Download - Genetics of Alcoholism Part II
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Genetics of Alcoholism
Part II
Ian GizerUniversity of Missouri-Columbia
Columbia, MO, [email protected]
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Definitions• Chromosomes – threadlike
structures on which individual genes are located
Karyotype of normalhuman male
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• Locus (location) and allele (alternative form)
• Centromere, short (p) and long (q) arms
Chromosome #9
ABO locus
p
q
Centromere
(9q34.1)
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Definitions• Chromatin: genetic material
contained in chromosomes – DNA & proteins (histones and nonhistones)
• Euchromatin – less condensed/light bands; coding DNA
• Heterochromatin – compacted/dark bands, usually noncoding DNA
Chr 21
UM Bauer
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Definitions• DNA: Deoxy ribonucleic acid• Purine and pyrimidine bases• Purines: Cytosine, Thymine• Pyrimidines: Adenine,
Guanine • Double stranded (each strand
has full information content)• Strands are held together by
(hydrogen) bonds that form between the nucleotide bases of the DNA molecule
Adenine (A) <====> Thymine (T)
Guanine (G) <====> Cytosine (C)
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Definitions• Gene: A sequence of DNA (a locus
on a chromosome) that is involved in (“codes for”) the synthesis of a functional polypeptide (proteins consist of one or more polypeptides, which are strings of amino acids).
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Gene Structure
EXON – EX-pressed or coding DNA that is converted into proteinINTRON – IN-active or noncoding DNA that is not converted to protein
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Definitions• Transcription: One of the two DNA
strands is transcribed to a single-stranded nucleic acid called ribonucleic acid (RNA) RNA has the same bases as DNA except uracil (U) substitutes for thymine (T).
• Translation: Conversion of the basic informational unit of 3 nucleotide bases (called a codon) into a single amino acid.
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Example
TTT TCCAAA AGG
UUU UCC
Transcription
Phenylalanine Serine
Translation
Non-transcribed DNA strand
Transcribed DNA strand
mRNA
Amino Acid
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Genetic Variation• 95% - 98% of human DNA does not
code directly for protein. • An estimated 99.8% - 99.9% of our
DNA is common.• But then .1% of 3,000,000,000 = 3
million differences!• We are interested in these
variations and the transmission and co-aggregation of these variations with AUDs.
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Two major types• Microsatellite/short tandem repeat
(STR): a stretch of DNA that is sequentially repeated a variable number of times. • Can cause disease (e.g.
CAG repeat expansion causes Huntington’s disease;
• Can also be benign variation;
• Assume it is close to a disease contributing gene;
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Single Nucleotide Polymorphism
• SNPs are single base pair changes that occur as natural variation in the human genome. They can code for protein change (non-synonymous) or not.
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Two major methods for identifying genes associated
with AUDs
• Linkage
• Association
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Linkage Analysis
AA (BB) Aa (Bb)
AA (BB) AA (BB) AA (BB)Aa (Bb)
Aa (Bb) Aa (Bb) AA (BB)AA (BB)
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LINKAGE• Basic idea is identity-by-descent
(IBD) or how often does an affected pair of relatives share the same ancestral DNA. If more often than expected by chance, then somewhere near this shared DNA is a gene that contributes to affection status.
• Need related individuals where multiple relatives are affected.
• Identifies large stretches of DNA.
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Linkage Analysis: The BasicsIBD – An Illustration
A. One allele IBS and one allele IBD.B. One allele IBS and zero alleles IBD.
C. Two alleles IBS and at least one allele IBD.
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IBD Sharing in pairs affected for disorder
Sib 1
Sib 2
4/16 = 1/4 sibs share BOTH parental alleles IBD = 2
8/16 = 1/2 sibs share ONE parental allele IBD = 1
4/16 = 1/4 sibs share NO parental alleles IBD = 0
AC AD BC BD
AC
BCBD
AD
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A/B C/D
AC AD BC BDAC 2 1 1 0AD 1 2 0 1BC 1 0 2 1BD 0 1 1 2
Sib 1 Sib 2
Sib 1
Sib
2
H(0): IBD (0) = 25%; IBD (1) = 50%; IBD (2) = 25%H(A): IBD (0) < 25%; IBD (1) > 50%; IBD (2) > 25%H(A) is evidence for linkage.
LINKAGE via IBD
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Linkage studies of AUDs• Most prominent is Collaborative
Study of the Genetics of Alcoholism (COGA).
• Has identified many important genetic regions using STRs and SNPs.
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COGA strategy
0
0.5
1
1.5
2
2.5
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160cM
Lod
Sco
res
Wave 1
Wave 2
Combined
1. Ascertain multiplex alcoholic families
2. Linkage analyses to identify chromosomal regions
3. Association analyses to identify specific genes
allele-sharing among affecteds within a family
Gene A Gene B Gene C
Polydiagnostic interviewElectrophysiological data262 Families, 2282 individuals
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LOD score
Williams et al., 1999
LOD = Likelihood of Odds;
LOD of 3.0 means it is 1000 times more likely than expected by chance that there is linkage.
