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Linkage scan of nicotine dependence in the University of California, San Francisco (UCSF) Family Alcoholism Study

  • I. R. Gizer (a1) (a2), C. L. Ehlers (a3), C. Vieten (a4), K. L. Seaton-Smith (a1), H. S. Feiler (a5), J. V. Lee (a6), S. K. Segall (a1), D. A. Gilder (a3) and K. C. Wilhelmsen (a1) (a2) (a7)...



Nicotine dependence has been shown to represent a heritable condition, and several research groups have performed linkage analysis to identify genomic regions influencing this disorder though only a limited number of the findings have been replicated.


In the present study, a genome-wide linkage scan for nicotine dependence was conducted in a community sample of 950 probands and 1204 relatives recruited through the University of California, San Francisco (UCSF) Family Alcoholism Study. A modified version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) with additional questions that probe nicotine use was used to derive DSM-IV nicotine dependence diagnoses.


A locus on chromosome 2q31.1 at 184 centiMorgans nearest to marker D2S2188 yielded a logarithm (base 10) of odds (LOD) score of 3.54 (point-wise empirical p=0.000012). Additional peaks of interest were identified on chromosomes 2q13, 4p15.33-31, 11q25 and 12p11.23-21. Follow-up analyses were conducted examining the contributions of individual nicotine dependence symptoms to the chromosome 2q31.1 linkage peak as well as examining the relationship of this chromosomal region to alcohol dependence.


The present report suggests that chromosome 2q31.1 confers risk to the development of nicotine dependence and that this region influences a broad range of nicotine dependence symptoms rather than a specific facet of the disorder. Further, the results show that this region is not linked to alcohol dependence in this population, and thus may influence nicotine dependence specifically.


Corresponding author

*Address for correspondence: I. R. Gizer, Ph.D., University of North Carolina at Chapel Hill, 120 Mason Farm Road, Room 5015 Genetic Medicine Building CB 7264, Chapel Hill, NC 27599-7264, USA. (Email:


