Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
- MeSH
- alkoholismus genetika MeSH
- celogenomová asociační studie MeSH
- depresivní porucha unipolární genetika MeSH
- fenotyp MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- poruchy příjmu potravy genetika MeSH
- poruchy spojené s užíváním psychoaktivních látek genetika MeSH
- poruchy vyvolané užíváním tabáku genetika MeSH
- rizikové faktory MeSH
- schizofrenie genetika MeSH
- vazebná nerovnováha MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, N.I.H., Extramural MeSH
We present an overview of genetic, metabolomic, proteomic and neurochemical studies done mainly in our laboratories that could improve prediction, mechanistic understanding and possibly extend to diagnostics and treatment of alcoholism and alcohol addiction. Specific polymorphisms in genes encoding for interleukins 2 and 6, catechol-O-methyl transferase (COMT), monaminooxidase B (MAO B) and several other enzymes were identified as associated with altered risks of alcoholism in humans. A polymorphism in the gene for BDNF has been linked to the risk of developing deficiences in colour vision sometimes observed in alcoholics. Metabolomic studies of acute ethanol effects on guinea pig brain cortex in vitro, lead to the identification of specific subtypes of GABA(A) receptors involved in the actions of alcohol at various doses. Acute alcohol affected energy metabolism, oxidation and the production of actaldehyde and acetate; this could have specific consequences not only for the brain energy production/utilization but could influence the cytotoxicity of alcohol and impact the epigenetics (histone acetylation). It is unlikely that brain metabolism of ethanol occurs to any significant degree; the reduction in glucose metabolism following alcohol consumption is due to ethanol effects on receptors, such as α4β3δ GABA(A) receptors. Metabolomics using post-mortem human brain indicated that the catecholaminergic signalling may be preferentially affected by chronic excessive drinking. Changes in the levels of glutathione were consistent with the presence of severe oxidative stress. Proteomics of the post-mortem alcoholic brains identified a large number of proteins, the expression of which was altered by chronic alcohol, with those associated with brain energy metabolism among the most numerous. Neurochemical studies found the increased expression of glutamate transporter GLAST/EAAT1 in brain as one of the largest changes caused by alcoholism. Given that GLAST/EAAT1 is one of the most abundant proteins in the nervous tissue and is intimately associated with the function of the excitatory (glutamatergic) synapses, this may be among the most important effects of chronic alcohol on brain function. It has so far been observed mainly in the prefrontal cortex. We show several experiments suggesting that acute alcohol can translocate GLAST/EAAT1 in astrocytes towards the plasma membrane (and this effect is inhibited by the GABA(B) agonist baclofen) but neither the mechanism nor the specificity (to alcohol) of this phenomenon have been established. Furthermore, as GLAST/EAAT1 is also expressed in testes and sperm (and could also be affected there by chronic alcohol), the levels of GLAST/EAAT1 in sperm could be used as a diagnostic tool in testing the severity of alcoholism in human males. We conclude that the reviewed studies present a unique set of data which could help to predict the risk of developing alcohol dependence (genetics), to improve the understanding of the intoxicating actions of alcohol (metabolomics), to aid in assessing the extent of damage to brain cells caused by chronic excessive drinking (metabolomics and proteomics) and to point to molecular targets that could be used in the treatment and diagnosis of alcoholism and alcohol addiction.
- MeSH
- acetylace MeSH
- alkoholismus genetika metabolismus MeSH
- epigeneze genetická MeSH
- ethanol metabolismus MeSH
- histony metabolismus MeSH
- lidé MeSH
- metabolomika MeSH
- mozek MeSH
- proteiny přenášející glutamát přes plazmatickou membránu metabolismus MeSH
- proteomika MeSH
- receptory GABA metabolismus MeSH
- signální transdukce MeSH
- transportní systém aminokyselin X-AG metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Alcohol intake and tobacco smoking have significant negative health consequences and both are influenced by genetic predispositions. Some studies suggest that the FTO gene is associated with alcohol consumption. We investigated whether a tagging variant (rs17817449) within the FTO gene is associated with alcohol intake, problem drinking and smoking behaviour. METHODS: We analysed data from 26,792 Caucasian adults (47.2% of males; mean age 58.9 (±7.3) years), examined through the prospective cohort HAPIEE study. The primary outcomes were daily alcohol consumption, binge drinking, problem drinking (CAGE score 2+) and smoking status in relation to tagging variants within the FTO and ADH1B genes. RESULTS: We found no significant association of the FTO polymorphism with smoking status in either sex. The associations of the FTO polymorphism with drinking pattern were inconsistent and differed by gender. In men, GG homozygote carriers had lower odds of problem drinking (OR 0.85, 95% CI 0.75-0.96, p = 0.03). In women, the combination of the FTO/ADH1B GG/+A genotypes doubled the risk of binge drinking (OR 2.10, 95% CI 1.19-3.71, p < 0.05), and the risk was further increased among smoking women (OR 4.10, 95% CI 1.64-10.24, p = 0.008). CONCLUSIONS: In this large population study, the FTO gene appeared associated with binge and problem drinking, and the associations were modified by sex, smoking status and the ADH1B polymorphism.