Log101000 = 3
Higher the LOD, more likely genes are nearby
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Irish affected sib pair study
Prescott et al., 2006
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Problems with Linkage• Methodological
problems;• Need BIG sets
of families;• Home in on a
big chunk of DNA – possibility of hundreds of genes!!!
1 cM (centiMorgan) is approximately equal to 1 Megabase or 1000000 bp!!!!Genes may be anywhere in the 50cM region
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Cardon & Bell, 2001 Nat Rev Genet
Association Analysis
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Association• Family Based(transmission
disequilibrium test)
• How often is the risk allele transmitted to an affected child from a parent who is heterozygous (A/a) for the SNP?
A/a a/a A/a aa a/a A/a
A/a A/a a/a A/a
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Association• Case/Control Design
• Is the prevalence of the risk allele greater in affected versus unaffected people?
a/a a/a
A/a a/a
A/a A/a
A/a A/a
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Which Genes should I look at?
1. Genes in a linkage region
2. Genes that metabolize alcohol (candidates)
3. All genes
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Genes in the linkage region
GABRA2: gamma-amino butyric acid receptor A, subunit 2 gene
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• GABA & Alcohol (Buck, 1996; Grobin et al., 1998) – motor incoordination– anxiolytic effects – sedation– ethanol preference– withdrawal signs– tolerance & dependence
• GABAA receptor agonists tend to potentiate the behavioral effects of alcohol, while GABAA receptor antagonists attenuate these effects
GABAmajor inhibitory neurotransmitter of the central nervous
system
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GABRA2 and AUDs
Edenberg et al., 2004
Region contains:• GABRG1• GABRA2• GABRA4• GABRB1
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Many replications…• Many studies now show an
association between SNPs in GABRA2 and AUDs.
• SNPs are also associated with drug dependence, nicotine dependence, conduct problems and antisocial personality disorder – likely to be general vulnerability to thrill seeking.
• Replicated in family-based and case-control studies.
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Genes that metabolize alcohol
-1
-0.5
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0 50 100 150 200
chromosome 4 position (cM)
LOD
Symptom CountAlcohol Dependence
ADH cluster (1a,1b,1c,4,5,6,7)
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Flushing Response• Dysphoric effects that occur w/i 15
minutes of drinking:– Heart palpitation– Facial reddening– Nausea, dizziness
• There are large ethnic group differences in rate of flushing – metabolic not cultural
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Pathway of Alcohol Metabolism
Alcohol Acetaldehyde Acetate
ADH ALDH
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ALDH2 Deficiency• ADH1B*2, ADH1C*1 code for
protein subunits that have greater enzymatic activity, suggesting faster conversion to acetaldehyde
• ALDH2*2 – inactive enzyme, can’t break down acetaldehyde– Causes facial flushing, nausea
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ADH1B(2)*2 faster to acetaldehydeADH1C(3)*1 faster to acetaldehydeALDH2*2 slower breakdown acetaldehyde
PROTECTIVE EFFECTS
ADH2*2 less common in alcoholics
ADH3*1 less common in alcoholics
ALDH2*2 less common in alcoholics
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Wall et al. (2001)
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Wall et al. (2001)
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Edenberg et al., 2006
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MacGregor et al., 2009
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0
1
2
3-Log
10p
ADH5 ADH4 ADH6 ADH1A
ADH1B
ADH1C ADH7
Alcohol Dependence
Withdrawal
Severity
rs3762894
rs2066702
Gizer et al., 2011
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Examine ALL genes• Called GWAS: Genomewide
association study;• Saturate the genome with a million
SNPs and then test association with each SNP.
• Maybe find something new!
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Treutlin et al., 2009
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Bierut et al., 2010
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Problems with association studies
1. Population stratification (only when using unrelateds) –when an association between a SNP and AUDs is due to ethnic variation in that SNP.
2. P-values need to be adjusted for testing many markers (e.g. 0.05/#markers tested).
3. Replication in other samples.4. What does the gene/SNP do in the
etiology of AUDs?
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ENDOPHENOTYPES• Inherited mediators;• Associated with, but not a
consequence of, alcoholism; • Transmitted in families of alcoholics;• Present when disorder is not in active
phase;• Heritable;
• Examples: EEG, P300, Subjective response to alcohol.
Irv Gottesman
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Why study EEG for AUDs?• EEG (Electro-encephal0grams) of waves
suggest that certain EEG activity is associated with risk for AUDs;
• EEG is heritable;• In families with AUDs, unaffected
relatives of AUD individuals have distinct EEG patterns;
• EEG pattern is not modified when an individual goes into recovery;
• EEG is an ENDOPHENOTYPE for AUDs
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EEG readings
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EEG Waves• Alpha waves : major rhythm seen in normal
relaxed adults - it is present during most of life especially beyond the thirteenth year when it dominates the resting tracing.
• Beta activity : dominant rhythm in patients who are alert or anxious or who have their eyes open.
• Theta activity abnormal in awake adults but is perfectly normal in children upto 13 years and in sleep.
