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

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Presentation on theme: "Alcoholism: From Genotypes to Genes (and Back Again) Carol A. Prescott, Ph.D. University of Southern California"— Presentation transcript:

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

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

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) A1A1 A2A2 Generalized Anxiety Phobia Alcohol Dependence Drug Abuse/ Dependence Adult Antisocial Behavior 28211< AsAs Kendler, Prescott, Myers & Neale, Arch Gen Psychiatry, 60: , 2003 Major Depression Conduct Disorder AsAs 0 AsAs 5 AsAs 14 AsAs 3 AsAs 0 AsAs 21

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 Stages of alcohol involvement initiation experimentation regular use bingingchronic dependenceepisodic

17 Genetic influences on stages of alcohol involvement initiation experimentation regular use bingingchronic dependenceepisodic metabolism initial sensitivity metabolism negative reinforcement personality comorbidity positive reinforcement

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

19 Home Home Reference Maps Appendixes Download PDF Reference Maps Appendixes Download PDF

20 Collaborators 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

21 Other Acknowledgments 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 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

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

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

24 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%

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

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

27 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

28 Genome-wide scan results for DSM-IV Alcohol Dependence

29 Suggestive Linkage Regions for Alcohol Dependence (NP LOD >1.0) CHcMLOD Dick et al (alc factor) Bergen et al (max drinks) Bergen et al (max drinks)

30 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

31 IASPSAD Chromosome 4 Linkage Results Peak LOD = 4.59 (p< )

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

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

34 IASPSAD Chromosome 4 Linkage Results Peak LOD = 4.59 (p< )

35 Comparing the Alcohol Dependence (AD) and Symptom Count (SX) Linkage Evidence

36 Symptom Dropping Analyses NPL LOD Scores for AD Symptom count and Symptom count - Withdrawal all symptoms except withdrawal ADSX

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

38 Linkage Analysis Strategies Bivariate models: Alcohol dependence with comorbid disorders

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

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

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

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

43 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)

44 Follow-Up Work Psychometric Molecular Which genes?

45 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

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

47 Role of ADH in ethanol metabolism alcohol acetaldehydeacetate alcohol dehydrogenase (ADH) ADH1B ADH1C aldehyde dehydrogenase (ALDH) ALDH2

48 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

49 Block structure of ADH genes in IASPSAD sample a 1b 1c 7 from Haploview program

50 Haplotype association results block 4 – ADH7 haplotypefreqcase, control freqChi-sqp AC , CA , AA , CA haplotype is “protective” for Alcohol Dependence OR = 1.20

51 Association Work in Progress Ch 4 follow-up Additional markers within ADH SNPs within Ch4 linkage region GWA using pooled samples Functional candidates 133 alcoholism-susceptibility genes (1536 SNP) GABA cluster on Ch 5 (Kalsi et al., 2005) Candidates from animal models (mouse, C elegans, drosophila)

52 “Hangover” gene hangover involved in the development of alcohol tolerance in drosophila (Scholz et al Nature 2005) Human ortholog: ZNF699 (Ch19) 1061 cases, 609 controls from IASPSAD 7 SNPs by FP-TDI

53 ZNF699 association with Alcohol Dependence (Riley et al. submitted) 4 of 7 SNPs associated Single marker p<.001 Haplotype p<.00008; OR 2.2 Expression studies in postmortem brain (n=34) Individuals with risk haplotype mRNA expression significantly reduced (p<.02) in dorso-lateral prefrontal cortex Possible mechanism Down-regulation of transcriptional repressor facilitates neural changes in response to ethanol exposure

54 Conclusions Replicated susceptibility loci for alcohol dependence Distinct genes underlie different aspects of dependence, including tolerance, sensitivity and withdrawal Results from clinical studies, animal models and genetic epidemiology continue to guide the search for susceptibility loci

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