Madden, Pamela A

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Washington University School of MedicineDigital Commons@BeckerPresentations 2006: Alcohol and Tobacco Dependence: fromBench to Bedside2006Alcohol and nicotine use and dependence:Common genetic and other risk factorsPamela A. MaddenWashington University School of Medicine in St. LouisFollow this and additional works at: http://digitalcommons.wustl.edu/guzepresentation2006Part of the Medicine and Health Sciences CommonsThis Presentation is brought to you for free and open access by the 2006: Alcohol and Tobacco Dependence: from Bench to Bedside at DigitalCommons@Becker. It has been accepted for inclusion in Presentations by an authorized administrator of Digital Commons@Becker. For moreinformation, please contact engeszer@wustl.edu.Recommended CitationMadden, Pamela A., "Alcohol and nicotine use and dependence: Common genetic and other risk factors" (2006). Presentations. Paper5 Samuel B. Guze Symposium on Alcoholism.http://digitalcommons.wustl.edu/guzepresentation2006/5Alcohol and Nicotine Use and Dependence:Shared Genetic and Other Risk FactorsPamela Madden, Ph.D.Washington University School of MedicineGuze SymposiumPresenter’s Disclosure of InterestSources of Research SupportDA12854 (to PAFM)DA018660 (to MTL)DA015789 (to PAFM)AA13640 (to RDT)DA014374 (to EJS)AA011998 (to ACH)Stock Equity (> 10,000)• NoneSpeaker’s Bureau (s)• NoneConsulting Relationships• NoneName & Presentation Date: Overview: Alcohol and Nicotine Use and Dependence: Common Genetic and Other Risk Factors; March 2, 2006Why a Symposium on Smoking and Alcoholism?Very high rates of smoking among alcoholics (as high as 90%).– Many alcoholics who quit drinking but not smoking will be killed by their smoking.– Understanding the biology that underlies the association between smoking and alcoholism may give us important insights into the etiology of tobacco addiction.– Improved therapies to help ALL smokers quit.PERSISTENT LONG-TERM SMOKING # 1 PUBLIC HEALTH CHALLENGEUS Deaths Attributed to SmokingAges 35-69 yearsWOMEN MENAll Deaths 27.1% 29.5%Cancer Related Deaths 26.5% 44.4%(Peto et al., 2003)Cited in: Tobacco Control Country Profiles, second Edition, 2003 (Eds Shafey et al.)WHY IS RESEARCH ON CIGARETTE SMOKING IMPORTANT?Smoking throughout life: 10 years of life lostStopped by age 60: 7 years of life lostStopped by age 50: 4 years of life lostStopped by age 40: 1 year of life lostAverage mortality cost of long-term persistent smoking ** Doll. R, et al. (2004) BMJ 328:1519RISK OF ALCOHOLISM IS STRONGLY ASSOCIATED WITH REGULAR CIGARETTE SMOKING AND ESPECIALLY NICOTINE DEPENDENCE.  WHY??% Alcohol DependentNever smoked 3Experimented only 10Non-dependent smoker 12Nicotine dependent smoker 31NOTE. p < 0.001Those with a lifetime history of regular smoking, especially nicotine dependence, are more likely to report a history of alcohol dependence:AUSTRALIAN WOMEN (N = 3424)A 10-Fold Increase is Risk!% Alcohol DependentNever smoked 10Experimented only 22Non-dependent smoker 30Nicotine dependent smoker 47NOTE. p < 0.001…this is also true in men.AUSTRALIAN MEN (N = 2766)A 5-Fold Increase in Risk!More Severe Alcoholics are Especially Likely to be . . . 1) Regular Smokers2) If They’re Regular Smokers –Nicotine DependentNumber of Alcohol Symptoms % Regular Smokers0 311 492 593 654 755 836 857 82p < 0.001Those with a larger number of symptoms of alcohol dependence are much more likely to report a history of regular smokingAUSTRALIAN WOMEN (N=3424)Number of Alcohol Symptoms % Regular Smokers0 271 452 583 624 705 766 827 82p < 0.001… and the same is true in menAUSTRALIAN MEN (N=2766)Number of Alcohol Symptoms % Nicotine Dependent0 501 522 573 734 815 826 907NOTE. p < 0.00193Probability of progression to nicotine dependence by regular smokers increases as a function of number