• Delta activity : quite normal and is the dominant rhythm in infants up to one year and in stages 3 and 4 of sleep.
Ref: http://www.brown.edu/Departments/Clinical_Neurosciences/louis/eegfreq.html
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EEG HeritabilitiesDelta (1.5-3.5 Hz) 76%Theta (4-7.5 Hz) 89%Alpha (8-12.5 Hz) 89%Beta (13-25 Hz) 86%
Van Beijsterveldt et al., 1996
Frequency band
Mean h2
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Increased BETA Log Power in Alcoholics (F3-C3)
-0.05
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
BETA1 BETA2 BETA3p-values : 0.004 0.007 0.004
log
pow
er
CONTROL (n= 257) ALCOHOLICS (n=271)
Rangaswamy et al., 2002
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*Significant for all beta bands, particularly Beta 1 for males, and Beta 2 and Beta 3 for femalesHR=high risk; LR=low risk
Increased BETA Power in offspring of alcoholics
Rangaswamy et al., 2004
Beta 1 Beta 2 Beta 3
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P300• Event-related potential (ERP)• P300 /oddball task• Subject attends to rarer of two cues• Rarer the event = larger the
amplitude• Reflects context/memory updating
whereby current model of environment is updated with incoming info.
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Rangaswamy & Porjesz: P300 amplitude is reduced in alcoholics
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Carlson et al., 2004
Discordant stable: One twin has AUD, other does not;Newly discordant: One twin develops AUD, other does not;
20
25
30
Discordant stable Newly Discordant Unaffected
P300
am
plitu
de
Alc
No Alc
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Heritable across all levels of alcohol use
Perlman et al., 2009
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Sensitivity to Alcohol: SRE• Self-
rating of the effects of alcohol (Schuckit et al, 1997)
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Twin Study (Heath, et al.1999)
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Behavioral Sensitivity(Schuckit, 1984)
Family historypositive
Family historynegative
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Schuckit et al., 1994
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Problems with Endophenotypes
• Not specific (e.g. P300 amplitude reduction is also associated with schizophrenia);
• Links between endophenotype and phenotype maybe unknown;
• Underlying genetic architecture may not be any less complex;
• Requires special equipment/lab and subject consent;
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Genetic Strategies with Animals
• Forward Genetic Approaches (phenotype-driven)– Inbred strains– Selectively bred strains– Mutagenesis
• Reverse Genetic Approaches (genotype-driven)– Transgenics– Knockouts
QTL mapping
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Importance of the Mouse Genome
• Mouse genome (Nature, December 5, 2002):– 2.5Gb– ~27,000 – 30,500 genes
• Relationship to human genome:– ~99% of mouse genes have counterparts
(orthologs) in human– ~96% of human genes have orthologs in
mouse– Conservation of some non-coding regions– Synteny – stretches of DNA that are the same
in mouse and human
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Alcohol Preference• % of times in 14-day period animal
selects 10% ethanol solution vs. tap water (both a sweetened with saccharin)
• Marked differences between strains, 0-80%
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Selection for Alcohol Preference
Li et al., 1993
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Sleep Time: Loss of Righting Reflex (LORR)
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Markel et al., 1997
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Behavioral Examples –NPY
(Theile et al. Nature, 1998)
• Neurotransmitter known to be a potent stimulator of appetite
• Relevance to alcohol:– QTL studies of rat preference map to NPY
region– Inbred strain comparisons
• Knock-out (loss-of-function) – increased ETOH consumption & decreased sleep time
• Transgenic (gain-of-function) – decreased consumption and increased sleep time
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Why we are not animals…• Animals self administer alcohol and
drugs – so do we – but, often, there is a social context for alcohol use in humans.
• The motivational model of alcohol use is strongly linked to continued drinking.
• Environmental modified.• Rather complex to study in animals.
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Drinking motives (Cooper et al.)• Drinking motives (How often do you drink to …?)
stem from a motivational model of alcohol use – we drink to achieve a certain socio-cognitive outcome (e.g. drink to reduce stress and/or drink to fit in with friends);
• Motives have both valence (positive/negative) and source (internal/external).
• Motives are moderately heritable (Prescott et al., 2004; Agrawal et al., 2008).
• They share genetic influences with alcohol consumption (Prescott et al., 2004) – they moderate the genetic links between personality and alcohol consumption (Littlefield et al., in prep).
M. Lynne CooperAndrew Littlefield
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Why do we DRINK?
Kuntsche et al., 2005, Clin Psych Rev
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WHY DO WE DRINK?• Coping motives
– How often do you drink to forget your worries?
• Enhancement Motives– How often do you drink because you
like the feeling?• Social Motives
– How often do you drink to be sociable?• Conformity Motives
– How often do you drink so you won’t be left out?
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Prescott et al., 2004
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PART II• Genetic regions have been identified
for alcoholism: chromosomes 2,4,5,7• Genes: GABRA2, ADH cluster• GWAS largely unsuccessful• Endophenotypes replicate results
with AUDs but tend to be generalizable to externalizing behaviors.
• Animal studies lack context of drinking.
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What next for the genetics of alcoholism?
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