Strategies for Identifying Genes Underlying Drug Abuse Susceptibility

Jc, Crabbe; Kj, Buck; Metten, Pamela; Jk, Belknap

doi:10.1037/e495702006-014

Cited by 5 publications

(3 citation statements)

References 26 publications

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“…QTL mapping studies in mice have identified different candidate gene regions for alcoholism [Radel and Goldman, 2001] including that for alcohol consumption and alcohol-induced hypothermia [Crabbe et al, 1994]. Chromosome 9 QTLs for alcohol-induced hypothermia, alcohol consumption, and the responses to some drugs coincide with each other and with the location of serotonin HTR1B gene [Crabbe et al, 1996a]. Furthermore, HTR1B knockout mice reported to consume more ethanol compared to controls and showed elevation in aggressive behavior indicating the role of this receptor in pathogenesis of the disorder [Saudou et al, 1994;Crabbe et al, 1996b].…”

Section: Discussionmentioning

confidence: 99%

Linkage disequilibrium and haplotype analysis between serotonin receptor 1B gene variations and subtypes of alcoholism

Sinha¹,

Cloninger²,

Parsian³

2003

American J of Med Genetics Pt B

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A number of studies have reported a possible association between serotonergic pathway genes and alcoholism. A silent polymorphism (G to C substitution) in the gene encoding the autoreceptor 5-HT1B was linked to antisocial alcoholism in Finnish and an American Indian populations [Lappalainen et al., 1998: Arch Gen Psychiatry 55:989-994]. Several other polymorphisms of this gene have been investigated for their association with neuropsychiatric disorders. In the present study, a sample of 133 alcoholics without and 39 alcoholics with medical complications, and 88 normal controls was screened for three single nucleotide polymorphisms (SNPs), G861C, G261T, and C129T, in the 5-HT1B gene. The goal was to investigate their association with the disease, to measure the strength of linkage disequilibrium (LD) between the SNPs, and to compare haplotype frequencies between alcoholic groups and normal controls. Data was also analyzed on the basis of Type I (n = 47) and Type II (n = 85) alcoholism. There was no significant difference in the allele frequencies or the genotype distribution between any alcoholic groups, alcoholic subgroups, and controls for any polymorphism. G861C and C129T polymorphisms were in complete LD. The pattern of distribution of haplotypes was similar in patients and controls. It is concluded that these SNPs are not playing any direct role in the development of susceptibility to alcoholism in our patient sample.

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Section: Discussionmentioning

confidence: 99%

Linkage disequilibrium and haplotype analysis between serotonin receptor 1B gene variations and subtypes of alcoholism

Sinha¹,

Cloninger²,

Parsian³

2003

American J of Med Genetics Pt B

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“…The m opioid receptor gene is located at the site of a QTL that affects consumption of alcohol and cocaine [75]. QTLs for alcoholinduced hypothermia, alcohol consumption, and certain responses to amphetamine and morphine are located on chromosome 1 [76], and also on chromosome 9 near the 5-HT1B receptor and D2 receptor genes [77]. These genetic interrelationships between different phenotypes indicate that the same genes influence different alcohol-associated behaviors, that several genes may affect one phenotype, and that some loci for drug abuse are not drug-specific.…”

Section: Rodent Models: Quantitative Trait Locus Analysesmentioning

confidence: 99%

The genetics of alcoholism and alcohol abuse

Enoch

Goldman

2001

Curr Psychiatry Rep

152

114

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Twin studies have established that there are substantial genetic influences on alcoholism (0.5-0.6) in both men and women. Our knowledge of behaviors predisposing to alcoholism, including anxiety and impulsivity, is advancing rapidly through animal and human studies. Although alcoholism is often comorbid with other substance abuse and psychiatric disorders, recent studies have shown that, with the exception of nicotine, the heritability of alcoholism is largely substance-specific. Increasing understanding of the neurobiology of addiction has identified neural pathways in which genetic variation at candidate genes could influence vulnerability. Some functional variants of these genes have been identified. Recent linkage analyses in humans and rodents have pointed to genomic regions harboring genes that influence alcoholism. Refinement of clinical phenotypes and use of intermediate phenotypes will improve chances of gene identification. All these advances in the understanding of the genetics of alcoholism should facilitate the development of more accurately targeted therapies using molecular diagnostic approaches.

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“…; 5 Actd1, 65 cM(Gill & Boyle, 2005 a ;Koyner et al 2000) ; 6 Ap7q, 25 cM (MGI), Ofca2, 53 cM(Steinberger et al 2003) ; 7 Alcw3, 18 cM(Bergeson et al 2003 ;Crabbe et al 1996) ; 8 Elmaz1, 57 cM(Cohen et al 2001) ; 9 Axtrb2(Turri et al 2001) ; 10 Axtq, 95 cM(Singer et al 2004 ;Turri et al 2001), Axtex(Willis-Owen & Flint, 2006) ; 11 Suggestive EtOH preference QTL, 29 cM (Gill & Boyle, 2005 a), Alcp21(Gill et al 1998) ; 12 Alcdp1, 95.8 cM(Buck et al 2002 ;Denmark & Buck, 2008 ;Kozell et al 2008) ; 13 Etohc, 28 cM(Belknap et al 2001 ;Fehr et al 2005 ;Phillips et al 1998 ;Saba et al 2006), EtOH consumption QTL, 105/107 cM(Vadasz et al 2000 b), EtOH preference, 107 cM…”

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confidence: 97%

Quantitative trait loci contributing to physiological and behavioural ethanol responses after acute and chronic treatment

Drews¹,

Rácz²,

Lacava³

et al. 2009

Int. J. Neuropsychopharm.

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The aim of the present study was the identification of gene loci that contribute to the development and manifestation of behaviours related to acute and chronic alcohol exposure, as well as to alcohol withdrawal. For this purpose, we performed a serial behavioural phenotyping of 534 animals from the second filial (F2) generation of a C57BL/6J and C3H/HeJ mice intercross in paradigms with relevance to alcohol dependence. First, ethanol-induced hypothermia was determined in ethanol-naive animals. The mice then received an ethanol solution for several weeks as their only fluid source. Ethanol tolerance, locomotor activity and anxiety-related behaviours were evaluated. The ethanol was next withdrawn and the withdrawal severity was assessed. The ethanol-experienced animals were finally analysed in a two-bottle choice paradigm to determine ethanol preference and stress-induced changes in ethanol preference. The genotypes of these mice were subsequently assessed by microsatellite marker mapping. We genotyped 264 markers with an average marker distance of 5.56 cM, which represents a high-density whole genome coverage. Quantitative trait loci (QTL) were subsequently identified using univariate analysis performed with the R/qtl tool, which is an extensible, interactive environment for mapping QTL in experimental crosses. We found QTL that have already been published, thus validating the serial phenotyping protocol, and identified several novel loci. Our analysis demonstrates that the various responses to ethanol are regulated by independent groups of genes.

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Strategies for Identifying Genes Underlying Drug Abuse Susceptibility

Cited by 5 publications

References 26 publications

Linkage disequilibrium and haplotype analysis between serotonin receptor 1B gene variations and subtypes of alcoholism

Linkage disequilibrium and haplotype analysis between serotonin receptor 1B gene variations and subtypes of alcoholism

The genetics of alcoholism and alcohol abuse

Quantitative trait loci contributing to physiological and behavioural ethanol responses after acute and chronic treatment

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