of alcohol dependence symptomsAUSTRALIAN WOMEN (N = 1678)Number of Alcohol Symptoms % Nicotine Dependent0 511 512 583 644 705 836 797NOTE. p < 0.00182Probability of progression to nicotine dependence by regular smokers increases as a function of number of alcohol dependence symptomsAUSTRALIAN MEN (N = 1478)Adolescents who are nicotine dependent smokers are at especially high risk of alcohol problems regardless of whether or not they have a family history of alcoholism.Interaction of adolescent smoking status andfamily history of alcoholism (FH+ or FH-) predicts adolescent alcohol problemsProblem DrinkingOdds 95%Ratio CINever smoked, FH- 1.00 --Never smoked, FH+ 2.58 1.20-5.53Occasional smoker, FH- 7.29 4.26-12.48Occasional smoker, FH+ 7.58 4.09-14.03Regular non-dependent smoker, FH- 10.17 5.58-18.53Regular non-dependent smoker, FH+ 32.93 17.36-62.45Regular dependent smoker, FH- 37.21 20.22-68.46Regular dependent smoker, FH+ 35.99 18.81-68.89NOTE. ALCOHOL PROBLEMS: DSM-IV alcohol abuse or 2 or more symptoms of alcohol dependence.1) Is there a causal connection?  Does smoking increase risk of developing alcohol dependence?OR2) Are there shared risk-factors, and is the association between smoking and alcohol dependence indirect?(6250 young adult twins born 1964-71,aged 24-35 when interviewed) Heavy drinking cohort!<1% of women  lifetime abstainers<1% of men lifetime abstainers70% of women have had 7 or more drinks in a day90% of men have had 9 or more drinks in a dayAUSTRALIAN TWIN PANEL:YOUNG ADULT COHORTPsychiatric & sociodemographic risk factors are similar for nicotine vs. alcohol dependence.Comparison Groups1. Nicotine Dependent AND Alcohol Dependent2. Alcohol Dependent Only3. Nicotine Dependent Only4. Regular smoker, neither alcohol nor nicotine dependent5. Never smoked regularly, not alcohol dependenceAssociations with lifetime history of Major DepressionOR 95% CIAlcohol & Nicotine Dependence 2.97 2.44-3.61Alcohol Dependence ONLY 2.16 1.83-2.55Nicotine Dependence ONLY 1.63 1.32-2.00Never smoked, or regular non-Nicotine Dependent1.00 --Associations with history of childhood Conduct DisorderWOMENOR 95% CIAlcohol & Nicotine Dependence 10.72 6.82-16.86Alcohol Dependence only 2.92 1.57-5.44Nicotine Dependence Only 4.46 2.91-6.84Non-dependent regular smoker [4.46 2.91-6.84]Never smoked 1.00 --Associations with history of childhood Conduct DisorderWOMEN MENOR 95% CI OR 95% CIAlcohol & Nicotine Dependence 10.72 6.82-16.86 5.81 4.23-7.98Alcohol Dependence only 2.92 1.57-5.44 3.00 2.14-4.21Nicotine Dependence Only 4.46 2.91-6.84 3.07 2.29-4.12Non-dependent regular smoker [4.46 2.91-6.84] [3.07 2.29-4.12]Never smoked 1.00 1.00Associations with lifetime history of Panic disorderWOMENOR 95% CIAlcohol & Nicotine Dependence 1.89 1.12-3.21Alcohol Dependence only [1.89 1.12-3.21]Nicotine Dependence Only 1.18 NS 0.71-1.97Non-dependent regular smoker [1.18 NS 0.71-1.97] Never smoked 1.00 --Associations with lifetime history of Panic disorderWOMEN MENOR 95% CI OR 95% CIAlcohol & Nicotine Dependence 1.89 1.12-3.21 4.46 1.44-13.82Alcohol Dependence only [1.89 1.12-3.21] [4.46 1.44-13.82]Nicotine Dependence Only 1.18 NS 0.71-1.97 [4.46 1.44-13.82]Non-dependent regular smoker [1.18 NS 0.71-1.97] [4.46 1.44-13.82]Never smoked 1.00 -- 1.00 --Thus there are certain important shared risk factors:DepressionAnxietyAnti-Social TraitsAre these sufficient to account for co-occurrence of smoking and alcoholism?What About Genetics?It is well-known that genetic influences are important in alcoholism. How about smoking?Genetic & Environmental Contributions to Nicotine Dependence RiskUNADJUSTED ADJUSTED% 95% CI % 95% CIAdditive Genetic 62 44-68 47 28-54Shared environmental 0 0-14 0 0-15Non-shared environmental 38 32-45 53 46-61NOTE. ADJUSTED:controlling for significant psychiatric & sociodemographic predictors of