Endophenotypes Successfully Lead to Gene Identification: Results from the Collaborative Study on the Genetics of Alcoholism

Dick, Danielle M.; Jones, Kevin; Saccone, Nancy L.; Hinrichs, Anthony L.; Wang, Jen C.; Goate, Alison M.; Bierut, Laura J.; Almasy, Laura; Schuckit, Marc A.; Hesselbrock, Victor; Tischfield, Jay A.; Foroud, Tatiana; Edenberg, Howard J.; Porjesz, Bernice; Begleiter, Henri

doi:10.1007/s10519-005-9001-3

Cited by 121 publications

(80 citation statements)

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“…That is, no locus individually appears to contribute a substantial fraction of the vulnerability to any addictive substance. There is a caveat: these data come from subjects that largely have European ethnic/racial backgrounds [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41]. Nevertheless, as with many complex human disorders in which initial hopes for a tractable underlying genetic architecture supported use of linkage approaches, linkage peaks may be more likely to arise when polygenes that each contribute modest amounts to addiction vulnerability happen to lie near each other on human chromosomes rather than when there is a single gene variant of major effect for addiction vulnerability [42].…”

Section: A Studies Of Human Addiction Vulnerabilitiesmentioning

confidence: 99%

“Higher order” addiction molecular genetics: Convergent data from genome-wide association in humans and mice

Uhl

Drgon

Johnson

et al. 2008

Biochemical Pharmacology

127

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Family, adoption and twin data each support substantial heritability for addictions. Most of this heritable influence is not substance-specific. The overlapping genetic vulnerability for developing dependence on a variety of addictive substances suggests large roles for "higher order" pharamacogenomics in addiction molecular genetics. We and others have now completed genomewide association (GWA) studies of DNAs from individuals with dependence on a variety of addictive substances vs appropriate controls. Recently reported replicated GWA observations identify a number of genes based on comparisons between controls and European-American and African-American polysubstance abusers. Here we review the convergence between these results and data that compares control samples and a) alcohol dependent European Americans, b) methamphetamine dependent Asians and c) nicotine dependent samples from European backgrounds. We also compare these human data to quantitative trait locus (QTL) results from studies of addiction-related phenotypes in mice that focus on alcohol, methamphetamine and barbiturates. These comparisons support a genetic architecture built from largely-polygenic contributions of common allelic variants to dependence on a variety of legal and illegal substances. Many of the gene variants identified in this way are likely to alter specification and maintenance of neuronal connections. KeywordsAssociation genome scanning; substance dependence; microarray; pooled; neuronal connections * To whom correspondence should be addressed at: Molecular Neurobiology, Box 5180, Baltimore, MD 21224 phone: (410) 550-2843 x 146, fax: (410) 550-1535, guhl@intra.nida.nih.gov. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access A. Studies of human addiction vulnerabilitiesVulnerability to addictions is a complex trait with strong genetic influences that are largely shared by abusers of different legal and illegal addictive substances [1][2][3][4]. This conclusion comes from family, adoption and twin studies. Family studies clearly document that first degree relative (eg sibs) of addicts display greater risk for developing substance dependence than more distant relatives [1,5]. Adoption studies consistently find greater similarities between substance abuse phenotypes with biological relatives than with adoptive family members [1]. In twin studies, differences in concordance between genetically identical and fraternal twins also support heritability for vulnerability to addictions [3,[6][7][8][9][10][11][12]. Twin data allows quantitation of the amount, about 50%, of ad...

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Section: A Studies Of Human Addiction Vulnerabilitiesmentioning

confidence: 99%

“Higher order” addiction molecular genetics: Convergent data from genome-wide association in humans and mice

Uhl

Drgon

Johnson

et al. 2008

Biochemical Pharmacology

127

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“…Few genes have been identified, although recently the long allele of the SLC6A4 gene, which encodes the serotonin transporter, and the Ser 385 variant of the GABRA6 gene, which encodes the a6 subunit of GABA A receptors, have been associated with a low level of response to alcohol in humans (Hu et al, 2005). The Collaborative Study on the Genetics of Alcoholism has identified the GABRA2 gene located on chromosome 4 encoding the a2-subunit of the GABA A receptor, the GABRB1 gene on chromosome 4 coding for the b1 subunit of the GABA A receptor, and the CHRM2 gene on chromosome 7, which encodes the type 2 muscarinic receptor as susceptibility genes for alcoholism (Dick et al, 2005), although it is not known if they contribute to the level of response to alcohol. In addition, animal studies have identified several other genes that alter acute responses to alcohol in rodents as candidates for the regulation of the level of response in humans (Schuckit et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Acute Functional Tolerance to Ethanol Mediated by Protein Kinase Cɛ

Wallace

Newton

Oyasu

et al. 2006

Neuropsychopharmacol

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A low level of response to ethanol is associated with increased risk of alcoholism. A major determinant of the level of response is the capacity to develop acute functional tolerance (AFT) to ethanol during a single drinking session. Mice lacking protein kinase C epsilon (PKCe) show increased signs of ethanol intoxication and reduced ethanol self-administration. Here, we report that AFT to the motorimpairing effects of ethanol is reduced in PKCe (À/À) mice when compared with wild-type littermates. In wild-type mice, in vivo ethanol exposure produced AFT that was accompanied by increased phosphorylation of PKCe and resistance of GABA A receptors to ethanol. In contrast, in PKCe (À/À) mice, GABA A receptor sensitivity to ethanol was unaltered by acute in vivo ethanol exposure. Both PKCe (À/À) and PKCe ( + / + ) mice developed robust chronic tolerance to ethanol, but the presence of chronic tolerance did not change ethanol preference drinking. These findings suggest that ethanol activates a PKCe signaling pathway that contributes to GABA A receptor resistance to ethanol and to AFT. AFT can be genetically dissociated from chronic tolerance, which is not regulated by PKCe and does not alter PKCe modulation of ethanol preference.

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“…An elegant and instructive exception is a series of studies by the Collaborative Study of the Genetics of Alcoholism (COGA) in which electrophysiological endophenotypes were studied in addition to clinical diagnoses. 17 Here the use of endophenotypes substantially improved both the strength and localization of linkage findings and allowed the identification of GABRA2 and CHRM2 as genes associated with predisposition to alcohol dependence. 17,18 In this case, the utility of analysing electrophysiological data seems to have been that it allowed broad linkage signals reflecting linkage to more than one locus to be decomposed into constituent signals reflecting variation in individual genes; gains in power resulted from a combination of greater genetic homogeneity and the use of quantitative phenotypes.…”

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confidence: 99%

“…17 Here the use of endophenotypes substantially improved both the strength and localization of linkage findings and allowed the identification of GABRA2 and CHRM2 as genes associated with predisposition to alcohol dependence. 17,18 In this case, the utility of analysing electrophysiological data seems to have been that it allowed broad linkage signals reflecting linkage to more than one locus to be decomposed into constituent signals reflecting variation in individual genes; gains in power resulted from a combination of greater genetic homogeneity and the use of quantitative phenotypes. Further studies have used individual and combined endophenotypes in genetic linkage studies of schizophrenia, although as yet these studies have not resulted in the unambiguous identification of susceptibility genes.…”

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confidence: 99%

“…In our view, the use of endophenotypes in gene finding, by both linkage and association approaches, is most likely to add value when multiple measures are employed in combination with clinical data. 17,20,24 Putative endophenotypes should be chosen on the basis of robust evidence that they are not only associated with the disease but also that association reflects shared genes (Table 1). Fortunately, increasing attention is now being given to this latter issue.…”

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confidence: 99%

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