Margaret Robertson

University of California, San Francisco, San Francisco, CA, United States

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Publications (9)32.13 Total impact

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    ABSTRACT: Background: Common variants in the CHRNA5-A3-B4 gene cluster have been shown to be associated with nicotine dependence and alcohol use disorders (AUDs) and related traits, including the level of response (LR) to alcohol. Recently, rare variants (MAF < 0.05) in CHRNB4 have been reported to be associated with a decreased risk of developing nicotine dependence. However, the role of rare variants in the CHRNA5-A3-B4 gene cluster to the LR to alcohol has not yet been established. Methods: To determine whether rare variants in the CHRNA5-A3-B4 gene cluster contribute to the LR to alcohol, the coding regions of these 3 genes were sequenced in 538 subjects from the San Diego Sibling Pair study. Results: The analyses identified 16 rare missense variants, 9 of which were predicted to be damaging using in silico analysis tools. Carriers of these variants were compared to noncarriers using a family-based design for each gene and for the gene cluster as a whole. In these analyses, a CHRNA5 carrier status was significantly associated with the phenotype related to the feeling of intoxication experienced during the alcohol challenge (p = 0.039). Conclusions: These results indicate that rare genetic variation in the CHRNA5-A3-B4 gene cluster contributes modestly to the LR to alcohol in the San Diego Sibling Pair study and may protect against AUDs. However, replication studies are needed to confirm our findings.
    No preview · Article · Mar 2013 · Alcoholism Clinical and Experimental Research
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    Dataset: Figure S1
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    ABSTRACT: Flies carrying the MB06458 insertion do not show altered ethanol absorption. For each sample, 25 male control and MB06458 flies were exposed for 15 min to ethanol at a dose of 100∶50 (ethanol vapor∶air) and immediately frozen. Ethanol concentration was measured using a NAD∶ADH enzymatic assay on homogenized flies. Shown is the % ethanol concentration obtained in each group of flies. Error bars, SEM, n = 5. (EPS)
    Preview · Dataset · Jul 2011
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    Dataset: Figure S3
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    ABSTRACT: Increased MEK phosphorylation in the striatum of AlkKO mice. Striatum was dissected from the brains of adult male mice and analyzed using the PathScan® Phospho-MEK1 and Total MEK1 Sandwich ELISA kits from Cell Signaling Technology. Shown is the ratio of phosphorylated MEK to total MEK (pMEK/MEK) in wild-type (+/+) and AlkKO (−/−) mice. *P = 0.005 by Student's t-test, n = 5–7. (EPS)
    Preview · Dataset · Jul 2011
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    ABSTRACT: Anaplastic lymphoma kinase (Alk) is a gene expressed in the nervous system that encodes a receptor tyrosine kinase commonly known for its oncogenic function in various human cancers. We have determined that Alk is associated with altered behavioral responses to ethanol in the fruit fly Drosophila melanogaster, in mice, and in humans. Mutant flies containing transposon insertions in dAlk demonstrate increased resistance to the sedating effect of ethanol. Database analyses revealed that Alk expression levels in the brains of recombinant inbred mice are negatively correlated with ethanol-induced ataxia and ethanol consumption. We therefore tested Alk gene knockout mice and found that they sedate longer in response to high doses of ethanol and consume more ethanol than wild-type mice. Finally, sequencing of human ALK led to the discovery of four polymorphisms associated with a low level of response to ethanol, an intermediate phenotype that is predictive of future alcohol use disorders (AUDs). These results suggest that Alk plays an evolutionary conserved role in ethanol-related behaviors. Moreover, ALK may be a novel candidate gene conferring risk for AUDs as well as a potential target for pharmacological intervention.
    Full-text · Article · Jul 2011 · PLoS ONE
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    Dataset: Figure S2
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    ABSTRACT: Generation of AlkKO mice. (A) Scheme for generating AlkKO mice. An EcoRI fragment of the Alk genomic DNA locus was used to develop the Alk targeting vector, in which the exons coding for juxtamembrane domain of the ALK protein and the ATP binding pocket of the kinase domain, and their flanking sequences were replaced by a neo expression cassette. An EcoRI site was introduced into the targeted locus by the neo cassette. A herpes simplex virus–thymidine kinase gene cassette mediating negative ES cell selection with ganciclovir was inserted in the 5′ end of the Alk-neo construct. Correctly targeted ES cell clones with normal karyotypes were injected into blastocysts to generate chimeric mice for subsequent breeding to obtain germline transmission. Letters indicate restriction enzyme sites (B) Example of PCR genotyping of the AlkKO mice. Shown is a representative agarose gel illustrating PCR product. Mice were genotyped using primers to Alk at the neo insertion site to determine the presence or absence of the wild-type allele and to neo to determine the presence or absence of the insertion (NEO). The genotype (+/+, +/−, −/−) based on the PCR is indicated above the gel, with a negative control (no template DNA) for PCR and the 100 bp molecular weight marker on the right side of the gel. Note the presence of a single PCR product indicates either wild-type (+/+) or homozygote (−/−), while the presence of both Alk and NEO PCR products indicates a heterozygote (+/−). (EPS)
    Preview · Dataset · Jul 2011
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    Dataset: Table S1
