Agrawal, A.

Bertelsen, S.

Bierut, L.

Dick, D. M

Dunn, G.

Foroud, T.

Goate, A.

Heath, A.

Hesselbrock, V.

Hinrichs, A.

Madden, P.

Pergadia, M.

Rice, J.

Saccone, S.

Wang, J.

Digital Commons@Becker

Washington University School of MedicineDigital Commons@BeckerPosters 2005: Alcoholism and Comorbidity2005Linkage findings on chromosome 2 suggest a genepredisposing to multiple behavioral undercontrolphenotypesD. M. DickWashington University School of Medicine in St. LouisG. DunnWashington University School of Medicine in St. LouisA. GoateWashington University School of Medicine in St. LouisT. ForoudIndiana University School of MedicineV. HesselbrockUniversity of Connecticut School of MedicineSee next page for additional authorsFollow this and additional works at: http://digitalcommons.wustl.edu/guzeposter2005Part of the Medicine and Health Sciences CommonsThis Poster is brought to you for free and open access by the 2005: Alcoholism and Comorbidity at Digital Commons@Becker. It has been accepted forinclusion in Posters by an authorized administrator of Digital Commons@Becker. For more information, please contact engeszer@wustl.edu.Recommended CitationDick, D. M.; Dunn, G.; Goate, A.; Foroud, T.; Hesselbrock, V.; Bierut, L.; Rice, J.; Wang, J.; Hinrichs, A.; Bertelsen, S.; Madden, P.;Agrawal, A.; Pergadia, M.; Saccone, S.; and Heath, A., "Linkage findings on chromosome 2 suggest a gene predisposing to multiplebehavioral undercontrol phenotypes" (2005). Posters. Paper 5 Samuel B. Guze Symposium on Alcoholism.http://digitalcommons.wustl.edu/guzeposter2005/5AuthorsD. M. Dick, G. Dunn, A. Goate, T. Foroud, V. Hesselbrock, L. Bierut, J. Rice, J. Wang, A. Hinrichs, S.Bertelsen, P. Madden, A. Agrawal, M. Pergadia, S. Saccone, and A. HeathThis poster is available at Digital Commons@Becker: http://digitalcommons.wustl.edu/guzeposter2005/5Linkage Findings on Chromosome 2 Suggest a Gene Predisposing To Multiple Behavioral Undercontrol PhenotypesDM Dick1, G Dunn1, A Goate1, T Foroud2, V Hesselbrock3, L Bierut1, J Rice1, J Wang1, A Hinrichs1, S Bertelsen1, P Madden1, A Agrawal1, M Pergadia1, S Saccone1, A Heath1, & other COGA/NAG Collaborators 1Washington University School of Medicine, St. Louis, MO   2Indiana University School of Medicine 3University of Connecticut School of MedicineABSTRACTEvidence from independent studies is converging tosuggest that a region on chromosome 2p contains a gene(or genes) that predispose to multiple behavioralphenotypes related to behavioral undercontrol. Here wepresent data from the Collaborative Study of the Geneticsof Alcoholism (COGA) and the Nicotine Addiction GeneticsProject (NAG) demonstrating linkage to chromosome 2with multiple, related phenotypes.INTRODUCTIONConsiderable overlap is observed between manypsychiatric disorders. Twin studies have suggested thatsome of this overlap may be due to common genes thatinfluence multiple phenotypes (also called pleiotropy). Inparticular, several studies have demonstrated thatdisorders characterized by behavioral undercontrol maybe related through share genetic vulnerabilities. Alcoholuse and smoking (Hopfer et al., 2001), conduct disorder,and other drug use (Kendler et al., 2003) have all beendemonstrated to have shared genetic liability.SAMPLESCOGA. The Collaborative Study on the Genetics ofAlcoholism (COGA, PI Henri Begleiter, MD) is a multi-sitecollaborative project designed to identify genes thatcontribute to the development of alcoholism and relateddisorders. Densely affected alcoholic families wereascertained from inpatient and outpatient treatmentcenters at several sites across the United States.Genome-wide linkage analyses have been conducted on asample of 2273 individuals from 262 alcoholic families. AllCOGA subjects were interviewed using the Semi-Structured Assessment for the Genetics of Alcoholism(SSAGA).NAG. The Nicotine Addition Genetics Project (NAG, PIPam Madden, PhD) was initiated with the goal ofidentifying genes involved in nicotine addiction and relatedphenotypes. Nuclear families containing at least one pairof heavy smoking siblings have been ascertained fromAustralia and Finland. Only data from Australian familiesare presented here. Linkage analyses on chromosome 2are based on a sample of 1501 individuals from 289families. NAG participants were interviewed using a semi-structured polydiagnostic interview developed from theSSAGA.ANALYTIC METHODSLinkage analyses were carried out on the binary COGAphenotypes using the program ASPEX. All possible pairswere analyzed using the SIB_IBD routine, which uses ibdsharing estimates from pairs with genotyped parents.Binary phenotypes in the NAG project were analyzedusing the program Merlin. Quantitative and semi-quantitative traits in both studies were analyzed using theMerlin-regress