risk (but NOT alcoholism).Genetic & Environmental Contributions to Alcohol Dependence RiskUNADJUSTED ADJUSTED% 95% CI % 95% CIAdditive Genetic 52 33-60 48 23-57Shared environmental 0 0-15 0 0-19Non-shared environmental 48 40-56 52 43-61NOTE. ADJUSTED: controlling for significant psychiatric & sociodemographic predictors (but NOT alcoholism).What is the genetic correlation between Alcohol and Nicotine Dependence?Unadjusted 0.67 (95% CI: 0.60-0.81)Adjusted 0.58 (95% CI: 0.26-1.00)… Genetic effects on risk of nicotine dependence account for 45% (unadjusted) or 34% (adjusted) of the genetic variance in risk of alcohol dependence in this sample.So …There is a substantial overlap of genetic risk for alcohol & nicotine dependence. …and this is only partially explained by shared psychiatric & sociodemographic  risk factors. What accounts for the partial genetic correlation between alcohol & nicotine dependence?  At what stage(s) in the progression of smoking does the genetic correlation arise?HERITABILITY ESTIMATES FOR SMOKING INITIATION(Retrospective Data:  Adult Samples)NOTE: %AG represents percent of phenotypic variance due to additive genetic effects; %SE due to shared environmental effects; and %NSE due to non-shared environmental effects.WOMEN MEN%AG %AGSweden (Medlund et al., 1977)Denmark (Raachou-Nieken, 1960)44795184Finland (Kaprio et al  1988) 37 50Australia (1981 Survey: Heath et al., 1993)77 28Australia (1989 Survey: Madden etal., 1993)60 80U.S.A.  WWII Veterans (Carmelli, et al 1992)U.S.A. Virginia (Heath, et al, 1993)--845984U.S.A. Vietnam-era Veterans(True et al., 1997)-- 39We can use family history data to discern differences in degree of genetic risk in those who have NOT become alcoholic.Especially powerful with twin data!1. Alcohol Dependent2. Non-Alcohol Dependent, High Genetic RiskMZ cotwin is alcohol dependent3. Non-Alcohol Dependent, Intermediate Genetic RiskDZ twin sister or brother is alcohol dependent4. Non-Alcohol Dependent, Low Genetic RiskCotwin also has NO history of alcohol dependenceALCOHOL COMPARISON GROUPSWOMEN MEN% %Alcohol dependent 73 70Non-alcohol dependent- High genetic risk 68 58- Intermediate genetic risk 57 52- Low genetic risk 41 42AMONG ALL PARTICIPANTSRISK OF BECOMING A REGULAR SMOKER AS A FUNCTION OF GENETIC RISK OF ALCOHOLISMWOMEN MEN% %Alcohol dependent 80 72Non-alcohol dependent- High genetic risk 55 59- Intermediate genetic risk 54 56- Low genetic risk 52 55AMONG REGULAR SMOKERSRISK OF PROGRESSION TO NICOTINE DEPENDENCE AS A FUNCTION OF GENETIC RISKOF ALCOHOLISMInterpretation?1) Genetic correlation between nicotine dependence and alcohol dependence seems to be largely driven by genetic correlation between regular smoking and alcohol dependence.2) Among regular smokers, the correlation between alcohol dependence and nicotine dependence is largely determined by non-shared environmental factors.The critical comparison for testing theassumption of a direct causal influence isof MZ pairs discordant for both alcoholdependence and smoking status.If there is a causal link, the twin who hassmoked regularly should also be morelikely to have a history of alcoholdependence (But there may be non-causalexplanations!).In MZ twins discordant for nicotine dependence, where only ONE twin had become alcohol dependent:58 Cases: Nicotine Dependent Twin was Alcohol Dependent21 Cases: Non-nicotine Dependent Twin was Alcohol DependentHIGHLY SIGNIFICANT:  Odds Ratio 2.70p < .001In contrast, in MZ pairs discordant for regular cigarette smoking, where only ONE twin had become alcohol dependent:27 Cases: Regularly Smoking Twin was Alcohol Dependent19 Cases: Non-Regularly Smoking Twin was Alcohol DependentOdds Ratio 1.42,  p < .001Which comes first: Alcohol or Nicotine Dependence?