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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Drug and alcohol seeking behaviour has become a great global problem affecting millions of inhabitants with a cost to society in the billions. Dopaminergic reward pathways have frequently been implicated in the etiology of addictive behaviour. While other neurotransmitters have also been implicated, to date the only molecular genetic defect which has been found to associate with alcoholism, drug dependency, obesity, smoking, pathological gambling, attention-deficit-hyperactivity disorder (ADHD), Tourette syndrome, as well as other related compulsive behaviours, are the variants of the dopamine D2 receptor gene (DRD2). In this review of the available data on the subject, we report a number of independent meta-analyses that confirm an association of DRD2 polymorphisms and impulsive-additive-compulsive behaviour (IACB), which we have termed "Reward Deficiency Syndrome". While we agree that Meta-analyses of all exant studies support an association of variants of DRD2 and IACB, correct negative findings with alcoholism may be due to differences in assessing controls and inclusion/exclusion criteria for selection of diseased probands.
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PMID:Dopamine D2 receptor gene variants: association and linkage studies in impulsive-addictive-compulsive behaviour. 755 Mar 64

The prevalence of Taql A D2 dopamine receptor (DRD2) alleles was determined in 73 obese women and men. In this sample with a mean body mass index of 35.1, the A1 (minor) allele of the DRD2 gene was present in 45.2% of these nonalcohol, nondrug abusing subjects. The DRD2 A1 allele was not associated with a number of cardiovascular risk factors examined, including blood lipids (cholesterol, high-density lipoprotein [HDL]- and low-density lipoprotein [LDL]-cholesterol, and triglycerides). However, phenotypic factors characterized by the presence of parental history and postpuberty onset of obesity as well as carbohydrate preference were associated with obese subjects carrying the A1 allele. The cumulative number of these three factors was positively and significantly (p < .0002) related to A1 allelic prevalence. The data showing an association of the minor allele of the DRD2 gene with phenotypic characteristics suggest that this gene, located on q22-q23 region of chromosome 11, confers susceptibility to a subtype of this disorder.
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PMID:D2 dopamine receptor gene and obesity. 819

Dopamine plays a major role in the regulation of appetite and growth hormone. Dopaminergic agonists suppress appetite and dopamine D2 receptor antagonists enhance it. We examined the hypothesis that allelic variants of the DRD2 locus may be associated with weight and height. Sarkar and Sommer described two DRD2 polymorphisms that could be haplotyped by PCR. For weight, the mean Z score (National Center for Health Statistics) for 208 subjects without haplotype 4 was 0.086 versus 0.557 for 280 subjects with haplotype 4, P = 0.0003. Two separate sets of subjects were studied and these results were significant for both, providing an internal replication. For height, the mean Z score for 164 subjects without haplotype 4 was 0.1677 versus 0.6885 for 219 subjects with haplotype 4, P < 0.00001. These and other data suggest that the 4 haplotype is in linkage disequilibrium with allelic variants of the DRD2 gene that play a major role in the regulation of weight (obesity) and height, and may serve as a risk factor in late-onset non-insulin-dependent diabetes mellitus (NIDDM).
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PMID:The dopamine D2 receptor (DRD2) as a major gene in obesity and height. 826 Jan 95

In order to investigate the prevalence of the Taq I A1 allele of the dopamine receptor gene (DRD2) in obesity with and without comorbid substance use disorder, a total of 40 patients, from an outpatient neuropsychiatric clinic in Princeton, New Jersey, were genotyped for presence or absence of the Taq I DRD2 A1 allele. The primary inclusion criterion for 40 obese subjects was a body mass index (BMI) equal to or over 25 (uncharacterized); 11 obese subjects had severe substance use disorder; 20 controls had a BMI below 25; and, 33 substance use disorder (less severe) patients had a BMI below 25. The data were statistically compared with three different sets of controls divided into three separate groups (Group I, n = 20; Group II, n = 286; Group III, n = 714). They differed according to screening criteria (drug, alcohol, nicotine abuse/dependence, BMI below 25 and other related behaviours including parental history of alcoholism or drug abuse and DSM IV, Axis I and Axis II diagnoses). Groups II and III were population controls derived from the literature. The prevalence of the Taq I A1D2 dopamine receptor (DRD2) alleles was determined in 40 Caucasian obese females and males. In this sample with a mean BMI of 32.35 +/- 1.02, the A1 allele of the DRD2 gene was present in 52.5% of these obese subjects. Furthermore, we found that in the 23 obese subjects possessing comorbid substance use disorder, the prevalence of the DRD2 A1 allele significantly increased compared to the 17 obese subjects without comorbid substance use disorder. The DRD2 A1 allele was present in 73.9% of the obese subjects with comorbid substance use disorder compared to 23.5% in obese subjects without comorbid substance use disorder. Moreover, when we assessed severity of substance usage (alcoholism, cocaine dependence, etc.) increasing severity of drug use increased the prevalence of the Taq I DRD2 A1 allele; where 66.67% (8/12) of less severe probands possessed the A1 allele compared to 82% (9/11) of the most severe cases. Linear trend analyses showed that increasing use of drugs was positively and significantly associated with A1 allelic classification (p < 0.00001). These preliminary data suggest that the presence of the DRD2 A1 allele confirms increased risk not only for obesity, but also for other related addictive behaviours (previously referred to as the Reward Deficiency Syndrome) and that a BMI over 25 by itself (without characterization of macroselection or comorbid substance use disorders) is not a sufficient criterion for association with the DRD2 A1 allele.
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PMID:Increased prevalence of the Taq I A1 allele of the dopamine receptor gene (DRD2) in obesity with comorbid substance use disorder: a preliminary report. 887 16

The A1 (minor) allele of the D2 dopamine receptor (DRD2) gene has been shown to be associated with alcoholism, particularly the severe form of this disorder. This allele has also been found to be involved in a variety of other substance use disorders including, cocaine and nicotine dependence, polysubstance abuse and obesity. Moreover, reduced dopaminergic function has been found in subjects carrying the DRD2 A1 allele, suggesting that the DRD2 may be a reinforcement or reward gene. Analysis of the available data suggests that the DRD2 variants represent one of the most prominent single-gene determinants of susceptibility to severe alcoholism and other substance use disorders. However, environmental factors and other genes must, in combination, play the larger role.
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PMID:Polymorphisms of the D2 dopamine receptor gene and alcoholism and other substance use disorders. 897 14

To examine the possible role of genetic variants of the OB gene in obesity we examined alleles of a dinucleotide repeat polymorphism, D7S1875, close to the gene, in a group of adult, non-Hispanic Caucasians. There was a significant correlation with body mass index (BMI) at age 26-30 years for males and females combined (P = 0.04) and females only (P = 0.028). Because of the frequent association between obesity and psychiatric symptoms all subjects were screened with the Symptom List 90 (SCL-90). There was a significant increase in scores for anxiety (P = 0.0005), depression (P = 0.003), and other behaviors for subjects homozygous for the OB1875 < 208-bp alleles. Analysis of covariance indicated that this was directly related to the OB alleles and not secondary to the presence of obesity. There was a significant association between the BMI at ages 16 to 40 and homozygosity for the OB1875 < 208-bp alleles and/or the presence of the DRD2 Taq A1 allele for males and females combined (P = 0.002 to 0.005), and for females alone (P = 0.0017 to 0.0005). For females alone these two genes accounted for up to 22.8% of the variance of the BMI. These results are consistent with the polygenic inheritance of obesity, the greater involvement of genetic factors in women and younger individuals, and suggest that variants of the OB gene are causally involved not only in human obesity but its associated behavioral disorders.
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PMID:Genetic variants of the human obesity (OB) gene: association with body mass index in young women, psychiatric symptoms, and interaction with the dopamine D2 receptor (DRD2) gene. 911 59

Since 1990, association studies have amassed strong evidence implicating the D(2) dopamine receptor (DRD2) gene in alcoholism. Specifically, the TaqI A minor (A1) allele of the DRD2 gene has been associated with alcoholism. The DRD2 gene has also been found to be involved in other substance use disorders including cocaine, nicotine and opioid dependence, and obesity. Beyond association studies, pharmacologic studies have shown reduced brain D(2) dopamine receptor numbers in A1(+) allele carriers (A1A1 and A1A2 genotypes) compared to A1(-) allele carriers (A2A2 genotype). Through a number of other approaches, different phenotypes have also been identified in subjects with the A1(+) and A1(-) alleles. These include metabolic, neurophysiological, neuropsychological, personality, stress and treatment studies. It is hypothesized that in an effort to compensate for deficiencies in the dopaminergic system, substance abusers may seek to stimulate the mesocorticolimbic circuits of the brain, long thought to be important in behavioral reward and reinforcement. In effect, one form of the DRD2 gene, the A1 allele, renders the dopaminergic system inefficient and rewards substance abuse that increases brain dopamine levels.
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PMID:Addiction and its reward process through polymorphisms of the D2 dopamine receptor gene: a review. 1088 Dec 3