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    ABSTRACT: Transcripts showing significantly altered expression in dLmo mutants EP1306 and BxJ. Columns (from left to right) indicate the Affymetrix probe set identifier, the gene symbol, the FlyBase annotation, the cluster number from HOPACH clustering, the mean expression value of the transcript (normalized to expression in control w;iso flies and expressed as log2) in flies carrying the BxJ and EP1306 mutations, and the ANOVA p-value. (XLS)
    Preview · Dataset · Jul 2011
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    ABSTRACT: Opioids and their receptors have an important role in analgesia and alcohol and substance use disorders (ASUD). We have identified several naturally occurring amino acid changing variants of the human mu-opioid receptor (MOR), and assessed the functional consequences of these previously undescribed variants in stably expressing cell lines. Several of these variants had altered trafficking and signaling properties. We found that an L85I variant showed significant internalization in response to morphine, in contrast to the WT MOR, which did not internalize in response to morphine. Also, when L85I and WT receptor were coexpressed, WT MOR internalized with the L85I MOR, suggesting that, in the heterozygous condition, the L85I phenotype would be dominant. This finding is potentially important, because receptor internalization has been associated with development of tolerance to opiate analgesics. In contrast, an R181C variant abolished both signaling and internalization in response to saturating doses of the hydrolysis-resistant enkephalin [D-Ala2,N-MePhe4,Gly5-ol]enkephalin (DAMGO). Coexpression of the R181C and WT receptor led to independent trafficking of the 2 receptors. S42T and C192F variants showed a rightward shift in potency of both morphine and DAMGO, whereas the S147C variant displayed a subtle leftward shift in morphine potency. These data suggest that these and other such variants may have clinical relevance to opioid responsiveness to both endogenous ligands and exogenous drugs, and could influence a broad range of phenotypes, including ASUD, pain responses, and the development of tolerance to morphine.
    Preview · Article · Jul 2009 · Proceedings of the National Academy of Sciences
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    ABSTRACT: As with other genetically complex common psychiatric and medical conditions, multiple genetic and environmental components contribute to alcohol use disorders (AUDs), which can confound attempts to identify genetic components. Intermediate phenotypes are often more closely correlated with underlying biology and have often proven invaluable in genetic studies. Level of response (LR) to alcohol is an intermediate phenotype for AUDs, and individuals with a low LR are at increased risk. A high rate of concurrent alcohol and nicotine use and dependence suggests that these conditions may share biochemical and genetic mechanisms. Genetic association studies indicate that a genetic locus, which includes the CHRNA5-CHRNA3-CHRNB4 gene cluster, plays a role in nicotine consumption and dependence. Genetic association with alcohol dependence was also recently shown. We show here that two of the markers from the nicotine studies also show an association (multiple testing corrected P < 0.025) with several LR phenotypes in a sample of 367 siblings. Additional markers in the region were analyzed and shown to be located in a 250-kb expanse of high linkage disequilibrium containing three additional genes. These findings indicate that LR intermediate phenotypes have utility in genetic approaches to AUDs and will prove valuable in the identification of other genetic loci conferring susceptibility to AUDs.
    Preview · Article · Jan 2009 · Proceedings of the National Academy of Sciences
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    ABSTRACT: The tendency to choose lesser immediate benefits over greater long-term benefits characterizes alcoholism and other addictive disorders. However, despite its medical and socioeconomic importance, little is known about its neurobiological mechanisms. Brain regions that are activated when deciding between immediate or delayed rewards have been identified (McClure et al., 2004, 2007), as have areas in which responses to reward stimuli predict a paper-and-pencil measure of temporal discounting (Hariri et al., 2006). These studies assume "hot" and "cool" response selection systems, with the hot system proposed to generate impulsive choices in the presence of a proximate reward. However, to date, brain regions in which the magnitude of activity during decision making reliably predicts intertemporal choice behavior have not been identified. Here we address this question in sober alcoholics and non-substance-abusing control subjects and show that immediate reward bias directly scales with the magnitude of functional magnetic resonance imaging bold oxygen level-dependent (BOLD) signal during decision making at sites within the posterior parietal cortex (PPC), dorsal prefrontal cortex (dPFC), and rostral parahippocampal gyrus regions. Conversely, the tendency of an individual to wait for a larger, delayed reward correlates directly with BOLD signal in the lateral orbitofrontal cortex. In addition, genotype at the Val158Met polymorphism of the catechol-O-methyltransferase gene predicts both impulsive choice behavior and activity levels in the dPFC and PPC during decision making. These genotype effects remained significant after controlling for alcohol abuse history. These results shed new light on the neurobiological underpinnings of temporal discounting behavior and identify novel behavioral and neural consequences of genetic variation in dopamine metabolism.
    Full-text · Article · Jan 2008 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience