarette Smoking, Alcohol Use, Recreational Exercise and Obesity with Serum Lipid Atherogenicity: A Study of Self-Defense Officials in Japan

1998 ◽  
Vol 8 (4) ◽  
pp. 227-234 ◽  
Author(s):  
Takashi Umeda ◽  
Suminori Kono ◽  
Yutaka Sakurai ◽  
Koichi Shinchi ◽  
Koji Imanishi ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Cigarette Smoking ◽  
Serum Lipid ◽  
Self Defense ◽  
Recreational Exercise ◽  
Relationship Of
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