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Alcoholism: From Genotypes to Genes (and Back Again)

Alcoholism: From Genotypes to Genes (and Back Again). Carol A. Prescott, Ph.D. University of Southern California cprescot@usc.edu. Overview. Definitions Epidemiology Consequences Genetic Epidemiology Search for Susceptibility Genes. DSM-IV Criteria for Alcohol Dependence.

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Alcoholism: From Genotypes to Genes (and Back Again)

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  1. Alcoholism: From Genotypes to Genes (and Back Again) Carol A. Prescott, Ph.D. University of Southern California cprescot@usc.edu

  2. Overview • Definitions • Epidemiology • Consequences • Genetic Epidemiology • Search for Susceptibility Genes

  3. DSM-IV Criteria for Alcohol Dependence 3 or more of the following, lasting >1 month: withdrawal or drinking to avoid withdrawal tolerance inability to quit despite wanting to loss of control once start drinking continued use despite medical consequences drinking interferes with functioning time spent drinking to exclusion of important life activities

  4. Epidemiology of Alcohol Dependence Lifetime prevalences (among drinkers): Males: 8 -12% Females: 3 - 4% 1-yr prevalence in EU (Wittchen & Jacobi, 2005): Males: 5.6% Females: 1.3% ~ 7.2 Million

  5. Consequences of Alcoholism Formal Treatment: only ~10% of affected Success rate ~30% Personal Costs Impaired functioning Accidents, Health problems Societal Costs (billions annually) Important comorbidity: tobacco, depression (in top 10 of DALYs)

  6. A Growing Problem Finland: 50% of males aged 30-49 binge >1x/mo (WHO, 1993) Russia: 500K deaths annually (Lancet 2006) Poland: Sharp increase in alcohol-related mortality since mid-1980s (Wojtyniak et al 2005) UK: 31% increase in per capita consumption between 1980 and 2000 (Hall, 2005)

  7. Consequences of Moderate Alcohol Use Personal Benefits - stress reduction - cardioprotection - social lubrication Societal Benefits - tax revenue - employment

  8. Genetic Epidemiology • Adoption studies Rates of alcoholism higher in adopted offspring of alcoholic biological parents than non-alcoholic biological parents

  9. Risk of alcoholism among adoptees with and without biological alcoholic parents Studies of male adoptees Studies of female adoptees

  10. Genetic Epidemiology • Adoption studies Rates of alcoholism higher in adopted offspring of alcoholic biological parents than non-alcoholic biological parents • Twin studies Resemblance for alcoholism higher in MZ twin pairs than DZ pairs

  11. Genetic and environmental proportions of variance in alcoholism from studies of male twins

  12. Genetic and environmental proportions of variance in alcoholism from studies of female twins Clinical sample cotwin followup Volunteer registry personal interview Population registry archival diagnosis

  13. Alcoholism: A Complicated Complex Disorder • Important behavioral component • Cultural influences • Common (phenocopies) • Benefits of moderate use • Clinical heterogeneity • Etiological heterogeneity • Specific vs general risk

  14. Estimated Common and Specific Genetic Variance for Psychiatric and Substance Use Disorders(Males and Females Combined) A1 A2 29 6 28 2 11 <1 1 34 3 42 5 31 1 14 Major Depression Generalized Anxiety Phobia Alcohol Dependence Drug Abuse/ Dependence Adult Antisocial Behavior Conduct Disorder 0 0 5 14 21 0 3 As As As As As As As Kendler, Prescott, Myers & Neale, Arch Gen Psychiatry,60: 929-937, 2003

  15. Alcoholism: A Complicated Complex Disorder • Important behavioral component • Cultural influences • Common (phenocopies) • Benefits of moderate use • Clinical heterogeneity • Etiological heterogeneity • Specific vs general risk • Different influences for different stages of alcohol involvement

  16. initiation experimentation regular use binging episodic chronic dependence Stages of alcohol involvement

