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Genetics of Smoking Addiction Arch Gen Psychiatry 2000Sep;57(9):886-92 Dear friends: I just wanted to share the following abstract from Kendler. Its implications are quite telling in terms of the genetics of addiction to cigarettes and probably to all addictors. It clearly states that initiation and maintenance of smoking are strongly genetic, "The data from family, adoption, and twin studies strongly support a substantial genetic influence on the initiation and maintenance of smoking." This is exactly what Hypoism predicts, and thus proves that the basis for the hijacked brain hypothesis, voluntary initiation, is not only wrong but untenable. Despite this having been published in 1999 I didn't find it until today and I apologize for this. Moreover, the field of addictionology apparently has ignored these findings because it continues to use the hijacked brain hypothesis as its basis. How is this possible? How has the media not discovered this major contradiction in addiction theory? Why hasn't Kendler used this finding to demand a change in the paradigm? We all know the answers to these questions. It's because they don't want to. More evidence for the obvious conspiracy against the true addiction paradigm. How do we get this information published in the media? I hope you will all try to get this accomplished. My original article detailing the conspiracy is included for completeness in the link below for those of you who haven't read it. http://www.nvo.com/hypoism/15replacingalanleshneristheonlywaytoendthedrugwar/ Lastly, Kendler asks: "If such genes are located, by what biological mechanisms do they operate?" The funny thing is that I have spoken to him about "the mechansim" and have answered this question for him, yet he has actively ignored Hypoism, the mechanism he is asking about. Again I ask--where is the integrity, honesty, and objectivity in this field? Nowhere.Hypoism answers all of his questions but he and the field continue to ignore it because it's not what they want it to be. This is the scandal in addictionology today worse then Enron, pedophilic priests, etc. The underlines are mine Nicotine Tob Res 1999;1 Suppl 2:S51-7; The enormous personal and societal costs associated with tobacco are well documented. Unlike the large literature on the prevalence and consequences of tobacco use, there are fewer data on the genetic epidemiology (family, adoption, and twin studies) of tobacco use initiation and nicotine dependence. This review is limited to smoking as this has been the overwhelming focus of the literature. The data from family, adoption, and twin studies strongly support a substantial genetic influence on the initiation and maintenance of smoking. The literature supports the following hypothesis of the development of nicotine dependence. Smoking initiation is the obligatory first step. Liability to initiating smoking results from genetic influences (approximately 60%) and from environmental influences shared by members of a twin pair (approximately 20%) and that are specific to an individual (approximately 20%). The impact of shared environment may be particularly pronounced in mid-adolescence when many begin smoking. A subset of those who initiate smoking progress to nicotine dependence: genetic factors appear to be more prominent in this transition (approximately 70%) and shared environmental influences appear to be negligible. The genetic factors that predispose to smoking initiation appear to overlap substantially but not completely with those for nicotine dependence. The substantial impact of genetic factors on smoking behavior has engendered molecular genetic studies of this complex trait. We need to localize and identify the specific genes involved-which genes predispose to smoking initiation and which to nicotine dependence? If such genes are located, by what biological mechanisms do they operate? Do these genes act directly by altering or enhancing the pharmacokinetics or pharmacodynamics of nicotine? Do they act indirectly via personality or depression? Are these genes specific to nicotine or are they also involved in dependence on other licit and illicit psychoactive substances? Are there different mechanisms in men and women? What are the specific environmental factors and how do genes and environment interact?
Illicit psychoactive substance use, heavy use, abuse, and dependence in a US population-based sample of male twins. Kendler KS, Karkowski LM, Neale MC, Prescott CA. Department of Psychiatry, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0126, USA. BACKGROUND: In order to develop informed approaches to prevention and treatment of illicit psychoactive substance use, abuse, and dependence, we need to understand the sources of individual differences in risk. METHODS: In personal interviews with 1198 male-male twin pairs (708 monozygotic and 490 dizygotic) ascertained from a population-based registry, we assessed lifetime use, heavy use, and abuse of and dependence on cannabis, sedatives, stimulants, cocaine, opiates, and hallucinogens. Twin resemblance was assessed by probandwise concordance, odds ratio, tetrachoric correlations, and biometrical model fitting. RESULTS: Twin resemblance for substance use, heavy use, abuse, and dependence was substantial, and consistently greater in monozygotic than in dizygotic twins. For any drug use and for cannabis and hallucinogen use, model fitting suggested that twin resemblance was due to both genetic and familial-environmental factors. Twin resemblance for sedative, stimulant, cocaine, and opiate use, however, was caused solely by genetic factors. With 2 exceptions (cocaine abuse and stimulant dependence), twin resemblance for heavy use, abuse, and dependence resulted from only genetic factors, with heritability of liability usually ranging from 60% to 80%. No consistent evidence was found for violations of the equal environment assumption. CONCLUSIONS: In accord with prior results in studies of women, the family environment plays a role in twin resemblance for some forms of substance use in men. However, twin resemblance for heavy use, abuse, and dependence in men is largely caused by genetic factors, and heritability estimates are high.