(based on retrospective reports)WOMEN MEN(%) (%)Nicotine Dependence 39 43Both same year 22 16Alcohol Dependence 39 41Which comes first: Regular smoking versus Nicotine Dependence?WOMEN MEN(%) (%)Regular smoking 91 90Both same year 6 4Alcohol Dependence 3 6UpdateIndividuals at high genetic risk of alcohol dependence are on average also at increased genetic risk of becoming regular smokers, an outcome that usually precedes the onset of alcohol dependence.Among regular smokers, there may be a unidirectional or reciprocal causal relationship between nicotine and alcohol dependence- in discordant MZ pairs, who are genetically identical, the nicotine dependent twin issignificantly more likely to also be alcohol dependent.Gene-mapping studies aim to identify genes that contribute to risk of alcoholism on nicotine dependence.We are using a genetic linkage approach –studying the co-inheritance of dependence phenotypes and genetic markers to try to identify chromosomal regions containing risk-increasing genes.Are the same regions identified for smoking and for alcoholism?NICOTINE ADDICTION GENETICS PROJECT (NAG)Large-scale linkage study to identify specific chromosomal locations that may contain genes that influence heavy smoking and/or nicotine dependence.Heavy smoking index cases and their siblings were ascertained through two twin panels:(i) Finnish Twin Panel(Senior Co-Investigators Kaprio & Peltonen)(ii) Australian Twin Panel(Senior Co-Investigator Martin)AUSTRALIAN TARGET SAMPLE:Information about smoking history and heaviness of smoking on individuals from >11,000 families was used to identify most informative sibships. FINNISH TARGET SAMPLE:SOURCE: Older Finnish Twin Cohort(65% born 1931-1950),with few surviving parents.NICOTINE ADDICTION GENETICS PROJECT (NAG)Dx Telephone InterviewBlood/Buccal SamplesAUSTRALIA 3453 (52% Women) 3056 (54% Women)FINLAND 2043 (46% Women) 2022 (46% Women)NICOTINE ADDICTION GENETICS PROJECT (NAG)Genome Scans Completed:289 Australian families(another 100 families still to be scanned)159 Finnish familiesNote: ABI Prism Linkage Mapping Set (400 markers, average distance of 10 cM)PHENOTYPE  DEFINITIONFOR NICOTINE DEPENDENCEGUIDED  BY  QUANTITATIVE  GENETIC ANALYSES  OF DATA FROM  A  SAMPLE  OF  TWIN  PAIRS FROM THE  AUSTRALIAN  TWIN  PANEL.(N=977 MZ, 1316 DZ pairs)Genetic Factor Loadings of DSM-IV and the Heaviness of Smoking Dependence SymptomsAUSTRALIAN WOMENAdditive Genetic Factor #1Additive Genetic Factor #2Time to first cigarette .78 .03Cigarettes smoked per day .86 -.08Tolerance .88 -.09Withdrawal .67 -.15More than intended .83 -.08Difficulty quitting .76 -.31Ever chain smoked .70 .05Gave up activities .57 -.49Smoke despite problems .71 .00(Lessov, et al. Psychological Medicine, 34:865-879, 2004) PHENOTYPE DEFINITION for HEAVINESS OF SMOKING“Maximum cigarettes smoked in a 24-hour period”• Tolerance measure that has a high factor loading in our phenotypic factor analysis, and a high genetic factor loading.• Avoids problem with typical quantity measure.  Prohibitions against smoking (e.g., in workplace) have reduced the utility of average quantity measures.Genetic Correlation MaxCigs and ND Factor Scorerg 95% CIWOMEN 0.84 0.78-0.89MEN 0.88 0.84-0.92MaxCigs: Maximum cigarettes smoked in a 24-hour period ND Factor Score: Nicotine dependence factor score derived from DSM-IV and HSI itemsQUANTITATIVE  PHENOTYPE:DEPENDENCE  FACTOR  SCORE:Australian + Finnish Families CombinedMultipoint ResultsChromosome Position (cM) Nearest Marker Lod Score2 78.7 D2S337 2.2613 81.0 D13S265 1.8422 57.1 D22S274 3.23NOTE: Quantitative trait analyses using MERLIN-REGRESSQUANTITATIVE PHENOTYPE:Fagerstrom Nicotine Dependence (FTND)Australian + Finnish Families CombinedMultipoint ResultsChromosome Position (cM) Nearest Marker Lod Score2 78.7 D2S337 2.3022 57.1 D22S274 3.69QUANTITATIVE PHENOTYPE:DSM-IV Nicotine Dependence Symptom CountAustralian + Finnish Families CombinedMultipoint