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Abecasis, GR, Cherny, SS, Cookson, WO, Cardon, LR (2002). Merlin – rapid analysis of dense genetic maps using sparse gene flow trees. Nature Genetics 30, 97–101.
Almasy, L, Blangero, J (1998). Multipoint quantitative-trait linkage analysis in general pedigrees. American Journal of Human Genetics 62, 11981211.
Amos, CI, Krushkal, J, Thiel, TJ, Young, A, Zhu, DK, Boerwinkle, E, de Andrade, M (1997). Comparison of model-free linkage mapping strategies for the study of a complex trait. Genetic Epidemiology 14, 743748.
APA (1994). Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. American Psychiatric Association: Washington.
Bergen, AW, Korczak, JF, Weissbecker, KA, Goldstein, AM (1999). A genome-wide search for loci contributing to smoking and alcoholism. Genetic Epidemiology 17 (Suppl.), S55S60.
Bierut, LJ, Madden, PA, Breslau, N, Johnson, EO, Hatsukami, D, Pomerleau, OF, Swan, GE, Rutter, J, Bertelsen, S, Fox, L, Fugman, D, Goate, AM, Hinrichs, AL, Konvicka, K, Martin, NG, Montgomery, GW, Saccone, NL, Saccone, SF, Wang, JC, Chase, GA, Rice, JP, Ballinger, DG (2007). Novel genes identified in a high-density genome wide association study for nicotine dependence. Human Molecular Genetics 16, 2435.
Bierut, LJ, Rice, JP, Goate, A, Hinrichs, AL, Saccone, NL, Foroud, T, Edenberg, HJ, Cloninger, CR, Begleiter, H, Conneally, PM, Crowe, RR, Hesselbrock, V, Li, TK, Nurnberger, JI Jr., Porjesz, B, Schuckit, MA, Reich, T (2004). A genomic scan for habitual smoking in families of alcoholics: common and specific genetic factors in substance dependence. American Journal of Medical Genetics 124A, 1927.
Bucholz, KK, Cadoret, R, Cloninger, CR, Dinwiddie, SH, Hesselbrock, VM, Nurnberger, JI Jr., Reich, T, Schmidt, I, Schuckit, MA (1994). A new, semi-structured psychiatric interview for use in genetic linkage studies: a report on the reliability of the SSAGA. Journal of Studies on Alcohol 55, 149158.
Carmelli, D, Swan, GE, Robinette, D, Fabsitz, RR (1990). Heritability of substance use in the NAS-NRC Twin Registry. Acta Geneticae Medicae et Gemellologiae (Roma) 39, 9198.
Carre, N, Cauzac, M, Girard, J, Burnol, AF (2008). Dual effect of the adapter growth factor receptor-bound protein 14 (grb14) on insulin action in primary hepatocytes. Endocrinology 149, 31093117.
Duggirala, R, Almasy, L, Blangero, J (1999). Smoking behavior is under the influence of a major quantitative trait locus on human chromosome 5q. Genetic Epidemiology 17 (Suppl.), S139S144.
Duggirala, R, Blangero, J, Almasy, L, Arya, R, Dyer, TD, Williams, KL, Leach, RJ, O'Connell, P, Stern, MP (2001). A major locus for fasting insulin concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans. American Journal of Human Genetics 68, 11491164.
Duggirala, R, Williams, JT, Williams-Blangero, S, Blangero, J (1997). A variance component approach to dichotomous trait linkage analysis using a threshold model. Genetic Epidemiology 14, 987992.
Ehlers, CL, Wilhelmsen, KC (2006). Genomic screen for loci associated with tobacco usage in Mission Indians. BMC Medical Genetics 7, 19.
Faraone, SV, Su, J, Taylor, L, Wilcox, M, Van Eerdewegh, P, Tsuang, MT (2004). A novel permutation testing method implicates sixteen nicotinic acetylcholine receptor genes as risk factors for smoking in schizophrenia families. Human Heredity 57, 5968.
Goode, EL, Badzioch, MD, Kim, H, Gagnon, F, Rozek, LS, Edwards, KL, Jarvik, GP; Framingham Heart Study (2003). Multiple genome-wide analyses of smoking behavior in the Framingham Heart Study. BMC Genetics 4 (Suppl.), S102.
Goring, HH (2002). Hlod (Homo v. 0.2) documentation. SOLAR Online User's Manual (
Heath, AC, Madden, PA (1995). Genetic influences on smoking behavior. In Behavior Genetic Approaches in Behavioral Medicine (ed. Turner, J. R., Cardon, L. R. and Hewitt, J. K.), pp. 4566. New York: Plenum.
Heatherton, TF, Kozlowski, LT, Frecker, RC, Fagerström, KO (1991). The Fagerström Test for Nicotine Dependence: a revision of the Fagerström Tolerance Questionnaire. British Journal of Addiction 86, 11191127.
