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Genetic Validation in Alcoholism

Genetic Validation in Alcoholism. Ru -Band Lu, MD Professor Department of Psychiatry National Cheng Kung University, Taiwan. Genetic Component and Alcoholism. Family studies ( Merigangas 1990) Twin studies (Pickens et al. 1991) Adoption studies ( Cadoret et al. 1985)

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Genetic Validation in Alcoholism

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  1. Genetic Validation in Alcoholism Ru-Band Lu, MD Professor Department of Psychiatry National Cheng Kung University, Taiwan

  2. Genetic Component and Alcoholism • Family studies (Merigangas 1990) • Twin studies (Pickens et al. 1991) • Adoption studies (Cadoret et al. 1985) • Genetic component in alcoholism–More than 50 % (Reich et al. 1999)

  3. The Importance of Subtypes Alcoholism • Heterogenesis of mental illnesses • Understanding different pathogenesis • Different treatments and prognosis

  4. Alcoholism Subtypes • Jellineck (1960) : 2 subtypes • Morey and Skinner (1986) : 3 subtypes • Lesch (1988): 4 subtypes • Zucker (1987) : 4 subtypes • Cloninger (1987) : 2 subtypes • Babor (1992) : 2 subtypes

  5. Limitations • Lack of cutting point • Different risk factors in different cultures • Inconvenience for clinical use • Lack of genetic validation

  6. Clinical Subtyping of Alcoholism(Huang et al., 2004) • Alcoholic patient often meeting most of the diagnostic criteria (DSM-IV-TR, 2000) • More homogeneous mental illness from the diagnostic criteria perspective. • Higher frequent comorbidity with other mental illnesses

  7. Clinical Subtyping of Alcoholism(Huang et al., 2004) • Pure Alcoholism • Anxiety-Depression Alcoholism • Antisocial Alcoholism • Mixed Alcoholism

  8. Clinical Subtypes of Alcoholism • Pure Alcoholism (Pure ALC) • late onset • without comorbidity with mental illnesses • less alcohol related problems • Anxiety- Depression Alcoholism (ANX/DEP ALC) • early adult onset • comorbid anxiety or depression • heavy alcohol consumption

  9. Clinical Subtypes of Alcoholism • Antisocial Alcoholism (Antisocial ALC) • adolescent onset (very early onset) • comorbid antisocial personality disorder • more alcohol related problems • social consequence • Mixed Alcoholism (Mixed ALC) • comorbid major mental illnesses • comorbid multiple substance disorder • Alcoholism with bipolar disorders among Han Chinese

  10. DRD2 Gene and Alcoholism (Blum et al. 1990) • An important candidate gene of alcoholism • Controversial results or borderline significance (Reich et al., 1999) • No association with non-subtyped alcoholism among Han Chinese population in Taiwan (Lee et al., 1999)

  11. DRD2 Gene and Alcoholism A: Alcoholics; C: Controls; P: Percentage; F: Allele Frequency (Huang et al.,2004)

  12. Genes and Clinical Subtypesof Alcoholism

  13. DRD2 Gene and Subtypes of Alcoholism • Association • Anxiety-Depression Alcoholism (Huang et al., 2004) • No Association • Pure Alcoholism (Huang et al., 2004) • Antisocial Alcoholism and Non-Alcoholism (Lu et al., 2002) • Mixed Alcoholism (data not shown)

  14. DRD2TaqIA and TaqIB Haplotypes Chinese Han Alcohol Dependence in ANX/DEP, and Controls a pvalue of Fisher’s Exact test b p value of linkage disequilibrium in each of the four study groups c Controls vs. Pure ALC vs. ANX/DEP ALC χ2 value=15.788,df=9 d ANX/DEP ALC, anxiety-depressive alcohol dependence ; Pure ALC, pure alcohol dependence; ANX/DEP, anxiety-depressive disorders; p value of the haplotype difference between ANX/DEP (p=0.023, χ2 =8.324,df=3); ANX/DEP ALC vs. pure ALC (p=0.122, χ2 =4.057,df=2) e Controls vs. Pure ALC ; χ2 value=3.155,df=3 f Controls vs. ANX/DEP ALC ; χ2 value=11.834 , df=3 g Controls vs. ANX/DEP ; χ2 value=1.444 , df=3 (Huang et al., 2004)