ResultsChromosome Position (cM) Nearest Marker Lod Score2 86.8 D2S337 2.16CHROMOSOME 2  SUGGESTIVE  LINKAGE FOR  FACTOR SCORE,  FTND  ARE  IN THE SAME  APPROXIMATE  LOCATION  WHERE A MAJOR US ALCOHOLISM GENE-MAPPING STUDY (“COGA”)  HAS  POSITIVE  FINDINGS  FOR “HABITUAL  SMOKING  AND ALCOHOLISM”  PHENOTYPE,  OTHER MEASURES  THAT  MAY  BE CHARACTERIZED  AS  “IMPULSIVE /BEHAVIORAL  UNDERCONTROL”.QUANTITATIVE PHENOTYPE:Maximum Cigarettes Smoked in a 24-Hour PeriodAustralian + Finnish families combinedChromosome Position (cM) Lod Score20 72.6 3.0422 27.1 5.64CHROMOSOME 22Maximum Cigarettes in a 24-hr periodLOD SCOREcM Position (based on 2cM grid)Maximum Cigarette ConsumptionCombined MultipointCombined SinglepointAustralian MultipointFinnish MultipointFOR  THE  FINNISH  FAMILIES  ONLY, WE  ALSO  FIND  SUGGESTIVE EVIDENCE  FOR LINKAGE  ON  CHROMOSOME  20,  IN THE  REGION  OF  THE  ALPHA 4 NEURONAL  NICOTINIC  RECEPTOR (CHRNA4)  GENE. EVIDENCE IS STRONGEST FOR HEAVINESS OF SMOKING MEASURES.CHROMOSOME 20Nicotine Dependence Factor Score (NDFS), Quantity smoked per day & Maximum Cigarettes in 24-hoursLOD SCOREcM Position (based on 2cM grid)Finnish Maximum cigarettes in 24-hrsMultipointSinglepointFinnish Quantity smoked per day MultipointSinglepointFinnish NDFSMultipointSinglepointFor a Heaviness-of-Drinking measure (Maximum Drinks in 24-Hours) we find a chromosome 7 linkage signal in the same region the COGA finds linkage for the same phenotype.But, also a “BLIP” for a Heaviness-of-Smoking phenotype.Australian Maximum cigarettes in 24 hrsMultipointSinglepointAustralian Maximum drinks in 24 hrsMultipointSinglepointCHROMOSOME 7Maximum Cigarettes & Maximum Drinks in a 24 hour periodcM Position (based on 2cM grid)LOD SCORESUMMARY1) One of our probable linkage peaks on chromosome 2 coincides with a linkage peak for co-morbid alcoholism and habitual smoking  (Bierut et al., 2004).2)   Our highest linkage peak is on chromosome 22 (LOD=5.64) for the MaxCigs. We know of no alcoholism linkage in this region. 3) We also obtain a multipoint LOD of 3.69 for a second smoking phenotype (FTND), at a different location. A region where an alcoholism signal has been reported.SUMMARY cont’d4) In our Finnish subsample only, we observe a linkage peak for measures of quantity smoked, and for our nicotine dependence factor score, near the location of the alpha-4 neuronal nicotinic receptor gene, on chromosome 20. 5) One of our probable linkage peaks on chromosome 7 for maximum number of drinks in a 24-hour period is in the same location as a smaller peak for maxcigs.CONCLUSIONWe are far from having a complete answer about why alcoholics are especially likely to be nicotine dependent smokers.But, overlap of genetic risk-factors does appear to be a contributing factor.COLLABORATORS John Rice, Ph.D.Alison Goate, D.Phil.Andrew Heath, D.Phil.Richard Todd, Ph.D., M.D.Kathleen Bucholz, Ph.D.Michael Lynskey, Ph.D.Alexandre Todorov, Ph.D. Scott Saccone, Ph.D.Michele Pergadia, Ph.D.Arpana Agrawal, Ph.D. Jen Wang, Ph.D.Danielle Dick, Ph.D.Washington University School of Medicine, USACOLLABORATORS  CONT’DNicholas Martin, Ph.D.Grant Montgomery, Ph.D.Queensland Institute of Medical Research, AustraliaJaakko Kaprio, M.D., Ph.D.Leena Peltonen, M.D., Ph.D.Anu-Maria Loukola, Ph.D.Ulla Broms, Grad StudentHeidi MaunuKauko HeikkiläElisabeth WidenUniversity of Helsinki, FinlandSupported by NIH grant DA12854, AA11992, and grants from the Australian National Health and Medical Research Council, the Academy of Finland, and the European Union (QLG2-CT-2002-01254).ACKNOWLEDGEMENTS

Alcohol and nicotine use and dependence: Common genetic and other risk factors

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Alcohol and nicotine use and dependence: Common genetic and other risk factors

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