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Alcohol and genetics: Is your child at risk?

Alcoholism or alcohol dependence is devastating. Genes that impact risk for this disorder can be inherited and passed on to one’s children. How genetic information is obtained, current genetic findings, and other important, influential factors will be discussed in this lecture.


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Why Study the Genetics of Alcoholism?

  • The genetic risk for alcoholism is high; it runs in families.

  • Identifying genetic factors that influence risk and protection for alcoholism may lead to better interventions.

  • But, study is difficult because the influence is not monogenic – alcoholism does not exhibit a Mendelian pattern of inheritance.


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L/H

L/L

H/H

A Single Gene Trait



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Small Genetic Differences Can Have Big Effects

From Simpson et al. (1997) Nature Genetics 16:19.


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Alcoholism:

A Complex Trait

Multiple Environments

Gene x Environment Interaction

Gene x Gene Interaction or Epistasis

Multiple Genes

Adapted from Phillips et al. (2002) Genes Brain Behav 1:14.


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Results May be Dependent Upon Environmental Conditions

“Although dolphins have long been celebrated for their high intelligence and for appearing to have a complex language, a team of researchers at the University of Florida reported Monday that these traits are markedly less evident on dry land.”

[the ONION, Feb 15, 2006]


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Genomics Allows Direct Translational Research

  • There is remarkable synteny between human and other species (including mouse).

  • Synteny means that functionally and ancestrally identical genes are found in the same order on the chromosomes of two species.

  • About 90% of the human and mouse genomes lie in conserved syntenic segments.


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Use of Animals to Identify Direct and Indirect Alcohol Targets Can Lead to Development of Pharmacotherapies for Alcohol Abuse and Alcoholism

From Lovinger & Crabbe (2005) Nature Neurosci 8:1471.


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Approaches Targets Can Lead to Development of Pharmacotherapies for Alcohol Abuse and Alcoholism

to the Study of Genetics

Approaches used for Human and Animal Populations

•Twin & Adoption Studies • Haplotype Analyses

• Association Studies • Natural Mutations

• Family Linkage Studies • mRNA Differential Display

• Microarray Expression Profiling• QTL Mapping

• Association Genome Scanning

Unique Approaches used for Animal Populations

•Targeted Mutations • Random Mutagenesis

• Viral Gene Transfection • Selective Breeding

• Antisense Approaches • Inbred Strain Studies

• RNA interference • Chimera Analysis


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Proof: Gene=Phenotypic Effect Targets Can Lead to Development of Pharmacotherapies for Alcohol Abuse and Alcoholism

  • There is no single “gold standard” of proof.

  • Proof relies on the careful assembly of multiple sources of evidence.

  • The strategy might include the combination of any of the approaches just listed (as well as pharmacological and other approaches); some complementary approaches may provide the best evidence.


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Quantitative Trait Locus (QTL) Targets Can Lead to Development of Pharmacotherapies for Alcohol Abuse and Alcoholism

• Genes that influence a quantitative trait may each have a small effect.

• A QTL identifies the location of a gene that influences a complex trait.

• QTL Mapping is a method for pinpointing chromosomal regions where trait-specific genes reside.

• Several QTL can work together to account for individual differences; their effects may “add up” or they may interact with each other.


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The Goal of Genetic Studies of Alcoholism Targets Can Lead to Development of Pharmacotherapies for Alcohol Abuse and Alcoholism

The ultimate goal of QTL mapping and other genetic studies is to identify the influential genes (the quantitative trait genes or QTG) and determine what they do that heightens risk for alcoholism or affords protection.


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Alcohol-Related Traits: Targets Can Lead to Development of Pharmacotherapies for Alcohol Abuse and AlcoholismWhat Genes Have Been Found?

  • Metabolic genes – alcohol (ADH1B; previously, ADH2) and aldehyde (ALDH2) dehydrogenase polymorphisms are known to be protective against the development of alcoholism.

  • Are there other genes that are candidates for protection or risk?


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Alcohol-Related Traits: Targets Can Lead to Development of Pharmacotherapies for Alcohol Abuse and AlcoholismA Gene Found with QTL Mapping

  • MPDZ, multiple PDZ domain protein. A determinant of alcohol withdrawal severity.

  • A scaffolding protein that aids in the coupling of other proteins that are involved in the transfer of signals in the cell.

  • MPDZ was not a gene previously predicted to be involved in alcohol effects.


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Selective Breeding Targets Can Lead to Development of Pharmacotherapies for Alcohol Abuse and Alcoholism

Genetically heterogeneous

population

1st selectedgeneration

2nd selectedgeneration3rd selectedgeneration


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Selective Breeding for Targets Can Lead to Development of Pharmacotherapies for Alcohol Abuse and Alcoholism

Voluntary Alcohol Consumption

Adapted from Phillips et al. (2005) Behav Neurosci 119:892.


