Host Genetic Liability for Severe COVID-19 Associates with Alcohol Drinking Behavior and Diabetic Outcomes in Participants of European Descent.
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ABSTRACT:
SUBMITTER: Wendt FR
PROVIDER: S-EPMC8711039 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The sex steroid hormone estrogen is a key modulator of numerous physiological processes and adaptive behaviors, but it may also be co-opted to drive maladaptive behaviors. While many behavioral roles for estrogen signaling have been shown to occur through canonical genomic signaling mechanisms via nuclear receptors, estrogen can also act in a neurotransmitter-like fashion at membrane-associated estrogen receptors to rapidly regulate neuronal function. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high circulating estrogen but a causal role for estrogen in alcohol drinking has not been established. Here, we demonstrate that gonadally intact female mice consume more alcohol and display an anxiolytic phenotype when they have elevated levels of ovarian-derived estrogen across the estrous cycle. We found that rapid, nongenomic estrogen signaling at membrane-associated estrogen receptor alpha in the bed nucleus of the stria terminalis (BNST) is necessary and sufficient for the pro-alcohol drinking effects of ovarian estrogen signaling, regardless of the transcriptional program of a high ovarian estrogen state. We further show that a population of corticotropin-releasing factor (CRF) BNST neurons (BNSTCRF) is a critical mediator of these effects, as high estrogen rapidly enhances synaptic excitation of BNSTCRF neurons and promotes their role in driving binge alcohol drinking. These findings show a causal role for endogenous, ovarian-derived estrogen in hormonal modulation of risky alcohol consumption and provide the first demonstration of a purely rapid, nongenomic signaling mechanism of ovarian estrogen in the brain controlling behavior in gonadally intact females.
| S-EPMC10635092 | biostudies-literature
Project description:OBJECTIVES:We have previously reported a top-ranked risk gene [i.e., serine incorporator 2 gene (SERINC2)] for alcohol dependence in individuals of European descent by analyzing the common variants in a genome-wide association study. In the present study, we comprehensively examined the rare variants [minor allele frequency (MAF)<0.05] in the NKAIN1-SERINC2 region to confirm our previous finding. MATERIALS AND METHODS:A discovery sample (1409 European-American patients with alcohol dependence and 1518 European-American controls) and a replication sample (6438 European-Australian family participants with 1645 alcohol-dependent probands) were subjected to an association analysis. A total of 39,903 individuals from 19 other cohorts with 11 different neuropsychiatric and neurological disorders served as contrast groups. The entire NKAIN1-SERINC2 region was imputed in all cohorts using the same reference panels of genotypes that included rare variants from the whole-genome sequencing data. We stringently cleaned the phenotype and genotype data, and obtained a total of about 220 single-nucleotide polymorphisms in individuals of European descent and about 450 single-nucleotide polymorphisms in the individuals of African descent with 0<MAF<0.05 for an association analysis. RESULTS:Using a weighted regression analysis implemented in the program SCORE-Seq, we found a rare variant constellation across the entire NKAIN1-SERINC2 region that was associated with alcohol dependence in European-Americans (Fp: overall, P=1.8×10(-4); VT: overall, P=1.4×10(-4); Collapsing, P=6.5×10(-5)) and European-Australians (Fp: overall, P=0.028; Collapsing, P=0.025), but not in African-Americans, and not associated with any other disorder examined. Association signals in this region came mainly from SERINC2, a gene that codes for an activity-regulated protein expressed in the brain that incorporates serine into lipids. In addition, 26 individual rare variants were nominally associated with alcohol dependence in European-Americans (P<0.05). The associations of five of these rare variants that lay within SERINC2 showed region-wide significance (P<?=0.0006) and 25 associations survived correction for a false discovery rate (q<0.05). The associations of two rare variants at SERINC2 were replicated in European-Australians (P<0.05). CONCLUSION:We concluded that SERINC2 was a replicable and significant risk gene specific for alcohol dependence in individuals of European descent.
