Autosomal Linkage Analysis for the Level of Response to Alcohol

Schuckit, Marc A.; Wilhelmsen, Kirk C.; Smith, Tom L.; Feiler, Heidi S.; Lind, Penelope A.; Lange, Leslie A.; Kalmijn, Jelger

doi:10.1097/01.alc.0000187598.82921.27

Cited by 58 publications

(62 citation statements)

References 42 publications

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“…Strikingly, Zubenko and colleagues have reported linkage for mood disorders at 76 and 113 cM in their family study of recurrent unipolar major depressive disorder (Zubenko et al, 2003b). The latter peak at 116 cM also maps to within 10 cM of the region where Schuckit et al, (2005) report linkage for the Subjective High Assessment Scale (SHAS), a measure of alcohol response.…”

Section: Discussionmentioning

confidence: 99%

“…A smaller linkage peak at 90-110 cM encompasses candidate genes such as HTR7 (5-Hydroxytryptamine receptor 2B) and VMAT2 (vesicular monoamine oxidase 2), as well as KCNMA1 (calcium activated channel). SNPs in VMAT2 and KCNMA1 have been shown to be associated with alcoholism and the endophenotype of subjective responses to ethanol (Lin et al, 2005;Schuckit et al, 2005). Also located at 83 cM is CTNNA3 (catenin alpha 3) which was recently identified in genomewide association studies of substance dependence vulnerability and nicotine dependence (Bierut et al, 2007;Liu et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

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Linkage scan for quantitative traits identifies new regions of interest for substance dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample

Agrawal

Hinrichs

Dunn

et al. 2008

Drug and Alcohol Dependence

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Dependence on alcohol and illicit drugs frequently co-occur. Results from a number of twin studies suggest that heritable influences on alcohol dependence and drug dependence may substantially overlap. Using large, genetically informative pedigrees from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed quantitative linkage analyses using a panel of 1717 SNPs. Genome-wide linkage analyses were conducted for quantitative measures of DSM-IV alcohol

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Linkage scan for quantitative traits identifies new regions of interest for substance dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample

Agrawal

Hinrichs

Dunn

et al. 2008

Drug and Alcohol Dependence

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“…Although the chr 14 region was identified in cohorts 1 and 3 (Table 2), and in all three mapping packages (in at least one sex), the support intervals do not overlap. This ambiguity makes it difficult to pursue this QTL, despite its overlap with a human QTL for ethanol sensitivity (Schuckit et al, 2005). The chr 18 and 19 regions illustrate a different problem.…”

Section: Discussionmentioning

confidence: 99%

Confirmation and Fine Mapping of Ethanol Sensitivity Quantitative Trait Loci, and Candidate Gene Testing in the LXS Recombinant Inbred Mice

Bennett

Carosone-Link²,

Zahniser³

et al. 2006

J Pharmacol Exp Ther

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In previous studies, we have mapped quantitative trait loci (QTLs) for hypnotic sensitivity to ethanol using a small recombinant inbred (RI) panel and a large F 2 backcross. Alcohol sensitivity is a major predictor of long-term risk for alcoholism. We remapped hypnotic sensitivity using a new set of 75 RI strains, the LXS, derived from Inbred Long Sleep and Inbred Short Sleep strains. We expected to improve mapping resolution in the QTL regions and to identify novel QTLs for loss of the righting reflex due to ethanol. We used three common mapping algorithms (R/qtl, QTL Cartographer, and WebQTL) to map QTLs in the LXS, and we compared the results. Most mapping studies use only a single algorithm, an approach that may result in failure to identify minor QTLs. We confirmed most of our previously reported QTLs, although one major QTL from earlier work (Lore2) failed to replicate, possibly because it represented multiple linked genes separated by recombination in the RI strains. We also report narrowed confidence intervals, based on mapping with a new genetic resource of more than 4000 polymorphic single-nucleotide polymorphism markers. These narrowed confidence intervals will facilitate candidate gene identification and assessment of overlap with human regions specifying risk for alcoholism. Finally, we present an approach for using these RI strains to assess evidence for candidate genes in the narrowed intervals, and we apply this method to a strong candidate, the serotonin transporter.

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“…The subjects used were from the San Diego Sibling Pair study (46,47), and consisted of college age students from the San Diego (mean ؎ SEM) for morphine and DAMGO in MOR1, MOR1A, A6V-MOR1A, S42T-MOR1A, S147C-MOR1A, or C192F-MOR1A metropolitan area. This collection was designed to identify families enriched for alcoholism susceptibility genes.…”

Section: Methodsmentioning

confidence: 99%

Functional characterization of human variants of the mu-opioid receptor gene

Ravindranathan

Joslyn

Robertson

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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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.OPRM1 ͉ SNP ͉ tolerance ͉ morphine ͉ opiate

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Autosomal Linkage Analysis for the Level of Response to Alcohol

Abstract: These evaluations from the largest known alcohol challenge-based genetic study to date highlight the potential importance of genes on chromosome 10 as possible contributors to the low LR to alcohol as a risk factor for alcoholism.

Cited by 58 publications

References 42 publications

Linkage scan for quantitative traits identifies new regions of interest for substance dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample

Linkage scan for quantitative traits identifies new regions of interest for substance dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample

Confirmation and Fine Mapping of Ethanol Sensitivity Quantitative Trait Loci, and Candidate Gene Testing in the LXS Recombinant Inbred Mice

Functional characterization of human variants of the mu-opioid receptor gene

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