Genome-Wide Association for Methamphetamine Dependence

Uhl, George R.; Drgon, Tomás; Liu, Qingrong; Johnson, Catherine; Walther, Donna; Komiyama, Tokutaro; Harano, Mutsuo; Sekine, Yoshimoto; Inada, Toshiya; Ozaki, Norio; Iyo, Masaomi; Iwata, Nakao; Yamada, Mitsuhiko; Sora, Ichiro; Chen, Chih Ken; Liu, Hsing Cheng; Ujike, Hiroshi; Lin, Shih Ku

doi:10.1001/archpsyc.65.3.345

Cited by 133 publications

(118 citation statements)

References 85 publications

(127 reference statements)

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“…The molecular genetic results from these independent samples display substantial convergence with each other; the nominally positive results cluster in small chromosomal regions to extents much more than we would expect by chance. These results also display more modest convergence with molecular genetic data for vulnerability to dependence on nicotine and other addictive substances (8,(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 58%

Genome-Wide Association for Smoking Cessation Success: Participants in a Trial with Adjunctive Denicotinized Cigarettes

Drgon

Johnson

Walther

et al. 2009

Mol Med

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The ability to quit smoking successfully displays substantial heritability in classical and molecular genetic studies. Twin studies suggest that some of the genetics for the ability to quit overlap with genetic components of nicotine dependence, but many do not. Genome-wide association (GWA) studies have demonstrated haplotypes that distinguish successful quitters from individuals who were not able to quit smoking in: i) clinical trials that employed nicotine replacement; ii) clinical trials that employed bupropion; and iii) community quitter samples. We now report novel GWA results from participants in a clinical trial that document the efficacy of adjunctive use of denicotinized cigarettes. These results buttress data from our prior GWA studies of smoking cessation. They suggest that ability to change smoking behavior using denicotinized cigarettes shares substantial underlying genetics with the ability to change this behavior in community settings or in response to treatments with nicotine replacement or bupropion.

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Section: Introductionmentioning

confidence: 58%

Genome-Wide Association for Smoking Cessation Success: Participants in a Trial with Adjunctive Denicotinized Cigarettes

Drgon

Johnson

Walther

et al. 2009

Mol Med

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“…These findings suggest that GAPDH may participate in METH-induced neurotoxicity. This observation may contribute to a better understanding of the brain damage in METH abusers who exhibit various neuropsychiatric manifestations (27).…”

Section: Discussionmentioning

confidence: 86%

Glyceraldehyde-3-phosphate Dehydrogenase Aggregate Formation Participates in Oxidative Stress-induced Cell Death

Nakajima

Amano

Kubo

et al. 2009

Journal of Biological Chemistry

123

122

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Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)2 is a classic glycolytic enzyme that also mediates cell death by its nuclear translocation under oxidative stress. Meanwhile, we previously presented that oxidative stress induced disulfide-bonded GAPDH aggregation in vitro. Here, we propose that GAPDH aggregate formation might participate in oxidative stress-induced cell death both in vitro and in vivo. We show that human GAPDH amyloidlike aggregate formation depends on the active site cysteine-152 (Cys-152) in vitro. In SH-SY5Y neuroblastoma, treatment with dopamine decreases the cell viability concentration-dependently (IC 50 ‫؍‬ 202 M). Low concentrations of dopamine (50 -100 M) mainly cause nuclear translocation of GAPDH, whereas the levels of GAPDH aggregates correlate with high concentrations of dopamine (200 -300 M)-induced cell death. Doxycycline-inducible overexpression of wild-type GAPDH in SH-SY5Y, but not the Cys-152-substituted mutant (C152A-GAPDH), accelerates cell death accompanying both endogenous and exogenous GAPDH aggregate formation in response to high concentrations of dopamine. Deprenyl, a blocker of GAPDH nuclear translocation, fails to inhibit the aggregation both in vitro and in cells but reduced cell death in SH-SY5Y treated with only a low concentration of dopamine (100 M). These results suggest that GAPDH participates in oxidative stress-induced cell death via an alternative mechanism in which aggregation but not nuclear translocation of GAPDH plays a role. Moreover, we observe endogenous GAPDH aggregate formation in nigra-striatum dopaminergic neurons after methamphetamine treatment in mice. In transgenic mice overexpressing wildtype GAPDH, increased dopaminergic neuron loss and GAPDH aggregate formation are observed. These data suggest a critical role of GAPDH aggregates in oxidative stress-induced brain damage.Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a classic glycolytic enzyme that is also involved in cell death and neuropsychiatric conditions (1, 2). GAPDH mediates cell death under oxidative stress conditions at least in part through nuclear translocation together with Siah (3). In the nucleus, GAPDH activates p300/CBP and regulates gene transcription (4). The pathway can be blocked by deprenyl (Selegiline), a neuroprotective compound (5). Although nuclear translocation of GAPDH is known to cause cell death, other mechanisms of GAPDH-associated cell death may also exist.Several neurodegenerative diseases are characterized by the accumulation of misfolded proteins, resulting in intracellular and extracellular protein aggregates (6, 7). For instance, conformational changes in ␤-amyloid (A␤) in Alzheimer disease and ␣-synuclein in Parkinson disease lead to the formation of abnormal oligomers and amyloid fibrils (8). Similar to A␤ and ␣-synuclein, GAPDH is also amyloidogenic (9 -14). We previously reported the molecular mechanism underlying oxidative stressinduced amyloid-like aggregation of GAPDH using the purified rabbit GAPDH and demonstrated the critical role of the act...

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“…These data and altered cocaine reward in mice with adult reductions in CDH13 expression support CDH13 as a novel therapeutic target. DISCLOSUrEcase versus control allele frequency differences (5,7,9,10,14,16,45,(50)(51)(52)(53)(54)(55)(56)(57)(58). Cautions in interpreting this human data, taken alone, included the lack of large effects of any single CDH13 variant.…”

Section: Discussionmentioning

confidence: 99%

“…For addiction vulnerability and attention deficit hyperactivity disorder (ADHD), the CDH13 locus is marked by groups of clustered, nearby single nucleatide polymorphisms (SNPs) that display associations with 10 -2 > p > 10 -8 statistical significance in numerous independent case versus control genome wide association (GWAS) studies (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). CDH13 associations with the numbers of cigarettes smoked per day, reward reported after CDH13 mRNA is prominently expressed by ventral tegmental area and substantia nigra pars compacta neurons that are implicated in reward, locomotor control and cognitive modulation (3,4).…”

mentioning

confidence: 99%

Cadherin 13: Human cis-Regulation and Selectively Altered Addiction Phenotypes and Cerebral Cortical Dopamine in Knockout Mice

Drgonová

Walther

Hartstein

et al. 2016

Mol Med

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The cadherin 13 (CDH13) gene encodes a cell adhesion molecule likely to influence development and connections of brain circuits that modulate addiction, locomotion and cognition, including those that involve midbrain dopamine neurons. Human CDH13 mRNA expression differs by more than 80% in postmortem cerebral cortical samples from individuals with different CDH13 genotypes, supporting examination of mice with altered CDH13 expression as models for common human variation at this locus. Constitutive CDH13 knockout mice display evidence for changed cocaine reward: shifted dose response relationship in tests of cocaine-conditioned place preference using doses that do not alter cocaine-conditioned taste aversion. Reduced adult CDH13 expression in conditional knockouts also alters cocaine reward in ways that correlate with individual differences in cortical CDH13 mRNA levels. In control and comparison behavioral assessments, knockout mice display modestly quicker acquisition of rotarod and water maze tasks, with a trend toward faster acquisition of 5-choice serial reaction time tasks that otherwise displayed no genotype-related differences. They display significant differences in locomotion in some settings, with larger effects in males. In assessments of brain changes that might contribute to these behavioral differences, there are selective alterations of dopamine levels, dopamine/metabolite ratios, dopaminergic fiber densities and mRNA encoding the activity dependent transcription factor npas4 in cerebral cortex of knockout mice. These novel data and previously reported human associations of CDH13 variants with addiction, individual differences in responses to stimulant administration and attention deficit hyperactivity disorder (ADHD) phenotypes suggest that levels of CDH13 expression, through mechanisms likely to include effects on mesocortical dopamine, influence stimulant reward and may contribute modestly to cognitive and locomotor phenotypes relevant to ADHD.

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Genome-Wide Association for Methamphetamine Dependence

Abstract: These data support polygenic contributions to methamphetamine dependence from genes that include those whose variants contribute to dependence on several addictive substances, success in quitting smoking, and mnemonic processes.

Cited by 133 publications

References 85 publications

Genome-Wide Association for Smoking Cessation Success: Participants in a Trial with Adjunctive Denicotinized Cigarettes

Genome-Wide Association for Smoking Cessation Success: Participants in a Trial with Adjunctive Denicotinized Cigarettes

Glyceraldehyde-3-phosphate Dehydrogenase Aggregate Formation Participates in Oxidative Stress-induced Cell Death

Cadherin 13: Human cis-Regulation and Selectively Altered Addiction Phenotypes and Cerebral Cortical Dopamine in Knockout Mice

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