| S-EPMC4287355 | biostudies-literature
Project description:The ?-Ca(2+)/calmodulin-dependent protein kinase II (?CaMKII) is a crucial enzyme controlling plasticity in the brain. The autophosphorylation of ?CaMKII works as a 'molecular memory' for a transient calcium activation, thereby accelerating learning. We investigated the role of ?CaMKII autophosphorylation in the establishment of alcohol drinking as an addiction-related behavior in mice. We found that alcohol drinking was initially diminished in ?CaMKII autophosphorylation-deficient ?CaMKII(T286A) mice, but could be established at wild-type level after repeated withdrawals. The locomotor activating effects of a low-dose alcohol (2 g/kg) were absent in ?CaMKII(T286A) mice, whereas the sedating effects of high-dose (3.5 g/kg) were preserved after acute and subchronic administration. The in vivo microdialysis revealed that ?CaMKII(T286A) mice showed no dopamine (DA) response in the nucleus accumbens to acute or subchronic alcohol administration, but enhanced serotonin (5-HT) responses in the prefrontal cortex. The attenuated DA response in ?CaMKII(T286A) mice was in line with altered c-Fos activation in the ventral tegmental area after acute and subchronic alcohol administration. In order to compare findings in mice with the human condition, we tested 23 single-nucleotide polymorphisms (SNPs) in the CAMK2A gene for their association with alcohol dependence in a population of 1333 male patients with severe alcohol dependence and 939 controls. We found seven significant associations between CAMK2A SNPs and alcohol dependence, one of which in an autophosphorylation-related area of the gene. Together, our data suggest ?CaMKII autophosphorylation as a facilitating mechanism in the establishment of alcohol drinking behavior with changing the DA-5-HT balance as a putative mechanism.
| S-EPMC3717547 | biostudies-literature
Project description:A common two-exon deletion distinguishes the gene encoding the free hemoglobin capturing protein-haptoglobin (HP)-into two alleles: HP1 and HP2. To evaluate the impact of this copy number variant (CNV) on neurocognitive impairment (NCI) in people living with HIV, we imputed this variant in 432 European-descent (EUR) and 491 African-descent (AFR) participants from the CNS HIV Antiretroviral Therapy Effects Research Study using an optimized imputation pipeline and evaluated its associations with NCI. At baseline, in AFR, the HP2 allele decreased the odds of NCI (defined by a global deficit score, GDS, ⩾0.5 ; Odds Ratio, OR = 0.584, p = 0.022). However, in EUR, HP2 increased the odds (OR = 2.081, p = 0.040) of NCI suggesting a detrimental effect. These effects were extended to longitudinal analyses using repeated measurements where the protective effect of the HP2 allele in AFR became marginally significant (p = 0.054) and in EUR the detrimental effect increased in significance (p = 0.037). In EUR, the HP2 allele slightly reduced the risk of NCI over time (OR = 0.028 per allele per year, p = 0.024). Further analyses of cognitive domain-specific impairment revealed that the HP-NCI effect was based on changes in learning, speed of information processing, and verbal domains over time differing by ancestry groups. Overall, these findings suggest that these functional HP CNV alleles influence the likelihood of NCI and contribute to changes in neurocognitive function over time in people living with HIV.
| S-EPMC8727522 | biostudies-literature
Project description:ObjectiveTo investigate associations of frequency, quantity, binge, and problem drinking with cognitive function in older Eastern European adults.MethodsThe investigation included 14,575 participants, aged 47 to 78 years at cognitive assessment in 2006-2008 from Novosibirsk (Russia), Krakow (Poland), and 6 Czech towns participating in the HAPIEE (Health, Alcohol, and Psychosocial Factors in Eastern Europe) prospective cohort study. Average response rates were 59% at baseline (2002-2005) and 63% in 2006-2008. Alcohol consumption was assessed at baseline and in 2006-2008. Cognitive tests included immediate and delayed word recall, semantic fluency (animal naming), and letter cancellation. Associations between alcohol indices and cognitive scores were analyzed cross-sectionally (all measures from 2006 to 2008) and prospectively (alcohol and covariates from 2002 to 2005 and cognition from 2006 to 2008).ResultsIn cross-sectional analyses, nondrinkers had lower cognitive scores and female moderate drinkers had better cognitive performance than light drinkers. Heavy, binge, and problem drinking were not consistently associated with cognitive function. Few associations were replicated in prospective analyses. Participants who stopped drinking during follow-up had worse cognition than stable drinkers; in men, regression coefficients (95% confidence interval) ranged from -0.26 (-0.36, -0.16) for immediate recall to -0.14 (-0.24, -0.04) for fluency.ConclusionRegular and episodic heavy drinking were not consistently associated with cognitive function. Worse cognition in participants who stopped drinking during follow-up suggests that inclusion of less healthy ex-drinkers may partly explain poorer cognition in nondrinkers.