  15. Haplotype Frequency of the DRD2 TaqI A and TaqI B polymorphisms †p value of Fisher’s Exact test ‡p value of linkage disequilibrium in each of two groups a Antisocial ALC vs. Antisocial Non-ALC vs. Normal Controls, χ2 value= 10.65, df = 6 b Antisocial ALC vs. Normal Controls, χ2 value = 5.74 df = 3 c Antisocial Non-ALC vs. Normal Controls, χ2 value = 5.54 df = 3 § Antisocial ALC, subjects with antisocial personality disorder and alcohol dependence; Antisocial Non-ALC, subjects with antisocial personality disorder but without alcohol dependence (Lu et al., 2002)

  16. MAOA Gene and Subtype Alcoholism • Association • Pure Alcoholism (Huang et al., 2007) • Mixed Alcoholism (Hu et al., 2013) • No Association • Anxiety-Depression Alcoholism (Huang et al., 2007) • Antisocial ALC or Non-Alcoholism (Lu et al., 2003; Wang et al., 2007)

  17. Frequencies of MAOA polymorphisms in Han Chinese men with alcoholism and control subjects MAO A= monoamine oxidase-A; VNTR= variable number of tandem repeats; EcoRV=restriction enzyme rs 1137070; pure ALC= pure alcohol dependence; ANX/DEP ALC= alcohol dependence and anxiety or depression or both. *Control subjects v.s. pure ALC v.s. ANX/DEP ALC; df=3 +Control subjects v.s. pure ALC Control subjects v.s. ANX/DEP ALC (Huang et al., 2007)

  18. MAOA-uVNTR and DRD2 gene interaction for the risk of BP with ALC ALC+BP: alcoholism with bipolar disorder.B, coefficients; CI, confidence interval; OR, odds ratio. Reference groups are: MAOA-uVNTR 4-repeat, DRD2 TaqI A2/A2 genotypes, and controls;covarying for age. ** pb0.05. (Hu et al., 2013)

  19. MAOA Haplotypes for the uVNTR and EcoRVRFLP Polymorphisms in Different Groups ASPD: Antisocial Personality Disorder without meeting the diagnosis of Alcohol Dependence Antisocial ALC: Antisocial Personality Disorder with meeting the diagnosis of Alcohol Dependence ASB: Antisocial Behavior without meeting the diagnosis of ASPD-S-ALC or ASPD-C-ALC MAO A-uVNTR : Variable number of tandem repeat locating at upstream of the MAO A gene 2R, 3R and 4R= 2 repeats, 3 repeats and 4 repeats (+) and (-) = Presence and absence of restriction sites for EcoRV (Wang et al., 2007)

  20. ADH1B , ALDH2 Gene and Subtypes of Alcoholism ADH1B*2and/or ALDH2*2 Allele • Protection • Pure, Anxiety-Depression, Mixed (data not shown) and Antisocial NON-Alcoholism (Lu et al., 2005; 2012) • No protection • Antisocial Alcoholism (Lu et al., 2005; 2012)

  21. ADH1B for the Risk of Antisocial Alcoholics aCoding of ADH1B genotypes are *1/*1 and *1/ *2=0, *2/ *2=1;referencegroup is ADH1B *1/ *1 and *1/ *2. (Lu et al., 2005;2012)

  22. Logistic regression of ALDH2 and DRD2 genes for ASPD, antisocial ALC and non ALC (Lu et al., 2005;2012) aAntisocial Participants (Antisocial ALC and Antisocial Non-ALC) vs. Healthy Controls. b Antisocial ALC vs. Healthy Controls. c Antisocial Non-ALC vs. Healthy Controls; A1+ (*A1/*A1 or*A1/*A2) Reference category: normal control, DRD2 A2A2 genotype, ALDH2*1*2+*2*2 genotype.

  23. SpecificMeanings • A candidate gene reported for many times, still controversial; this gene still the pathogenesis of the subtype mental illness • The commonly reason (Parsian et al., 1991) • phenotypic heterogeneity • different definitions of control groups • different racially or ethnically mixed study populations • DRD2 gene a pathogenesis of ANX/DEP alcoholism

  24. Specific Meanings • The ALDH2*1 risk drinking and un-subtype alcoholism (Chen et al. 1999) • 50% of Han Chinese belonging ALDH2*1/*1 but nearly 100% in Western populations (Agarwal and Goedde, 1992) • ASPD only 0.1 - 0.3% in Han Chinese (Hwu et al. 1988),but 3.3% among Caucasian Americans (Goodwin & Hamilton 2003)

  25. SpecificMeanings • 70% ASPD with alcoholism higher than 15-20% alcoholism from community in Western population (Goodwin & Hamilton 2003) • 6% ASPD with alcoholism (from jail) higher than1.5-3%alcoholism from community in Han Chinese (Hwu et al. 1988; Lu et al., 2013) • ASPD demonstration higher prevalence rate of alcoholism than general population in Han Chinese and Western populations • Alcoholism one of the symptoms of ASPD?