Jia, J, Han, Q, Borregaard, N, Lollike, K, Cygler, M (2000). Crystal structure of human grancalcin, a member of the penta-EF-hand protein family. Journal of Molecular Biology 300, 12711281.
Jung, J, Weeks, DE, Feingold, E (2006). Gene-dropping vs. empirical variance estimation for allele-sharing linkage statistics. Genetic Epidemiology 30, 652665.
Kendler, KS, Myers, J, Prescott, CA (2007). Specificity of genetic and environmental risk factors for symptoms of cannabis, cocaine, alcohol, caffeine, and nicotine dependence. Archives of General Psychiatry 64, 13131320.
Kendler, KS, Neale, MC, Sullivan, P, Corey, LA, Gardner, CO, Prescott, CA (1999). A population-based twin study in women of smoking initiation and nicotine dependence. Psychological Medicine 29, 299308.
Kong, A, Cox, NJ (1997). Allele-sharing models: LOD scores and accurate linkage tests. American Journal of Human Genetics 61, 11791188.
Lander, E, Kruglyak, L (1995). Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genetics 11, 241247.
Lessov, CN, Martin, NG, Statham, DJ, Todorov, AA, Slutske, WS, Bucholz, KK, Heath, AC, Madden, PAF (2004). Defining nicotine dependence for genetic research: evidence from Australian twins. Psychological Medicine 34, 865879.
Li, MD (2008). Identifying susceptibility loci for nicotine dependence: 2008 update based on recent genome-wide linkage analyses. Human Genetics 123, 119131.
Li, MD, Cheng, R, Ma, JZ, Swan, GE (2003). A meta-analysis of estimated genetic and environmental effects on smoking behavior in male and female adult twins. Addiction 98, 2331.
Li, MD, Ma, JZ, Payne, TJ, Lou, XY, Zhang, D, Dupont, RT, Elston, RC (2008). Genome-wide linkage scan for nicotine dependence in European Americans and its converging results with African Americans in the Mid-South Tobacco Family sample. Molecular Psychiatry 13, 407416.
Lou, XY, Ma, JZ, Payne, TJ, Beuten, J, Crew, KM, Li, MD (2006). Gene-based analysis suggests association of the nicotinic acetylcholine receptor β1 subunit (CHRNB1) and M1 muscarinic acetylcholine receptor (CHRM1) with vulnerability for nicotine dependence. Human Genetics 120, 381389.
Loukola, A, Broms, U, Maunu, H, Widen, E, Heikkila, K, Siivola, M, Salo, A, Pergadia, ML, Nyman, E, Sammalisto, S, Perola, M, Agrawal, A, Heath, AC, Martin, NG, Madden, PA, Peltonen, L, Kaprio, J (2008). Linkage of nicotine dependence and smoking behavior on 10q, 7q and 11p in twins with homogeneous genetic background. Pharmacogenomics Journal 8, 209219.
McPeek, MS, Sun, L (2000). Statistical tests for detection of misspecified relationships by use of genome-screen data. American Journal of Human Genetics 66, 10761094.
Miller, NS, Gold, MS (1998). Comorbid cigarette and alcohol addiction: epidemiology and treatment. Journal of Addictive Diseases 17, 5566.
Mokdad, AH, Marks, JS, Stroup, DF, Gerberding, JL (2004). Actual causes of death in the United States, 2000. Journal of the American Medical Association 291, 12381245.
Morley, KI, Medland, SE, Ferreira, MA, Lynskey, MT, Montgomery, GW, Heath, AC, Madden, PA, Martin, NG (2006). A possible smoking susceptibility locus on chromosome 11p12: evidence from sex-limitation linkage analyses in a sample of Australian Twin Families. Behavior Genetics 36, 8799.
Munafö, M, Clark, T, Johnstone, E, Murphy, M, Walton, R (2004). The genetic basis for smoking behavior: a systematic review and meta-analysis. Nicotine & Tobacco Research 6, 583597.
North, BV, Curtis, D, Sham, PC (2002). A note on the calculation of empirical P values from Monte Carlo procedures. American Journal of Human Genetics 71, 439441.
Nussbaum, J, Xu, Q, Payne, TJ, Ma, JZ, Huang, W, Gelernter, J, Li, MD (2008). Significant association of the neurexin-1 gene (NRXN1) with nicotine dependence in European- and African-American smokers. Human Molecular Genetics 17, 15691577.
O'Connell, JR, Weeks, DE (1998). PedCheck: a program for identification of genotype incompatibilities in linkage analysis. American Journal of Human Genetics 63, 259266.