| S-EPMC4335999 | biostudies-literature
Project description:Alcohol is the most common drug among youth and a major contributor to morbidity and mortality worldwide. Billions of dollars are spent annually marketing alcohol.To examine the reach of television alcohol advertising and its effect on drinking among underage youth.Longitudinal telephone- and web-based surveys conducted in 2011 and 2013 involving 2541 US adolescents 15 to 23 years of age at baseline, with 1596 of these adolescents completing the follow-up survey. Cued recall of television advertising images for top beer and distilled spirits brands that aired nationally in 2010-2011 (n = 351). Images were digitally edited to remove branding, and the respondents were queried about 20 randomly selected images. An alcohol advertising receptivity score was derived (1 point each for having seen the ad and for liking it, and 2 points for correct brand identification). Fast-food ads that aired nationally in 2010-2011 (n = 535) were similarly queried to evaluate message specificity.Among the underage youth at baseline, we determined (1) the onset of drinking among those who never drank, (2) the onset of binge drinking among those who were never binge drinkers, and (3) the onset of hazardous drinking among those with an Alcohol Use Disorders Identification Test consumption subscore of less than 4. Multivariate regressions were used to predict each outcome, controlling for covariates (demographics, drinking among friends and parents, and sensation seeking), weighting to the US population, and using multiple imputation to address loss to follow-up.Underage participants were only slightly less likely than participants of legal drinking age to have seen alcohol ads (the mean percentage of ads seen were 23.4%, 22.7%, and 25.6%, respectively, for youth 15-17, 18-20, and 21-23 years of age; P <?.005). The transition to binge and hazardous drinking occurred for 29% and 18% of youth 15 to 17 years of age and for 29% and 19% of youth 18 to 20 years years of age, respectively. Among underage participants, the alcohol advertising receptivity score independently predicted the onset of drinking (adjusted odds ratio [AOR], 1.69 [95% CI, 1.17-2.44]), the onset of binge drinking (AOR, 1.38 [95% CI, 1.08-1.77]), and the onset of hazardous drinking (AOR, 1.49 [95% CI, 1.19-1.86]). Fast-food advertising receptivity was not associated with any drinking outcome.Receptivity to television alcohol advertising predicted the transition to multiple drinking outcomes. The findings are consistent with the idea that marketing self-regulation has failed to keep television alcohol advertising from reaching large numbers of underage persons and affecting their drinking patterns.
| S-EPMC4450856 | biostudies-literature
Project description:The monetary incentive delay (MID) task is a widely used probe for isolating neural circuitry in the human brain associated with incentive motivation. In the present functional magnetic resonance imaging (fMRI) study, 82 young adults, characterized along dimensions of impulsive sensation seeking, completed a MID task. fMRI and behavioral incentive functions were decomposed into incentive valence and magnitude parameters, which were used as predictors in linear regression to determine whether mesolimbic response is associated with problem drinking and recent alcohol use. Alcohol use was best explained by higher fMRI response to anticipation of losses and feedback on high gains in the thalamus. In contrast, problem drinking was best explained by reduced sensitivity to large incentive values in mesolimbic regions in the anticipation phase and increased sensitivity to small incentive values in the dorsal caudate nucleus in the feedback phase. Altered fMRI responses to monetary incentives in mesolimbic circuitry, particularly those alterations associated with problem drinking, may serve as potential early indicators of substance abuse trajectories.