routine.01234560 50 100 150 200 250 300cM PositionLOD scoreCDSuicideADCD or SUIPhenotype # Pairs Maxlod Position Allele-sharingCD 113 2.4 117cM 64%Suicide 58 2.7 117cM 68%Alcoholism 797 2.9 114cM 55%CD or SUI 239 5.0 117cM 63%CD, SUI, or Alcoholism 988 3.7 114cM 56%In the COGA sample, the phenotypes alcohol dependence (measured using DSMIII-R and Feighner Definite criteria),conduct disorder (CD), and suicide attempts (SUI) all show linkage to chromosome 2p. A maximum lod score of 5.0 isobserved in the region with the phenotype CD or SUI.In the COGA sample, a series of quantitative phenotypeswere constructed from the substance classes: alcohol,tobacco, opioids, sedatives, stimulants, cocaine andmarijuana. Phenotypes for each class were defined basedon the number of DSMIII-R dependency criteria. The eightphenotypes we analyzed were alcohol, tobacco, averageof alcohol and tobacco, average of alcohol and drugs,average of alcohol, tobacco and drugs, sum of alcohol andtobacco, sum of alcohol and drugs, sum of alcohol,tobacco and drugs (Dunn et al., in preparation). Resultsfrom linkage analyses of these phenotypes onchromosome 2 are shown below.DISCUSSIONMultiple phenotypes related to behavioral undercontrolevidence linkage to chromosome 2p, across independentdatasets. In the COGA project, we find linkage with thephenotypes alcohol dependence, conduct disorder, suicideattempts, and quantitative indices of multiple substanceuse. In the NAG project, we find linkage with severalsmoking-related phenotypes to a similar region onchromosome 2. The marker yielding the maximum lodscore in the NAG project is approximately 10cM from themarker yielding the maximal lod score in the COGAsample. These peaks are sufficiently close as to bebeyond the resolution of linkage analyses (Roberts et al.,1999), and provide converging evidence of a gene in theregion that influences multiple substance use phenotypesand related behavioral problems. Several candidategenes are located in the region, including G-proteincoupled receptors and zinc finger proteins. Next, we planto initiate association studies of candidate genes in theregion.ACKNOWLEDGMENTSThe Collaborative Study on the Genetics of Alcoholism(COGA) (Principal Investigator: H. Begleiter; Co-PrincipalInvestigators: L. Bierut, H. Edenberg, V. Hesselbrock,Bernice Porjesz) includes nine different centers wheredata collection, analysis, and storage take place. The ninesites and Principal Investigators and Co-Investigators are:University of Connecticut (V. Hesselbrock); IndianaUniversity (H. Edenberg, J. Nurnberger Jr., P.M.Conneally, T. Foroud); University of Iowa (R. Crowe, S.Kuperman); SUNY HSCB (B. Porjesz, H. Begleiter);Washington University in St. Louis (L. Bierut, J. Rice, A.Goate); University of California at San Diego (M.Schuckit); Howard University (R. Taylor); RutgersUniversity (J. Tischfield); Southwest Foundation (L.Almasy). Lisa Neuhold serves as the NIAAA StaffCollaborator. This national collaborative study issupported by the NIH Grant U10AA08403 from theNational Institute on Alcohol Abuse and Alcoholism(NIAAA).In memory of Theodore Reich, M.D., Co-PrincipalInvestigator of COGA since its inception and one of thefounders of modern psychiatric genetics, we acknowledgehis immeasurable and fundamental scientific contributionsto COGA and the field.The Nicotine Addiction Genetics (NAG) Project is fundedby NIDA and NCI (grant DA12854). Senior Investigatorsinclude Pamela Madden, Ph.D., John Rice, Ph.D., AndrewHeath, D.Phil., Alison Goate, D. Phil., Richard Todd, Ph.D.,M.D., Alexandre Todorov, Ph.D. (Washington UniversitySchool of Medicine, USA); Nick Martin, Ph.D.(Queensland Institute of Medical Research, Australia);Jaakko Kaprio, M.D., Ph.D., Leena Peltonen, M.D., Ph.D.,Markku Koskenvuo, M.D., Ph.D. (University of Helsinki,Finland).In the NAG sample, several primary smokingphenotypes show linkage to chromosome 2p. Theseinclude Nicotine Dependence Scores, Fagerstrom Testfor Nicotine Dependence (FTND) Scores, the MaximumNumber of Cigarettes Smoked, and quantitative factorscores derived from DSM and FTND nicotinedependence items. Each of these phenotypes was log-transformed and age, age2, and sex were regressed out.The analyses were conditioned on ever smoking. Theresults from linkage analyses of these phenotypes onchromosome 2 are shown in the graph below.00.511.522.50 50 100 150 200 250 300cM PositionLod scoreNicotineDependenceFTNDMax CigarettesFactor Scores

Linkage findings on chromosome 2 suggest a gene predisposing to multiple behavioral undercontrol phenotypes

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Linkage findings on chromosome 2 suggest a gene predisposing to multiple behavioral undercontrol phenotypes

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