Seaton, KL, Cornell, JL, Wilhelmsen, KC, Vieten, C (2004). Effective strategies for recruiting families ascertained through alcoholic probands. Alcoholism: Clinical and Experimental Research 28, 7884.
Sherva, R, Wilhelmsen, K, Pomerleau, CS, Chasse, SA, Rice, JP, Snedecor, SM, Bierut, LJ, Neuman, RJ, Pomerleau, OF (2008). Association of a single nucleotide polymorphism in neuronal acetylcholine receptor subunit α5 (CHRNA5) with smoking status and with ‘pleasurable buzz’ during early experimentation with smoking. Addiction 103, 15441552.
Straub, RE, Sullivan, PF, Ma, Y, Myakishev, MV, Harris-Kerr, C, Wormley, B, Kadambi, B, Sadek, H, Silverman, MA, Webb, BT, Neale, MC, Bulik, CM, Joyce, PR, Kendler, KS (1999). Susceptibility genes for nicotine dependence: a genome scan and followup in an independent sample suggest that regions on chromosomes 2, 4, 10, 16, 17 and 18 merit further study. Molecular Psychiatry 4, 129144.
Su, AI, Wiltshire, T, Batalov, S, Lapp, H, Ching, KA, Block, D, Zhang, J, Soden, R, Hayakawa, M, Kreiman, G, Cooke, MP, Walker, JR, Hogenesch, JB (2004). A gene atlas of the mouse and human protein-encoding transcriptomes. Proceedings of the National Academy of Sciences USA 101, 60626067.
Sullivan, PF, Kendler, KS (1999). The genetic epidemiology of smoking. Nicotine & Tobacco Research 1, S51–57.
Sullivan, PF, Kuo, PH, Webb, BT, Neale, MC, Vittum, J, Furberg, H, Walsh, D, Patterson, DG, Riley, B, Prescott, CA, Kendler, KS (2008). Genomewide linkage survey of nicotine dependence phenotypes. Drug and Alcohol Dependence 93, 210216.
Sullivan, PF, Neale, BM, van den Oord, E, Miles, MF, Neale, MC, Bulik, CM, Joyce, PR, Straub, RE, Kendler, KS (2004). Candidate genes for nicotine dependence via linkage, epistasis, and bioinformatics. American Journal of Medical Genetics 126B, 2336.
Swan, GE, Carmelli, D, Cardon, LR (1997). Heavy consumption of cigarettes, alcohol and coffee in male twins. Journal of Studies on Alcohol 58, 182190.
True, WR, Xian, H, Scherrer, JF, Madden, PA, Bucholz, KK, Heath, AC, Eisen, SA, Lyons, MJ, Goldberg, J, Tsuang, M (1999). Common genetic vulnerability for nicotine and alcohol dependence in men. Archives of General Psychiatry 56, 655661.
Vieten, C, Seaton, KL, Feiler, HS, Wilhelmsen, KC (2004). The University of California, San Francisco Family Alcoholism Study. I. Design, methods, and demographics. Alcoholism: Clinical and Experimental Research 28, 15091516.
Vink, JM, Smit, AB, de Geus, EJ, Sullivan, P, Willemsen, G, Hottenga, JJ, Smit, JH, Hoogendijk, WJ, Zitman, FG, Peltonen, L, Kaprio, J, Pedersen, NL, Magnusson, PK, Spector, TD, Kyvik, KO, Morley, KI, Heath, AC, Martin, NG, Westendorp, RG, Slagboom, PE, Tiemeier, H, Hofman, A, Uitterlinden, AG, Aulchenko, YS, Amin, N, van Duijn, C, Penninx, BW, Boomsma, DI (2009). Genome-wide association study of smoking initiation and current smoking. American Journal of Human Genetics 84, 367379.
Volk, HE, Scherrer, JF, Bucholz, KK, Todorov, A, Heath, AC, Jacob, T, True, WR (2007). Evidence for specificity of transmission of alcohol and nicotine dependence in an offspring of twins design. Drug and Alcohol Dependence 87, 225232.
Wang, D, Ma, JZ, Li, MD (2005). Mapping and verification of susceptibility loci for smoking quantity using permutation linkage analysis. Pharmacogenomics Journal 5, 166172.
Wilhelmsen, KC, Schuckit, M, Smith, TL, Lee, JV, Segall, SK, Feiler, HS, Kalmijn, J (2003). The search for genes related to a low-level response to alcohol determined by alcohol challenges. Alcoholism: Clinical and Experimental Research 27, 10411047.
Yang, HC, Chang, CC, Lin, CY, Chen, CL, Lin, CY, Fann, CS (2005). A genome-wide scanning and fine mapping study of COGA data. BMC Genetics 6 (Suppl.), S30.


Linkage scan of nicotine dependence in the University of California, San Francisco (UCSF) Family Alcoholism Study

  • I. R. Gizer (a1) (a2), C. L. Ehlers (a3), C. Vieten (a4), K. L. Seaton-Smith (a1), H. S. Feiler (a5), J. V. Lee (a6), S. K. Segall (a1), D. A. Gilder (a3) and K. C. Wilhelmsen (a1) (a2) (a7)...


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