- MeSH
- alkoholdehydrogenasa genetika MeSH
- alkoholismus genetika MeSH
- běloši genetika MeSH
- gen pro FTO genetika MeSH
- genetické asociační studie MeSH
- genotyp MeSH
- interakce genů a prostředí MeSH
- jednonukleotidový polymorfismus * MeSH
- kouření genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- nárazové pití alkoholu genetika MeSH
- pití alkoholu genetika MeSH
- prospektivní studie MeSH
- senioři MeSH
- sexuální faktory MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- alkoholdehydrogenasa genetika MeSH
- alkoholismus * genetika MeSH
- dopamin genetika MeSH
- genetická predispozice k nemoci * MeSH
- lidé MeSH
- nikotinové receptory genetika MeSH
- polymorfismus genetický MeSH
- poruchy spojené s užíváním psychoaktivních látek * genetika MeSH
- poruchy vyvolané užíváním tabáku * genetika MeSH
- receptory dopaminové genetika MeSH
- závislost (psychologie) MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
The aversive action of the pharmacological properties of ethanol was studied in selectively bred Warsaw Alcohol High-Preferring (WHP) and Warsaw Alcohol Low-Preferring (WLP) rats. For this study, a conditioned-taste aversion test was used. Male WHP and WLP rats were submitted to daily 20-min sessions for 5 days, in which a saccharin solution (1.0 g/L) was available (pre-conditioning phase). Next, this drinking was paired with the injection of ethanol (0, 0.5, 1.0 g/kg), intraperitoneally [i.p.] immediately after removal of the saccharin bottle (conditioning phase). Afterward, the choice between the saccharin solution and water was extended for 18 subsequent days for 20-min daily sessions (post-conditioning phase). Both doses of ethanol did not produce an aversion to saccharin in WLP and WHP rats in the conditioning phase. However, injection of the 1.0 g/kg dose of ethanol produced an aversion in WLP rats that was detected by a decrease in saccharin intake at days 1, 3, 7, and 10 of the post-conditioning phase, with a decrease in saccharin preference for 16 days of the post-conditioning phase. Conditioned taste aversion, measured as a decrease in saccharin intake and saccharin preference, was only visible in WHP rats at day 1 and day 3 of the post-conditioning phase. This difference between WLP and WHP rats was apparent despite similar blood ethanol levels in both rat lines following injection of 0.5 and 1.0 g/kg of ethanol. These results may suggest differing levels of aversion to the post-ingestional effects of ethanol between WLP and WHP rats. These differing levels of aversion may contribute to the selected line difference in ethanol preference in WHP and WLP rats.