| S-EPMC4257498 | biostudies-literature
Project description:Alcohol dependence (AD) is a complex disorder characterized by impaired control over drinking. It is determined by both genetic and environmental factors. The recent approach of genome-wide association study (GWAS) is a powerful tool for identifying complex disease-associated susceptibility alleles, however, a few GWASs have been conducted for AD, and their results are largely inconsistent. The present study aimed to screen the loci associated with alcohol-related phenotypes using GWAS technology.A genome-wide association study with the behavior of regular alcohol drinking and alcohol consumption was performed to identify susceptibility genes associated with AD, using the Affymetrix 500K SNP array in an initial sample consisting of 904 unrelated Caucasian subjects. Then, the initial results in GWAS were replicated in three independent samples: 1972 Caucasians in 593 nuclear families, 761 unrelated Caucasian subjects, and 2955 unrelated Chinese Hans.Several genes were associated with the alcohol-related phenotypes at the genome-wide significance level, with the ankyrin repeat domain 7 gene (ANKRD7) showing the strongest statistical evidence for regular alcohol drinking and suggestive statistical evidence for alcohol consumption. In addition, certain haplotypes within the ANKRD7 and cytokine-like1 (CYTL1) genes were significantly associated with regular drinking behavior, such as one ANKRD7 block composed of the SNPs rs6466686-rs4295599-rs12531086 (P = 6.51 × 10(-8)). The association of alcohol consumption was successfully replicated with rs4295599 in ANKRD7 gene in independent Caucasian nuclear families and independent unrelated Chinese Hans, and with rs16836497 in CYTL1 gene in independent unrelated Caucasians. Meta-analyses based on both the GWAS and replication samples further supported the observed significant associations between the ANKRD7 or CYTL1 gene and alcohol consumption.The evidence suggests that ANKRD7 and CYTL1 genes may play an important role in the variance in AD risk.
| S-EPMC4174677 | biostudies-literature
Project description:Neural mechanisms underlying alcohol use disorder remain elusive, and this lack of understanding has slowed the development of efficacious treatment strategies for reducing relapse rates and prolonging abstinence. While synaptic adaptations produced by chronic alcohol exposure have been extensively characterized in a variety of brain regions, changes in intrinsic excitability of critical projection neurons are understudied. Accumulating evidence suggests that prolonged alcohol drinking and alcohol dependence produce plasticity of intrinsic excitability as measured by changes in evoked action potential firing and after-hyperpolarization amplitude. In this chapter, we describe functional changes in cell firing of projection neurons after long-term alcohol exposure that occur across species and in multiple brain regions. Adaptations in calcium-activated (KCa2), voltage-dependent (KV7), and G protein-coupled inwardly rectifying (Kir3 or GIRK) potassium channels that regulate the evoked firing and after-hyperpolarization parallel functional changes in intrinsic excitability induced by chronic alcohol. Moreover, there are strong genetic links between alcohol-related behaviors and genes encoding KCa2, KV7, and GIRK channels, and pharmacologically targeting these channels reduces alcohol consumption and alcohol-related behaviors. Together, these studies demonstrate that chronic alcohol drinking produces adaptations in KCa2, KV7, and GIRK channels leading to impaired regulation of the after-hyperpolarization and aberrant cell firing. Correcting the deficit in the after-hyperpolarization with positive modulators of KCa2 and KV7 channels and altering the GIRK channel binding pocket to block the access of alcohol represent a potentially highly effective pharmacological approach that can restore changes in intrinsic excitability and reduce alcohol consumption in affected individuals.
| S-EPMC8252120 | biostudies-literature
Project description:BACKGROUND:Suggestibility, defined as an individual's inclination to accept and internalize messages, has not been studied in relation to alcohol use. Peer conformity, a component of suggestibility, may be related to alcohol use, as peer groups show similarities in patterns of alcohol use. Few studies have assessed how suggestibility and peer conformity relate to alcohol self-administration or to reinforcing effects of alcohol. AIMS:This study assessed whether suggestibility and peer conformity were associated with drinking behavior, alcohol self-administration, subjective response to alcohol, and drinking motives and expectancies. METHODS:Study 1 participants were alcohol drinkers (n=20), who completed a laboratory study of free-access intravenous alcohol self-administration. Study 2 participants were adolescents and young adults, age 14-25 (n=150), with lifetime alcohol use. Participants completed surveys of suggestibility and drinking patterns (Study 1 and 2), subjective alcohol effects (Study 1 only), and alcohol motives and expectancies (Study 2 only). RESULTS/OUTCOMES:In Study 1, participants with higher levels of suggestiblity self-administered more alcohol, and reported greater subjective alcohol effects. Peer conformity, though correlated with suggestibility, was not related to these measures. In Study 2, participants with higher suggestiblity reported more alcohol consumption, higher drinking motives and alcohol expectancies. Peer conformity was not related to alcohol consumption, but was related to coping and enhancement drinking motives, and all expectancies measures. CONCLUSIONS/INTERPRETATION:Results indicate that suggestibility, beyond peer conformity, may be a critical factor to study when examining alcohol consumption behavior, and may provide insight into the development of alcohol use disorder.
| S-EPMC6936214 | biostudies-literature