The dopaminergic and opioidergic reward pathways of the brain are critical for survival since they provide the pleasure drives for eating, love and reproduction; these are called 'natural rewards' and involve the release of dopamine in the nucleus accumbens and frontal lobes. However, the same release of dopamine and production of sensations of pleasure can be produced by 'unnatural rewards' such as alcohol, cocaine, methamphetamine, heroin, nicotine, marijuana, and other drugs, and by compulsive activities such as gambling, eating, and sex, and by risk taking behaviors. Since only a minority of individuals become addicted to these compounds or behaviors, it is reasonable to ask what factors distinguish those who do become addicted from those who do not. It has usually been assumed that these behaviors are entirely voluntary and that environmental factors play the major role; however, since all of these behaviors have a significant genetic component, the presence of one or more variant genes presumably act as risk factors for these behaviors. Since the primary neurotransmitter of the reward pathway is dopamine, genes for dopamine synthesis, degradation, receptors, and transporters are reasonable candidates. However, serotonin, norepinephrine, GABA, opioid, and cannabinoid neurons all modify dopamine metabolism and dopamine neurons. We have proposed that defects in various combinations of the genes for these neurotransmitters result in a Reward Deficiency Syndrome (RDS) and that such individuals are at risk for abuse of the unnatural rewards. Because of its importance, the gene for the [figure: see text] dopamine D2 receptor was a major candidate gene. Studies in the past decade have shown that in various subject groups the Taq I A1 allele of the DRD2 gene is associated with alcoholism, drug abuse, smoking, obesity, compulsive gambling, and several personality traits. A range of other dopamine, opioid, cannabinoid, norepinephrine, and related genes have since been added to the list. Like other behavioral disorders, these are polygenically inherited and each gene accounts for only a small per cent of the variance. Techniques such as the Multivariate Analysis of Associations, which simultaneously examine the contribution of multiple genes, hold promise for understanding the genetic make up of polygenic disorders.
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PMID:Reward deficiency syndrome: genetic aspects of behavioral disorders. 1110 55

The TaqIA D2 dopamine receptor (DRD2) minor (A1) allele was first associated with severe alcoholism a decade ago. Since then, studies both confirming and not confirmnning this finding were reported. However, a meta-analysis of a large number of Caucasian alcoholics (both more severe and less severe) and controls (both assessed and unassessed for substance use disorders) revealed a significantly higher frequency (p < 10(-6)) and prevalence (p < 10(-8)) of the DRD2 A1 allele in the alcoholics. Further analysis showed that the more severe alcoholics had a 3-fold higher prevalence of the DRD2 A1 allele than the assessed controls (p < 10(-10)), whereas no difference was found between the less severe alcoholics and the unassessed controls. DRD2 exonic or promoter mutations have not yet been associated with alcoholism, although two intronic variants at the TaqIB and intron 6 sites, which are in linkage disequilibrium with the TaqIA site, were associated with this disorder. Variants of the DRD2 gene have also been associated with cocaine, nicotine and opioid dependence, obesity and gambling. It is hypothesised that the DRD2 is a reinforcement or reward gene. Although less intensively studied than substance use disorders, the DRD2 gene has been implicated in Tourette's syndrome (TS), post-traumatic stress disorder (PTSD) and certain symptoms associated with affective disorders and schizophrenia. Further, DRD2 variants have been implicated in Parkinson's disease (PD) and in iatrogenically-induced movement disorders, as well as in certain migraineurs. Phenotypic differences have been associated with DRD2 variants. These include reduced D2 dopamine receptor numbers and diminished glucose metabolism in the brain of subjects who carry the DRD2 A1 allele. In addition, phenotypic differences have been found in neurocognitive and personality characteristics, and in treatment outcome of DRD2 variants. The involvement of the DRD2 gene in certain neuropsychiatric disorders opens up the potential of a targeted pharmacogenomic approach to the prevention and treatment of these disorders.
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PMID:The DRD2 gene in psychiatric and neurological disorders and its phenotypes. 1125 81

Brain dopaminergic pathways play a major role in the control of movement. Absence of the murine dopamine D2 receptor gene (drd2) produces bradykinesia and hypothermia. A Ser311Cys mutation of the human DRD2 produces a marked functional impairment of the receptor and is associated with higher BMI in some populations. We hypothesized that the Ser311Cys mutation of DRD2 may inhibit energy expenditure. Here we report that total energy expenditure (doubly labeled water) measured in 89 nondiabetic Pima Indians was 244 kcal/ day lower in homozygotes for the Cys311-encoding allele when compared with those heterozygous and homozygous for the Ser311-encoding allele (P = 0.056). The 24-h resting energy expenditure (respiratory chamber) measured in 320 nondiabetic Pimas was also 87 kcal/day lower in homozygotes for the Cys311-encoding allele when compared with those heterozygous and homozygous for the Ser311-encoding allele (P = 0.026). These findings are the first evidence that a genetic mutation is associated with reduced energy expenditure in humans. Because the impact of this mutation on human obesity is small, we suggest that either the energy deficit induced is not large enough to significantly influence body weight in this population and/or that the Cys311-encoding allele is also associated with reduced energy intake.
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PMID:A Ser311Cys mutation in the human dopamine receptor D2 gene is associated with reduced energy expenditure. 1128 60


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