  26. SpecificMeanings • A Dutch family with a MAOA deficiency in exon 8, male demonstration severe aggressive behavior and borderline mental retardation (Brunner et al., 1993) • Difference genotype frequencies in exons 8 and 14 of MAOA genes Higher ASPD with alcoholism than controls (Parsian., 1999) • MAOA 3-repeat & early childhood maltreatment development higher antisocial behavior in adult male (Capri., 2002)

  27. SpecificMeanings • Aggressive and/or antisocial behavior, the major symptoms of ASPD, but not the diagnosis of ASPD • Probable reasons for the positive or negative finding of ASPD lack of antisocial non-alcoholism as a controls(Lu et al., 2005; 2012)

  28. The Roles of MAO, ADH and ALDH in Dopamine Catabolism

  29. Dopamine Metabolism DOPET ARs ADH DOPAL DOPET: 3,4-dihydroxyphenylethanol ARs : aldose (aldehyde) reductase DOPAL:3,4-dihydroxyphenylacetaldehyde COMT:catechol-O-methyltransferase (Feldman et al., 1997)

  30. Gene to Gene and Clinical Subtypes of Alcoholism

  31. ALDH2andMAOA Gene • Association • MAOA-uVNTR 3-repeat and ALDH2 gene • Antisocial Alcoholism • Antisocial Non-Alcoholism • ALDH2 x MAOA in ANX/DEP, Antisocial & Mixed alcoholism (Lee et al., 2009; 2010; Hu et al., 2013)

  32. Antisocial ALC and Non-ALC after Stratification for MAOA-uVNTR polymorphisms Breslow-Day Homogeneity test of odds ratio: χ2=3.772, df=1, p=0.052 (Lee et al., 2009)

  33. Logistic regression of interaction for MAOA and ALDH2 gene and the risk of ANX/DEP ALC B, coefficients; SE, standard errors; p<0.05 is considered significant Reference group: normal control, MAOA-uVNTR 3 allele, ALDH2 *1*1 genotype aMAOA-uVNTR 4-repeat to 3-repeat allele bALDH2 *1*2+*2*2 to *1*1 genotype DRD2 xMAOA x ALDH2 gene in ANX/DEP Alcoholism (Lee et al., 2010)

  34. Logistic regression analysis of MAOA gene and ALDH2 gene and their interaction for the risk of Antisocial ALC a. The reference category is: Antisocial Non ALC, MAOA 4-repeat, ALDH2*1/*2+*2/*2 (Lee et al., 2009)

  35. MAOA-uVNTR and DRD2 gene interaction for the risk of (bipolar disorder) BP with ALC ALC+BP: alcoholism with bipolar disorder.B, coefficients; CI, confidence interval; OR, odds ratio. Reference groups are: MAOA-uVNTR 4-repeat, DRD2 TaqI A2/A2 genotypes, and controls;covarying for age.. (Hu et al., 2013)

  36. ALDH2andDRD2 Gene Interaction • Association • ALDH2*1/*1, DRD2 A1/A1genotypes and ANX/DEP Antisocial Non-Alcoholism and ASPD (Huang et al.,2004; Lu et el.,2012) • ALDH2 * DRD2 genein ASPD and Antisocial Non-Alcoholism (Lu et el., 2012) • No Association • ALDH2 &DRD2 gene and Pure (Huang et el., 2004) • Mixed Alcoholism (data not shown)

  37. Multiple Logistic Regression Analysis of the DRD2 TaqI Afor Risk of Alcohol Dependence with Stratification of ALDH2 genotypes The genotype of ALDH2* 2/* 2 was not found in the alcohol-dependence subjects. Reference group is DRD2 A2/A2. Model 1:Neither controlling for age, gender nor stratification of ADH1B and Model2:Stratification of ADH1B and controlling for gender and age. Model 3:Stratification of ALDH2 and controlling for gender and age. (Huang et al., 2004)

  38. DRD2TaqI A in Han Chinese Subjects after Stratification for ALDH2 polymorphisms (Lu et al., 2010; 2011)

  39. Logistic regression of ALDH2 and DRD2 genes for ASPD, antisocial ALC and non ALC aAntisocial Participants (Antisocial ALC and Antisocial Non-ALC) vs. Healthy Controls. b Antisocial ALC vs. Healthy Controls. c Antisocial Non-ALC vs. Healthy Controls; A1+ (*A1/*A1 or*A1/*A2) Reference category: normal control, DRD2 A2A2genotype, ALDH2*1*2+*2*2 genotype. (Lu et al., 2010; 2011)