- MeSH
- alkoholismus genetika MeSH
- chuť genetika MeSH
- ethanol aplikace a dávkování MeSH
- klasické podmiňování účinky léků fyziologie MeSH
- krysa rodu rattus MeSH
- pití alkoholu genetika MeSH
- sacharin aplikace a dávkování MeSH
- učení vyhýbat se účinky léků fyziologie MeSH
- výběrové chování účinky léků fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: ADHD and alcoholism are psychiatric diseases with pathophysiology related to dopamine system. DAT1 belongs to the SLC6 family of transporters and is involved in the regulation of extracellular dopamine levels. A 40 bp variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region of DAT1/SLC6A3 gene was previously reported to be associated with various phenotypes involving disturbed regulation of dopaminergic neurotransmission. METHODS: A total of 1312 subjects were included and genotyped for 40 bp VNTR polymorphism of DAT1/SLC6A3 gene in this study (441 alcoholics, 400 non-alcoholic controls, 218 ADHD children and 253 non ADHD children). Using miRBase software, we have performed a computer analysis of VNTR part of DAT1 gene for presence of miRNA binding sites. RESULTS: We have found significant relationships between ADHD and the 40 bp VNTR polymorphisms of DAT1/SLC6A3 gene (P < 0.01). The 9/9 genotype appeared to reduce the risk of ADHD about 0.4-fold (p < 0.04). We also noted an occurrence of rare genotypes in ADHD (frequency different from controls at p < 0.01). No association between alcoholism and genotype frequencies of 40 bp VNTR polymorphism of DAT1/SLC6A3 gene has been detected. CONCLUSIONS: We have found an association between 40 bp VNTR polymorphism of DAT1/SLC6A3 gene and ADHD in the Czech population; in a broad agreement with studies in other population samples. Furthermore, we detected rare genotypes 8/10, 7/10 and 10/11 present in ADHD boys only and identified miRNAs that should be looked at as potential novel targets in the research on ADHD.
- MeSH
- 3' nepřekládaná oblast genetika MeSH
- alkoholismus epidemiologie genetika MeSH
- dítě MeSH
- dospělí MeSH
- epigeneze genetická MeSH
- genotyp MeSH
- hyperkinetická porucha epidemiologie genetika MeSH
- impulzivní chování MeSH
- lidé středního věku MeSH
- lidé MeSH
- minisatelitní repetice genetika MeSH
- mladiství MeSH
- neuropsychologické testy MeSH
- počítačová simulace MeSH
- proteiny přenášející dopamin přes plazmatickou membránu genetika MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
Synaptically released L-glutamate, the most important excitatory neurotransmitter in the CNS, is removed from extracellular space by fast and efficient transport mediated by several transporters; the most abundant ones are EAAT1/GLAST and EAAT2/GLT1. The review first summarizes their location, functions and basic characteristics. We then look at genetics and epigenetics of EAAT1/GLAST and EAAT2/GLT1 and perform in silico analyses of their promoter regions. There is one CpG island in SLC1A2 (EAAT2/GLT1) gene and none in SLC1A3 (EAAT1/GLAST) suggesting that DNA methylation is not the most important epigenetic mechanism regulating EAAT1/GLAST levels in brain. There are targets for specific miRNA in SLC1A2 (EAAT2/GLT1) gene. We also note that while defects in EAAT2/GLT1 have been associated with various pathological states including chronic neurodegenerative diseases, very little is known on possible contributions of defective or dysfunctional EAAT1/GLAST to any specific brain disease. Finally, we review evidence of EAAT1/GLAST involvement in mechanisms of brain response to alcoholism and present some preliminary data showing that ethanol, at concentrations which may be reached following heavy drinking, can have an effect on the distribution of EAAT1/GLAST in cultured astrocytes; the effect is blocked by baclofen, a GABA-B receptor agonist and a drug potentially useful in the treatment of alcoholism. We argue that more research effort should be focused on EAAT1/GLAST, particularly in relation to alcoholism and drug addiction.