  17. metabolism initial sensitivity initiation positive reinforcement experimentation metabolism negative reinforcement personality comorbidity regular use binging episodic chronic dependence Genetic influences on stages of alcohol involvement

  18. Irish Affected Sib-Pair Study of Alcohol Dependence (IASPSAD) Background & Design Results Genome Scan Psychometric Follow-up Molecular Follow-up

  19. Study Design / Data Collection Kenneth Kendler Patrick Sullivan Molecular Genetics Brien Riley Gursharan Kalsi Jeff Alexander Jen Vittum Statistical Analysis Po-Hsiu Kuo Edwin van den Oord Michael Neale Todd Webb John Myers Irish Collaborators Dermot Walsh – Irish Health Research Board, Dublin Diana Patterson – Shaftsbury Square Hospital, Belfast Collaborators

  20. Project Management Lisa Halberstadt, U.S. Margaret Devitt, Dublin Victor Robinson, Belfast Interviewers Craig Barton, John Cosgrove, Michael Crossan, Sara Dineen, Phil Gavigan, Claire Killeen, Deirdre King, Siobhan McHugh, Amanda Mullan, Eileen Murphy, Brian O'Malley, Bernie Purcell Blood collection & genotyping Irish Blood Transfusion Service, Dublin Northern Ireland Blood Transfusion Service, Belfast Irish Gardai, Dublin deCODE Genetics, Iceland Funding NIAAA R01-AA-11408 Project Support Irish Health Research Board Ros Moran Carol Cronin Queens Hospital, Belfast F. Anthony O’Neill Virginia Commonwealth Univ. Stacey Garnett Jill Opalesky Indrani Ray Cheryl Smith Rebecca Ortiz NIAAA Robert Karp Project Consultants David Goldman, NIAAA John Crabbe, Oregon Health Sciences John Rice, Washington Univ, St. Louis Other Acknowledgments

  21. IASPSAD Study Design Probands ascertained Interview & DNA N=591 (M=364, F=227) Affected siblings referred Interview & DNA N=610 (M=413, F=197) 733 sib pairs (sibship size: 2-8) Parents contacted Brief Interview & DNA N=213 (M=82, F=131) Control Groups Fully Screened n = 72 Self-Screened n ~ 800 Prescott et al., Alc Clin Exp Res, 2005

  22. Study Inclusionary Criteria • DSM-IV Alcohol Dependence • >1 affected siblings • All four grandparents born in Ireland or UK (England, Scotland or Wales)

  23. Proband & Sibling Assessment • DSM-IV Alcohol Dependence • Semi-Structured Assessment of the Genetics of Alcoholism (SSAGA, Bucholz et al., 1989) • Treatment records • Other Clinical Measures Nicotine Dependence Other substance use, abuse & dependence Antisocial personality disorder Major depression Drinking expectancies Subjective response (SRE, Schuckit et al. 1997) Family history of alcoholism • DNA Blood 85%, Buccal cell 15%

  24. Measurement Issues • Clinical Diagnosis • Validity (convergent) Clinical characteristics • Reliability (inter-rater) Sibling reports • Genotyping • Genotyping error (0.3% in 17 repeat Ss) • Population substructure

  25. Distribution of DSM-IV Alcohol Dependence criteria in IASPSAD probands and siblings

  26. Genotyping and Data Analysis 4 cM autosomal genome scan (deCODE, 1081 markers) 474 families informative for linkage 700 sib pairs (all possible pairs) Outcomes AD: DSM-IV Alcohol dependence SX: DSM-IV AD symptom count(range 3-7) Linkage analysis NPL - Merlin (Abecasis et al., 2003) empirical p-values by bootstrapping

  27. Genome-wide scan results for DSM-IV Alcohol Dependence

  28. Suggestive Linkage Regions for Alcohol Dependence (NP LOD >1.0) Dick et al. 2002 (alc factor) Bergen et al. 2003 (max drinks) Bergen et al. 2003 (max drinks)