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Comparison of Targets Can Lead to Development of Pharmacotherapies for Alcohol Abuse and AlcoholismSyntaxin Binding Protein 1 (Stxbp1) Sequence

Between the C57BL/6J (B6) and DBA/2J (D2) Mouse Strains

Investigated sequence: 1- 1850 bp, coding sequence: 1-1782 bp (594 AA.)

Polymorphism: C57BL/6J: 646:GAT, DBA/2J: 646:AAT

Legend: Pos: position, AA: amino acid, GlycoS: glycosylation site,GORP: secondary structure after

Garnier-Osguthorpe-Robson; AA: D=Asp; A=Ala; Y=Tyr; K=Lys; P=Pro; T=Thr; M=Met.

GORP: H=alpha helix; T=beta turn


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Syntaxin Binding Protein 1 (Stxbp1) Allele Frequency in 4 Generations of Mice Bred for Low and High Alcohol Consumption


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Mapping in Human Populations Generations of Mice Bred for Low and High Alcohol Consumption

  • COGA – Collaborative Study on the Genetics of Alcoholism

  • Multicenter

  • More than 1,000 alcoholic subjects and their families; primary linkage data from ~250 of the most informative families

  • Goal: to determine the location of genes that influence susceptibility for developing alcohol dependence

  • Genome-wide search for genetic relationships with alcohol dependence and other traits


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What Trait(s) Should be Mapped? Generations of Mice Bred for Low and High Alcohol Consumption

  • Alcohol Dependence

  • Co-morbid traits (e.g., depression)

  • Quantitative Measures (maximum number of drinks)

  • Electrophysiological Traits

  • Low Level of Response


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The Serotonin Transporter Generations of Mice Bred for Low and High Alcohol Consumption

  • A candidate gene for low level of response to alcohol?

  • A long allele variant of this gene has been associated with low level of response to alcohol in humans.

  • In rhesus macaques, the long allele was also associated with reduced alcohol sensitivity.

  • A recent meta-analysis (Feinn, Nellissery, Kranzler, 2005, Am J Med Genet B Neuropsychiatr Genet 133:79): 17 studies for alcohol dependence - concluded that this gene does contribute to risk.


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Alcohol intake in Rhesus Monkeys is Correlated with Serotonin Transporter Availability

Spearman's R=0.76, P=0.006

From Heinz et al (2003) Molec Psychiat 8:231.


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Alcohol-Related Traits: Serotonin Transporter AvailabilityWhat Genes Have Been Found from Human Research?

  • γ-aminobutyric acid type A (GABAA) receptor genes.

  • A muscarinic cholinergic receptor gene (CHRM2).


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The GABA Serotonin Transporter AvailabilityA Receptor

  • GABA is a widely-distributed inhibitory chemical in the brain that dampens nerve cell activity.

  • The GABAA receptor is a pentameric molecule that forms a chloride ionophore.

  • Alcohol enhances the effects of GABA by acting at the GABAA receptor.


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GABA Serotonin Transporter AvailabilityA Genes and Alcohol

  • Human Chr 5; Mouse Chr 11:

    GABRA1 (Gabra1), GABRA6 (Gabra6), GABRB2, and GABRG2 (Gabrg2)

  • Human Chr 15: GABRG3

  • Human Chr 4:GABRA2

  • The ones shown in both CAPS and lower case are supported by evidence from both human and mouse studies; but there are negative data too.


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Other Genes Serotonin Transporter Availability

  • Too many to list, and with varying levels of support.

  • Examples:

    CHRM2 – muscarinic cholinergic receptor

    DRD2 – dopamine D2 receptor

    GAL – the neuropeptide, galanin

    OPRM1 – mu opioid receptor

    hTAS2R16 – a taste receptor for bitter substances


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Invertebrate Alcohol Genetics Serotonin Transporter Availability

This inebriometer was developed to measure ethanol-induced loss of postural control in Drosophila melanogaster.

From Singh & Heberlein (2000) Alcohol Clin Exp Res 24:1127.


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Invertebrate Alcohol Genetics Serotonin Transporter Availability

  • Drosophila melanogaster

    cheapdate mutant – increased ethanol sensitivity.

    hangover mutant– reduced ethanol tolerance.

    lush mutant – reduced avoidance of ethanol.

    slowpoke gene – BK channel gene; expression is increased by ethanol and induces ethanol tolerance.

  • Caenorhabditis elegans

    Slo-1 mutant – BK channel gene; decreased sensitivity to ethanol’s effects on movement


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Evolution of Newer Genetic Entities and Methods Serotonin Transporter Availability

  • Micro RNA (miRNA)

  • Short interfering RNA (siRNA)

  • Proteomics

  • Improvements in existing analytic and quantitative methods


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Evolution of Better Genetic Animal Models: Translation Serotonin Transporter Availability

  • More systematic alignment of animal and human data.

  • Concerted efforts to develop new genetic animal models that truly model human alcohol problems.

    – uncontrolled and escalated drinking

    – adolescent to adult transitions

  • Examination of the dynamic nature of addiction, rather than of addiction as a static trait; movement beyond diagnostic categories.