genetic association study principles:
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Genetic Association Study Principles:. Andrew C. Heath. UNUSUAL EXAMPLE: Asian Studies of Japanese Alcoholics and Community Controls. - PowerPoint PPT PresentationTRANSCRIPT
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Genetic Association Study Principles:
Andrew C. Heath
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UNUSUAL EXAMPLE:
Asian Studies of Japanese
Alcoholics and Community Controls
Work by Higuchi, Murumatsu and colleagues is documenting ways in
which genes that influence alcohol metabolism may be associated
with differences in alcohol dependence risk or alcohol
consumption levels.
(Higuchi et al., 1994,
Lancet)
(Murumatsu et al., 1996)
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Case-Control Study
• Usually the most powerful design, but need to address possible ‘population stratification’ effects
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ALCOHOL METABOLISM
ALCOHOL ACETALDEHYDE ACETATE
AlcoholDehydrogenase
(ADH)
AldehydeDehydrogenase
(ALDH)
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Higuchi Data -- Japanese Alcoholics
and Controls: ALDH2 locus
(Higuchi, 1994)
Controls Alcoholics
(N=461) (N=655)
Locus Genotype (%) (%)
ALDH2 *1 / *1 58 88
*1 / *2 35 12
*2 / *2 7 0p < .001
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Higuchi -- Changes in ALDH2*1/*2
Frequency in Japanese Alcoholics
(Higuchi, 1994)
1979 1986 1992
(N=400) (N=400) (N=500)
ALDH2 *2 / *2 0.0 0.0 0.0
*1 / *2 2.5 8.0*** 13.0**
*1 / *1 97.5 92.0 87.0
i.e. protective effect of a single *2 allele is being diminished
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From Higuchi’s community data, in individuals who are also
ALDH2*1/*1 homozygotes, we may estimate the penetrance of the
AHD1B*2/*2 genotype (the low risk genotype) as ~0.07, that of the high
risk ADH1B*1/*1 genotype as ~0.29.
Higuchi Data -- Japanese Alcoholicsand Controls: ADH1B locus
(in those who are ALDH2*1/*1 homozygotes)Population
Controls Alcoholics
ADH1B *2 / *2 58.1% 35.8%
*2 / *1 34.7% 33.7%
*1 / *1 7.3% 30.4%
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Higuchi Data -- Genetic effects on alcoholconsumption levels in a community sample
Average monthly alcohol consumption(ml pure alcohol)
Genotype MEN WOMEN
ALDH2*1/*1 1054.7 104.9
ALDH2*1/*2 390.9 46.6
ALDH2*2/*2 94.1 3.3
From other data, we can estimate that approximately one-third of the
variance in alcohol consumption levels in Japanese males is explained by
this genetic locus. (Higuchi et al., 1996b)
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• Conclusion: there are genes with powerful effects on behavioral traits waiting to be discovered!
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FREQUENCIES OF GENES INFLUENCINGALCOHOL METABOLISM
High Risk Japanese EuropeanLocus Allele Ancestry Ancestry
ALDH2 ALDH2*1 76% 100%
ADH1B ADH1B*1 25% 95%
ADH1C ADH1C*2 6% 45%
NOTE: Predicted magnitude of effects is ALDH2*1 >> ADH1B*1 >>
ADH1C*2.
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Table 2. Lifetime DSM-III-R Alcohol Dependenceby ADH1B (“ADH2”)
Type: Australian twin panel
ADH2*11 ADH2*12
Male affected 36 1
Male unaffected 101 18
Female affected 24 3
Female unaffected 144 7
Whitfield et al., 1998
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But how do we know this is THE gene?
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• See Kidd paper (Osier et al., Am J Hum Genet 71:84-99, 2002)
• ADH1B “2” allele is occurring on different haplotypes:
- East Asian (also ADH1C “1” allele);
- Middle Eastern, Ethiopian (also ADH1C “1” allele), rare in N. American European Ancestry (< 5% haplotype frequency).
Population Genetics of ADH gene region
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Population Genetics of ADH gene region (II)
• ADH1B “3” allele is mainly seen in African American, sub-saharan African populations, but at low frequency (6/1000) in N. Americans of European ancestry
• ADH1C “2” allele in European ancestry cases occurs on two different haplotypes, the higher frequency haplotype (30%) being rare in East Asians (< 2%), the other occurring at a lower frequency in Europeans (7-15%) except Finns (30%) and seen at slightly higher rate in East Asians (3-10%).
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POPULATION STRATIFICATIONHypothetical Example
Falsely infer that A1 allele is risk-factor for Roman Catholicism.
OR = 2.28, 95%CI 1.39 - 3.73
NO ASSOCIATION NO ASSOCIATION
SWEDISH ANCESTRY (N=200) IRISH ANCESTRY (N=200)
NOT A1 alleleA1 allele
NOTROMAN
CATHOLICROMAN
CATHOLIC
NOTROMAN
CATHOLICROMAN
CATHOLIC
16218
90%
182
10%
3515
25%
10545
75%
70%
30%
90%
10%
NOTROMAN
CATHOLICROMAN
CATHOLIC
19733
12347
NOT A1 alleleA1 allele
MINGLED IN U.S. POPULATION (N=400)
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HOW DO WE HANDLE
POPULATION STRATIFICATION?
SOLUTION 1: Make comparisons within (full) sibships, i.e. of
siblings who share the same biological mother and father
( same ancestry).
5 DZ twin pairs where one twin was ADH2*1/*1
second twin was ADH2*1/*2
In all 5 pairs, *1/*1 had higher consumption (p = .03)
(Whitfield et al., 1998)
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POPULATION STRATIFICATION -
SOLUTION 2
Genetic marker data collected on affected (e.g. alcohol dependent)
individuals and both their biologic parents.
For heterozygous parents, compare frequency of transmitted allele
(i.e. passed from a parent to the affected individual) and non-
transmitted allele.
TRANSMISSION DISEQUILIBRIUM TEST
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TRANSMISSION DISEQUILIBRIUM TEST
CONSISTENT WITHPREDICTION
AGAINSTPREDICTION
MOTHER
ADH2*1 / *2
FATHER
ADH2*1 / *1
MOTHER
ADH2*1 / *2
FATHER
ADH2*1 / *1
ADH2*1 / *1
ALCOHOLIC
ADH2*2 / *1
ALCOHOLIC
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TRANSMISSION-DISEQUILIBRIUM TEST:
A Medical Genetic Example
2 = 92.91, highly significant by permutation test
Ataxia-Telangiecstasia (AT) in Costa Rica
(Lange, 1997)
Transmission
Pattern 1 3 4 5 7 8 10 11 20 21
Transmitted 3 0 22 0 1 0 0 0 0 2
Not Transmitted 0 4 0 4 3 4 1 1 2 9
Allele
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Population stratification: solution 3: Genomic Control methods