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Genetic Association Study Principles:

Genetic Association Study Principles:. Andrew C. Heath. UNUSUAL EXAMPLE: Asian Studies of Japanese Alcoholics and Community Controls.

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Genetic Association Study Principles:

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  1. Genetic Association Study Principles: Andrew C. Heath

  2. 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)

  3. Case-Control Study • Usually the most powerful design, but need to address possible ‘population stratification’ effects

  4. ALCOHOL METABOLISM Alcohol Dehydrogenase (ADH) Aldehyde Dehydrogenase (ALDH) ALCOHOL ACETALDEHYDE ACETATE

  5. Higuchi Data -- Japanese Alcoholics and Controls: ALDH2 locus Controls Alcoholics (N=461) (N=655) Locus Genotype (%) (%) ALDH2 *1 / *1 58 88 *1 / *2 35 12 *2 / *2 7 0 p < .001 (Higuchi, 1994)

  6. Higuchi -- Changes in ALDH2*1/*2 Frequency in Japanese Alcoholics 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 (Higuchi, 1994)

  7. Higuchi Data -- Japanese Alcoholics and 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% 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.

  8. Higuchi Data -- Genetic effects on alcohol consumption levels in a community sample Average monthly alcohol consumption (ml pure alcohol) Genotype MENWOMEN 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)

  9. Conclusion: there are genes with powerful effects on behavioral traits waiting to be discovered!

  10. FREQUENCIES OF GENES INFLUENCING ALCOHOL METABOLISM High Risk Japanese European Locus Allele AncestryAncestry 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.

  11. Table 2. Lifetime DSM-III-R Alcohol Dependence by ADH1B (“ADH2”) Type: Australian twin panel Whitfield et al., 1998

  12. But how do we know this is THE gene?

  13. 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

  14. 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%).

  15. POPULATION STRATIFICATION Hypothetical Example SWEDISH ANCESTRY (N=200) IRISH ANCESTRY (N=200) NOT ROMAN CATHOLIC ROMAN CATHOLIC NOT ROMAN CATHOLIC ROMAN CATHOLIC 35 15 25% 105 45 75% 70% 30% 162 18 90% 18 2 10% 90% 10% NOT A1 allele A1 allele NO ASSOCIATION NO ASSOCIATION MINGLED IN U.S. POPULATION (N=400) NOT ROMAN CATHOLIC ROMAN CATHOLIC NOT A1 allele A1 allele 197 33 123 47 OR = 2.28, 95%CI 1.39 - 3.73 Falsely infer that A1 allele is risk-factor for Roman Catholicism.

  16. 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)

  17. POPULATION STRATIFICATION - SOLUTION 2 TRANSMISSION DISEQUILIBRIUM TEST 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.

  18. TRANSMISSION DISEQUILIBRIUM TEST CONSISTENT WITH PREDICTION AGAINST PREDICTION MOTHER ADH2*1 / *2 FATHER ADH2*1 / *1 MOTHER ADH2*1 / *2 FATHER ADH2*1 / *1 ADH2*1 / *1 ALCOHOLIC ADH2*2 / *1 ALCOHOLIC

  19. TRANSMISSION-DISEQUILIBRIUM TEST: A Medical Genetic Example Ataxia-Telangiecstasia (AT) in Costa Rica Allele 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 2 = 92.91, highly significant by permutation test (Lange, 1997)

  20. Population stratification: solution 3: Genomic Control methods

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