- MeSH
- aktivní transport MeSH
- alkoholismus genetika metabolismus MeSH
- epigeneze genetická genetika fyziologie MeSH
- kyselina glutamová metabolismus MeSH
- lidé MeSH
- mozek - chemie genetika MeSH
- přenašeč excitačních aminokyselin 1 genetika metabolismus MeSH
- proteiny přenášející glutamát přes plazmatickou membránu metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
predchádzajúcom klinickom sledovaní sme preukázali štatisticky významné rozdiely vo všetkých frekvenčných spektrách pokojového elektroencefalogarfického (EEG) záznamu u pacientov so závislosťou od alkoholu v porovnaní so zdravými dobrovoľníkmi. V pokračovaní tejto štúdie sme hodnotili magnitúdu EEG spektrálneho výkonu v delta, théta, alfa a beta frekvenčnom pásme za účelom popísania vzťahov medzi spektrálnymi zmenami EEG po použití aktivačných metód a diagnózou závislosti od alkoholu. Hodnotili sme EEG po použití aktivačných metód (otvorenie očí – Bergerova reakcia, hyperventilácia). Do sledovania bolo zaradených 54 mužov s diagnózou závislosti od alkoholu na základe začleňujúcich a vylučujúcich kritérií. Skupinu pacientov sme porovnávali s vekovo a pohlavím podobnou skupinou zdravých dobrovoľníkov. Výsledky spektrálnej analýzy EEG aktivovaného otvorením očí a hyperventiláciou ukázali štatisticky signifikantné rozdiely v reaktivite medzi sledovanými skupinami v odpovedi na aktivačné metódy. Najkontrastnejší bol rozdiel v modulácii alfa aktivity pri použití Bergerovej reakcie. Táto práca poukazuje na rozdielnosti v reaktivite na aktivačné metódy. Aby bolo možné tieto nálezy považovať za endofenotypové markery alkoholizmu, bude potrebné testovať aj potomkov tejto skupiny pacientov, ideálne ešte pred ich expozíciou alkoholu. Kľúčové slová: závislosť od alkoholu – EEG – kvantitatívna analýza – endofenotyp – aktivačné metódy – Bergerova reakcia – hyperventilácia
Elektrofyziologické nálezy u pacientov so závislosťou od alkoholu v porovnaní so zdravými dobrovoľníkmi poukazujú na odlišnosť aktivity centrálneho nervového systému a to vo viacerých charakteristických smeroch. Tieto rozdiely reflektujú nerovnováhu medzi excitačnými a inhibičnými procesmi v mozgu alkoholikov. V našej štúdii sledujúcej vzťah medzi zmenami v spektrálnom výkone elektroencefalografického záznamu (EEG) a závislosťou od alkoholu sme skúmali hodnoty spektrálneho EEG výkonu v delta, théta, alfa a beta frekvenčnom pásme. Do sledovania bolo zaradených 54 mužov s diagnózou závislosti od alkoholu na základe potvrdzujúcich a vylučujúcich kritérií. Skupinu pacientov sme porovnávali s vekovo a pohlavím podobnou skupinou zdravých dobrovoľníkov. Výsledky práce preukázali štatisticky signifikantné rozdiely medzi pacientmi a zdravými dobrovoľníkmi a to vo všetkých frekvenčných spektrách pokojového EEG záznamu. Pacienti so závislosťou od alkoholu v porovnaní so zdravými dobrovoľníkmi vykazovali vyšší relatívny spektrálny výkon v beta pásme nad celým skalpom, osobitne však nad centrálnymi regiónmi. Podobne pacienti porovnávaní s kontrolnou skupinou vykazovali v pokojovom zázname nižší spektrálny výkon v théta pásme bez rozdielnosti v distribúcii nad celým skalpom. Výsledky nášho výskumu podporujú údaje prác pojednávajúcich o zvýšenom výkone v beta frekvenčnom pásme ako o endofenotypovom indikátore geneticky podmienenej zložke závislosti od alkoholu.
Electroencephalography has shown that the brain activity of alcoholics and nonalcoholics differs in some characteristic ways. These differences are consistent with an imbalance between excitation and inhibition processes in the brains of alcoholics. In our study, the magnitude of EEG power spectra of delta, theta, alpha and beta power was examined to address the relationship between EEG spectral changes and alcohol dependence. A group of 54 male chronic alcoholics were selected according to inclusion and exclusion criteria. We compared this group with 54 age- and gender-matched control subjects from the group of healthy volunteers. The present study is demonstrated statistically significant differences in all frequency spectra of resting EEG between alcohol dependent subjects and healthy volunteers. Alcohol dependent subjects had higher beta power of resting EEG at all scalp location prominently in central regions compared to control subjects. Alcohol dependent subjects manifested lower theta power of resting EEG compared to control male subjects at most electrode locations. The results of present study support existing studies that have reported an increase of beta power spectrum as an endophenotype of genetically determined alcohol dependence.
- MeSH
- alkoholismus * genetika MeSH
- beta rytmus EEG MeSH
- centrální nervový systém fyziologie MeSH
- dospělí MeSH
- elektroencefalografie * statistika a číselné údaje využití MeSH
- elektrofyziologie MeSH
- endofenotypy MeSH
- lidé MeSH
- mozek fyziologie MeSH
- poruchy způsobené alkoholem MeSH
- prospektivní studie MeSH
- receptory GABA MeSH
- statistika jako téma MeSH
- theta rytmus EEG * MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