  29. Genome-wide Scan results for DSM-IV Alcohol Dependence and AD Symptoms CH4 Prescott, Sullivan, Webb, Vittum, Patterson, Thiselton, Devitt, Halberstadt, Robinson, Neale, van den Oord, Walsh, Riley & Kendler, Molecular Psychiatry, 2006

  30. IASPSAD Chromosome 4 Linkage Results Peak LOD = 4.59 (p<.000002)

  31. Chromosome 4 Linkage to AD Symptoms SW American Indians: AD - Long et al. 1998 COGA (US multiplex families): # symptoms - Reich et al. 1998 max drinks - Saccone et al. 2000 alc response - Schuckit et al. 2001 severity - Corbett et al. 2005 Mission American Indians: severity - Ehlers et al. 2004

  32. Follow-Up Work • Psychometric Where is the AD - SX difference coming from? What else can we learn from linkage studies?

  33. IASPSAD Chromosome 4 Linkage Results Peak LOD = 4.59 (p<.000002)

  34. Comparing the Alcohol Dependence (AD) andSymptom Count (SX) Linkage Evidence

  35. all symptoms except withdrawal ADSX Symptom Dropping AnalysesNPL LOD Scores for AD Symptom count and Symptom count - Withdrawal

  36. NPL LOD Scores for Symptom Dropping Analyses ADSX medical consequences lack of control restricted activities withdrawal failed to quit binging tolerance

  37. Linkage Analysis Strategies • Bivariate models: Alcohol dependence with comorbid disorders

  38. AD or MD AD only AD + MD MD only Ch 7 linkage to alcohol dependence and major depression from COGA study Wang et al, Human Molec Genet 2004

  39. Bivariate linkage results for Nicotine Dependence and Alcohol Dependence in IASPSAD Sullivan et al, under review

  40. Linkage Analysis Strategies • Bivariate models: Alcohol dependence with comorbid disorders • Components of alcohol dependence • Tolerance • Withdrawal • Initial Sensitivity

  41. Ch 1 Linkage Results for Ethanol Sensitivity and Tolerance In IASPSAD Kuo et al, under review

  42. Linkage Study Conclusions • Strong evidence for linkage of AD symptom count to chromosome 4 • Replicates findings from 3 independent samples • Psychometric follow-up implicates tolerance & binge drinking • Bivariate and component analyses suggest additional regions (and complex mechanisms)

  43. Follow-Up Work • Psychometric • Molecular Which genes?

  44. Association Study Strategy • Multi-stage design -- minimize False Discovery Rate (van den Oord et al., 2003) • Stage 1: Screening all candidate genes with case-control analyses select sample size adequate to detect genes with 10% effect size at p<.10; N=310 in each group • Stage 2: Internal replication: candidates which pass Stage 1 tested using remaining sample (N>800) • Stage 3: Replication in independent sample

  45. IASPSAD Chromosome 4 Linkage Results ADH cluster(1a,1b,1c,4,5,6,7)

  46. acetaldehyde acetate alcohol Role of ADH in ethanol metabolism alcohol dehydrogenase (ADH) ADH1B ADH1C aldehyde dehydrogenase (ALDH) ALDH2

  47. Association Studies of Alcohol Dehydrogenase (ADH) • 27 SNP markers identified in 7 ADH genes • Unrelated Case-Control association design Stage 1: • 328 cases (probands & affected siblings) • 328 screened population controls Stage 2: underway • Single-marker analyses • Two markers significant (p<.01, p<.06) • Haplotype analyses

  48. Block structure of ADH genes in IASPSAD sample 5 4 6 1a 1b 1c 7 from Haploview program

  49. Haplotype association results block 4 – ADH7 CA haplotype is “protective” for Alcohol Dependence OR = 1.20

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