Parenting and adult mood, anxiety and substance use disorders in female twins: an epidemiological, multi-informant, retrospective study. Kendler KS, Myers J, Prescott CA. Department of Psychiatry, Medical College of Virginia of Virginia Commonwealth University, Richmond 23298-0126, USA. BACKGROUND: Although parenting has long been considered an important risk factor for subsequent psychopathology, most investigations of this question have studied a single informant, clinical populations, one or a few disorders and did not consider relevant covariates. METHODS: Three dimensions of parenting (coldness, protectiveness and authoritarianism) were measured by combining the retrospective reports from adult female twins, their co-twins, and their mothers and fathers. We assessed by personal interview, lifetime history in the twins of eight common psychiatric and substance abuse disorders and a range of predictors of parenting. Analyses were performed using logistic regression. RESULTS: Examined individually, high levels of coldness and authoritarianism were modestly but significantly associated with increased risk for nearly all disorders, while the impact of protectiveness was more variable. These associations declined modestly when putative predictors of parenting were added as covariates. Maternal and paternal parenting were equally associated with outcomes in adult daughters. When coldness, protectiveness and authoritarianism were examined together, nearly all significant associations were seen solely with coldness. Few significant interactions were found between maternal and paternal parenting or between coldness, protectiveness and authoritarianism. The shared experience of these three dimensions of parenting predicts a quite small correlation in liability to these disorders in dizygotic twin pairs (e.g. r < 0.04). CONCLUSION: In women, parenting behaviour, especially levels of coldness, is probably causally related to risk for a broad range of adult psychiatric disorders. The impact of parenting on substance use disorders may be largely mediated through their co-morbidity with major depression, phobias and generalized anxiety disorder. In general population samples, the association of poor parenting with psychiatric illness is modest, largely non-specific and explains little of the observed aggregation of these disorders in families. Genetic and environmental contributions to obesity and binge eating. Bulik CM, Sullivan PF, Kendler KS. Int J Eat Disord. 2003 Apr;33(3):293-8. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, PO Box 980126, Richmond, VA 23298-0126, USA. cbulik@hsc.vcu.edu OBJECTIVE: Binge eating is present in a substantial proportion of obese individuals. A tendency toward obesity has been identified as a risk factor for eating disorders such as bulimia nervosa and binge eating disorder. The purpose of this article was to determine the extent of overlap between genetic and environmental factors that contribute to the liability to obesity and binge eating. RESEARCH METHOD: In a population-based sample of 2163 female twins, we conducted bivariate twin modeling to explore the relation between the genetic and environmental risk factors for obesity and binge eating. RESULTS: Bivariate twin modeling revealed substantial heritability for obesity (0.86: 95% CI, 0.77-0.94), moderate heritability for binge eating (0.49: 95% CI, 0.38-0.61), and a modest genetic correlation of +.34 (95% CI, 0.19-0.50) between the two traits. CONCLUSIONS: Both binge eating and obesity are heritable conditions, and there seems to be only modest overlap in the genetic risk factors that increase liability to each condition. Copyright 2003 by Wiley Periodicals, Inc.
The genetics of pathological gambling. Eisen SA, Slutske WS, Lyons MJ, Lassman J, Xian H, Toomey R, Chantarujikapong S, Tsuang MT. Medical and Research Services, St. Louis Department of Veterans Affairs Medical Center, St. Louis, MO 63106, USA. seisen@im.wustl.edu Problem and pathological gambling (PG) occurs in about 5% of Americans. Gambling is associated with substantial psychosocial and psychiatric health problems, and the increasing ease of access to gambling may increase its future prevalence. Therefore, it is important to gain greater insight into the causes of PG. Family studies of PG are consistent with a substantial familial impact on vulnerability to PG. However, family studies cannot distinguish genetic from family environmental influences. By contrast, the study of twin pairs permits the genetic and environmental influences on PG to be estimated. The study of gambling behavior among 3,359 twin pair members of the Vietnam Era Twin Registry suggests that: (1) inherited factors explain a substantial proportion of the variance in the report of symptoms of gambling; (2) there is a single continuum of genetic vulnerability that underlies gambling problems of varying severities; and, (3) the co-occurrence of PG with conduct disorder, antisocial personality disorder, and alcohol abuse/dependence is partially explained by genes that influence both PG and these other psychiatric disorders. Neurophysiological correlates of gambling problems and genetically based differences in neurotransmitter systems may provide biological mechanisms that explain the genetic basis for a predisposition to PG. Finally, someone other than me and in the field, has discovered that genetics is completely behind addictions. The review article is: "Genetic susceptibility to substance dependence," by N Hiroi1,2 and S Agatsuma 1, Molecular Psychiatry (2005) 10, 336–344 1Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA; 2Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA Get the full article and read it!! Here's the abstract: "Despite what is often believed, the majority of those who experiment with substances with a dependence potential do not develop dependence. However, there is a subpopulation of users that easily becomes dependent on substances, and these individuals exhibit pre-existing comorbid traits, including novelty seeking and antisocial behavior. There appears to be a genetic basis for the susceptibility to dependence and these comorbid traits. Animal studies have identified specific genes that can alter susceptibility to dependence and response to novelty. The mechanisms underlying the genetic susceptibility to dependence and response to novelty are complex, but genetic susceptibility plays a significant role in the transition from substance use to dependence and from chronic use to addiction. We discuss two models to explain how genetic variations alter dependence susceptibility. Identification of the specific genes involved in these processes would help to identify individuals that are vulnerable to dependence/addiction and to devise novel treatment strategies." Model 2. from their article is Hypoism, though they don't know it yet. I've written them about it, so, they should eventually admit it. We'll see. Gene Variant Suggests Link To Addiction Vulnerability http://pn.psychiatryonline.org/ Nov. 8, 2005Research on a polymorphism in the gene encoding the µ-opioid receptor may someday contribute to the development of treatments for addiction based on a person's genes. Because the µ-opioid receptor (OPRM1) is a primary docking station for opioid drugs, polymorphisms in the gene encoding OPRM1 are thought to be causative agents for a susceptibility to narcotic drug dependence. One variant in particular, the single nucleotide polymorphism A118G, has been associated with a vulnerability to addiction to heroin, nicotine, and alcohol. Also, A118G has been shown to affect a response to naltrexone therapy. But numerous studies have been unsuccessful in attempting to show how the A118G variant increases someone's chances of developing a drug addiction. Now researchers at Ohio State University have found that A118G causes a change in the expression of OPRM1 protein levels. It is the difference in protein expression that may make receptors on certain brain cells much more vulnerable to the effects of addictive drugs. In laboratory studies, this variation greatly reduced the amount of protein that the DNA produced in a cell. "It's very hard to prove that there is a causative link between one polymorphism and addiction, but the current study provides strong evidence that there is," lead author Wolfgang Sadee, M.D., Ph.D., told Psychiatric News. Sadee is the Felts Mercer Professor of Medicine and Pharmacology, chair of the Department of Pharmacology, and director of the Program in Pharmacogenomics at Ohio State University's College of Medicine and Public Health. The study was published in the September 23 Journal of Biological Chemistry. The researchers extracted and analyzed DNA and RNA from samples of human cadaver brain tissue taken from the cerebral cortex and the pons, areas both rich in cells that have µ-opioid receptors. They found that the µ-opioid receptor gene that carried the A118G variation produced less messenger RNA (mRNA) than did the common gene variant. When they injected the cloned genetic material into the ovary cells of Chinese hamsters and measured changes in the regulation and processing of mRNA, they again found reduced mRNA and very low protein levels with the A118G variant. Sadee said the finding that the A118G transition makes much less mRNA in the cell indicates that differences in protein production (this still needs to be confirmed in vivo) may leave brain cells with these receptors more open to the effects of alcohol and other drugs. "This is a bit puzzling as one would have expected less association with addiction in the A118G carriers since there is loss of function. Previous work was based on the assumption that the A118G enhances affinity to beta-endorphin, or a gain of function, and therefore maybe enhances the hedonic effects of endorphins. Unfortunately the enhanced beta-endorphin affinity study could not be reproduced, and yet clinical studies continue to refer to it," he said. "Those who carry the 118G allele would therefore be expected to have lower OPRM receptor levels. Most are heterozygous, and there are much fewer homozygous 118G carriers where we would expect greater effects," he said. Sadee said their study shows a definitive functional change—an important step in linking to clinical association studies. "How the functional change translates into a clinical phenotype is the next important question—and may shed light on this aspect of susceptibility to addiction. There are no clear-cut answers if one wishes to go from a molecular mechanism to a complex downstream response," he said. The abstract of the original paper: J. Biol. Chem., Vol. 280, Issue 38, 32618-32624, September 23, 2005 From the Program in Pharmacogenomics, Department of Pharmacology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio 43210 As a primary target for opioid drugs and peptides, the mu opioid receptor (OPRM1) plays a key role in pain perception and addiction. Genetic variants of OPRM1 have been implicated in predisposition to drug addiction, in particular the single nucleotide polymorphism A118G, leading to an N40D substitution, with an allele frequency of 10–32%, and uncertain functions. We have measured