  40. Specific Meanings • Stratification of ALDH2*1/*1, DRD2gene ASPD and ANX/DEP ALC (Lu et al., 2012). • 54.3% ASPD with anxiety disorder in western population • Positive correlation with ASPD and anxiety disorder. (Goodwin & Hamilton., 2003) • Anxiety disorders and ASPD associated with higher odds of alcohol use disorder (Goodwin and Hamilton, 2003)

  41. Specific Meanings • ALDH2 * DRD2 gene and BP (Lee et al., 2010) • 70-90% BP with anxiety disorder in Western, 20-40% in Han Chinese populations (Chang et al., 2012). • 50% of Han Chinese belonging ALDH2*1/*1 but nearly 100% in Western populations(Agarwal and Goedde, 1992) • ALDH2gene relation to alcoholism, ASPD, anxiety disorder & bipolar disorder.

  42. In Summary • DRD2 Association • ANX/DEP Alcoholism • MAOA Association • Pure and Mixed Alcoholism • ALDH2 Association • Pure, ANX/DEP Alcoholism and Antisocial non-alcoholism • ADH1B and ALDH2 Association • Pure, ANX/DEP and Mixed Alcoholism

  43. In Summary • ALDH2*1/*1, DRD2 A1 /A1 • Anxiety-Depression Alcoholism • ASPD and Antisocial Non-ALC • MAOA 3-repeat ,ALDH2 Association • Antisocial Alcoholism • MAOA X ALDH2 Association • Anxiety-Depression Alcoholism • Antisocial Alcoholism • Mixed Alcoholism • ALDH2 X DRD2 Association • ASPD and Antisocial Non-ALC

  44. OngoingStudies • Preliminary studies of low dose (5mg) of memantine : (6 M ) • Pure and anxiety-depression alcoholism 1/3 completing discontinue drinking; 1/3 markedly reduced drinking; 1/3 poor response • Antisocial and Mixed Alcoholism (bipolar alcoholism) Poorer response than pure and anxiety-depression alcoholism

  45. Comments • Possible mechanism of mematine effect • Inhibition NADPH in microglial and stimulation neurotrophic factors (BDNF etc.) in astroglial cells • Plasma level of memantine (5mg/day): 10-50 ng/ml (mean 16 ng/ml). No effect in NMDA receptor (required > 86.3 – 431.5 ng/ml)(Parsons et al., 1999)

  46. Conclusion • More studies about MAO,ADH1B , ALDH2 and dopamine/5-HT related genes in different ethnics of major mental illnesses • The lower prevalence of a disease, the higher statistic meaning for a fixed number of trait loci (Rice et al., 2001) • Han Chinese populations playing a specific contribution to the molecular genetic studies of alcoholism (Lu et al., 1999) • Inflammatory press & neurodegenoration involving alcoholism & substance use disorders. • Alcoholism: An important role in substance use disorder and addiction behavior

  47. Acknowledgements • Professor Kenneth K. Kidd, Ph. D. • Professor Ting-Kai Li, Ph. D. • Research Scientist Judy R. Kidd, Ph.D • Professor Jean-Shih Chen, Ph. D • Research Scientist Andrew J. Pakstis, Ph. D. • Professor Shin-Jiun Yin, Ph. D. • Professor Huei-Chen Ko, Ph. D • Associate Professor San-Yuan Huang, M.D., Ph. D. • Associate Professor Yaun-Hwa Chou, M.D., Ph. D. • Assistant Professor Wei-Wen Lin, M.D., Ph. D. • Assistant Professor Jia-Fu Lee, M.D., Ph. D.

  48. Acknowledgements • Assistant Professor Yi-Chyan Chen, M.D., Ph. D. • Assistant Professor Michael V. Osier, Ph. D. • Assistant Professor Tso-Jen Wang, M.D., Ph. D. • Hsin-Yi, Lo M.D., Ph. D. student • Cheng-Yi Hahn, M.D., M.S., Ph. D. student • Sheng-Yu Lee, M.D., M.S. • Ms. Ju-Ping Weng, M.S. • Ms. Yi-Syuan Wu, M.S. • Ms. Pei-Ling Wu, M.S. • Mr. Tsun-En Lu, M.S. • Ms. Yu-Shan Wang.

  49. THANK YOU FOR YOUR ATTENTION

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