allele-specific mRNA expression of OPRM1 in human autopsy brain tissues, using A118G as a marker. In 8 heterozygous samples measured, the A118 mRNA allele was 1.5–2.5-fold more abundant than the G118 allele. Transfection into Chinese hamster ovary cells of a cDNA representing only the coding region of OPRM1, carrying adenosine, guanosine, cytidine, and thymidine in position 118, resulted in 1.5-fold lower mRNA levels only for OPRM1-G118, and more than 10-fold lower OPRM1 protein levels, measured by Western blotting and receptor binding assay. After transfection and inhibition of transcription with actinomycin D, analysis of mRNA turnover failed to reveal differences in mRNA stability between A118 and G118 alleles, indicating a defect in transcription or mRNA maturation. These results indicate that OPRM1-G118 is a functional variant with deleterious effects on both mRNA and protein yield. Clarifying the functional relevance of polymorphisms associated with susceptibility to a complex disorder such as drug addiction provides a foundation for clinical association studies. Illicit psychoactive substance use, abuse and dependence in a population-based sample of Norwegian twins, Psychological Medicine, (2006), 36: 955-962 Cambridge University Press, KENNETH S. KENDLER , STEVEN H. AGGEN KRISTIAN TAMBS and TED REICHBORN-KJENNERUD Abstract: Background. Prior population-based twin studies from two Anglophonic countries with relatively high rates of drug use – the USA and Australia – suggest that genetic factors contribute substantially to individual differences in the use, abuse and dependence of illicit psychoactive substances. Would these results replicate in Norway, a Nordic country with a low prevalence of illicit drug use? Method. Lifetime use, abuse and dependence of five illicit drug categories (cannabis, stimulants, opiates, cocaine and psychedelics) were assessed at personal interview in 1386 complete young adult twin pairs ascertained from the Norwegian Institute of Public Health Twin Panel. Twin model fitting was performed using the Mx statistical package on three phenotypes: any lifetime use, endorsement of at least one DSM-IV symptom of abuse or dependence, and meeting DSM-IV criteria for abuse or dependence. Results. Significant lifetime use of illicit substances (defined as use 10 or more times) was reported by only 6·4% of the sample. Meaningful analyses were possible for use of any substance and each of the five substances individually, but for symptoms or a diagnosis of abuse/dependence meaningful analyses were possible only for any substance and cannabis. Full twin models uniformly found twin resemblance to be due largely or entirely to genetic factors. Best-fit models for all analyses included only genetic and individual-specific environmental effects with heritability estimates ranging from 58% to 81%. Conclusion. In accord with prior results from the USA and Australia, genetic factors appear to play an important role in the etiology of use and abuse/dependence of illicit drugs in Norway. Gene Variants of Brain Dopamine Pathways and Smoking-Induced Dopamine Release in the Ventral Caudate/Nucleus Accumbens Arch Gen Psychiatry. 2006;63:808-816. Context: Preclinical studies demonstrate that nicotine administration leads to dopamine release in the ventral striatum. However, human studies reveal considerable interindividual variability in the extent of smoking-induced dopamine release. Objective: To determine whether common gene variants of the brain dopamine pathway explain this observed phenotypic variability in humans. Design: Blood samples were drawn to determine gene variants of dopamine system components, and positron emission tomography scanning with the radiotracer raclopride labeled with radioactive carbon (11C) was performed to measure smoking-induced dopamine release. Setting: Academic brain imaging center. Participants: Forty-five tobacco-dependent smokers. Interventions: Subjects either smoked a cigarette (n = 35) or did not smoke (n = 10) during positron emission tomography scanning. Main Outcome Measures: Gene variants of dopamine system components (the dopamine transporter variable nucleotide tandem repeat, D2 receptor Taq A1/A2, D4 receptor variable nucleotide tandem repeat, and catechol-O-methyltransferase Val158Met polymorphisms) and change in [11C]raclopride binding potential in the ventral caudate/nucleus accumbens on positron emission tomography scans. Results: For subjects who smoked during scanning, those with at least one 9 allele of the dopamine transporter variable nucleotide tandem repeat, fewer than 7 repeats of the D4 variable nucleotide tandem repeat, and the Val/Val catechol-O-methyltransferase genotype had greater decreases in binding potential (an indirect measure of dopamine release) with smoking than those with the alternate genotypes. An overall decrease in ventral caudate/nucleus accumbens binding potential in those who smoked compared with those who did not smoke was also found but was smaller in magnitude than previously reported. Conclusions: Smokers with genes associated with low resting dopamine tone [HYPOISM] have greater smoking-induced (phasic) dopamine release than those with alternate genotypes. These findings suggest that dopamine system genotype variabilities explain a significant proportion of the interindividual variability in smoking-induced dopamine release and indicate that smoking-induced dopamine release has a genetic predisposition.
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You can take the addiction out of the hypoic, but you can't take the Hypoism out of the addict.
