|Grant Number:||5P01CA089392-10 Interpret this number|
|Primary Investigator:||Bierut, Laura|
|Project Title:||The Collaborative Genetic Study of Nicotine Dependence|
DESCRIPTION (provided by applicant): This application is for a 5-year renewal of the Collaborative Genetic Study of Nicotine Dependence. Through a genome wide association and candidate gene study, we successfully identified genes contributing to the development of nicotine dependence, such as the alpha5 nicotinic cholinergic receptor subunit, CHRNA5. The goals of this program are the further identification of genes, environmental features, and biological mechanisms that contribute to the onset and persistence of smoking and nicotine dependence. Project 1 builds upon the foundation laid in the past funding period. This project will use phenotypic refinement and sophisticated genetic modeling to analyze existing data, including the nicotine metabolism endophenotype. The goal of this project is to understand how genes affect the susceptibility to develop nicotine dependence and correlated characteristics. Project 2 will use a combination of genetic and functional approaches to further identify specific risk alleles. We will genotype the most significant SNPs from our previous study in an independent case control series. Genes that show evidence of replication will undergo fine mapping and those with the most compelling evidence of association will be examined in vivo and in vitro to determine functional consequences of the risk alleles. This will shed considerable light on the biological mechanisms underlying nicotine dependence. Project 3 adds a translational component to the program by incorporating mouse genetic models of Chrna5. This will identify and characterize reinforcing and aversive properties of nicotine exposure and basic neurobiological mechanisms through which Chrna5/alpha5 contributes to nicotine addiction. Project 4 examines questions central to understanding smoking cessation and relapse. The follow-up of nicotine dependent cases recruited during the past funding period will be the first longitudinal study of addicted smokers from a community based sample. We will test candidate genes for smoking cessation and relapse; test gene interactions; and test association between candidate genes and endophenotypes involved with cessation and relapse. Our synergistic program project uses a powerful trans-disciplinary approach to suggest novel strategies for reducing tobacco consumption and decreasing the morbidity and mortality that follow.
Functional characterization improves associations between rare non-synonymous variants in CHRNB4 and smoking behavior.
Authors: Haller G, Li P, Esch C, Hsu S, Goate AM, Steinbach JH
Source: PLoS One, 2014;9(5), p. e96753.
EPub date: 2014 May 7.
Variants near CHRNB3-CHRNA6 are associated with DSM-5 cocaine use disorder: evidence for pleiotropy.
Authors: Sadler B, Haller G, Agrawal A, Culverhouse R, Bucholz K, Brooks A, Tischfield J, Johnson EO, Edenberg H, Schuckit M, Saccone N, Bierut L, Goate A
Source: Sci Rep, 2014 Mar 28;4, p. 4497.
EPub date: 2014 Mar 28.
Cis-regulatory variants affect CHRNA5 mRNA expression in populations of African and European ancestry.
Authors: Wang JC, Spiegel N, Bertelsen S, Le N, McKenna N, Budde JP, Harari O, Kapoor M, Brooks A, Hancock D, Tischfield J, Foroud T, Bierut LJ, Steinbach JH, Edenberg HJ, Traynor BJ, Goate AM
Source: PLoS One, 2013;8(11), p. e80204.
EPub date: 2013 Nov 26.
Rare missense variants in CHRNB3 and CHRNA3 are associated with risk of alcohol and cocaine dependence.
Authors: Haller G, Kapoor M, Budde J, Xuei X, Edenberg H, Nurnberger J, Kramer J, Brooks A, Tischfield J, Almasy L, Agrawal A, Bucholz K, Rice J, Saccone N, Bierut L, Goate A
Source: Hum Mol Genet, 2014 Feb 1;23(3), p. 810-9.
EPub date: 2013 Sep 20.
Long-term effects of laws governing youth access to tobacco.
Authors: Grucza RA, Plunk AD, Hipp PR, Cavazos-Rehg P, Krauss MJ, Brownson RC, Bierut LJ
Source: Am J Public Health, 2013 Aug;103(8), p. 1493-9.
EPub date: 2013 Jun 13.
Dissection of the phenotypic and genotypic associations with nicotinic dependence.
Authors: Chen LS, Baker TB, Grucza R, Wang JC, Johnson EO, Breslau N, Hatsukami D, Smith SS, Saccone N, Saccone S, Rice JP, Goate AM, Bierut LJ
Source: Nicotine Tob Res, 2012 Apr;14(4), p. 425-33.
EPub date: 2011 Nov 18.
Rare missense variants in CHRNB4 are associated with reduced risk of nicotine dependence.
Authors: Haller G, Druley T, Vallania FL, Mitra RD, Li P, Akk G, Steinbach JH, Breslau N, Johnson E, Hatsukami D, Stitzel J, Bierut LJ, Goate AM
Source: Hum Mol Genet, 2012 Feb 1;21(3), p. 647-55.
EPub date: 2011 Oct 31.
Occupation and workplace policies predict smoking behaviors: analysis of national data from the current population survey.
Authors: Ham DC, Przybeck T, Strickland JR, Luke DA, Bierut LJ, Evanoff BA
Source: J Occup Environ Med, 2011 Nov;53(11), p. 1337-45.
DSM criteria for tobacco use disorder and tobacco withdrawal: a critique and proposed revisions for DSM-5.
Authors: Baker TB, Breslau N, Covey L, Shiffman S
Source: Addiction, 2012 Feb;107(2), p. 263-75.
Functional characterization of the ?5(Asn398) variant associated with risk for nicotine dependence in the ?3?4?5 nicotinic receptor.
Authors: Li P, McCollum M, Bracamontes J, Steinbach JH, Akk G
Source: Mol Pharmacol, 2011 Nov;80(5), p. 818-27.
EPub date: 2011 Aug 19.
Cigarette smoking reduction and changes in nicotine dependence.
Authors: Mooney ME, Johnson EO, Breslau N, Bierut LJ, Hatsukami DK
Source: Nicotine Tob Res, 2011 Jun;13(6), p. 426-30.
EPub date: 2011 Mar 2.
Meta-analysis of genome-wide association studies for personality.
Authors: de Moor MH, Costa PT, Terracciano A, Krueger RF, de Geus EJ, Toshiko T, Penninx BW, Esko T, Madden PA, Derringer J, Amin N, Willemsen G, Hottenga JJ, Distel MA, Uda M, Sanna S, Spinhoven P, Hartman CA, Sullivan P, Realo A, Allik J, Heath AC, Pergadia ML, Agrawal A, Lin P, Grucza R, Nutile T, Ciullo M, Rujescu D, Giegling I, Konte B, Widen E, Cousminer DL, Eriksson JG, Palotie A, Peltonen L, Luciano M, Tenesa A, Davies G, Lopez LM, Hansell NK, Medland SE, Ferrucci L, Schlessinger D, Montgomery GW, Wright MJ, Aulchenko YS, Janssens AC, Oostra BA, Metspalu A, Abecasis GR, Deary IJ, Räikkönen K, Bierut LJ, Martin NG, van Duijn CM, Boomsma DI
Source: Mol Psychiatry, 2012 Mar;17(3), p. 337-49.
EPub date: 2010 Dec 21.
Uncovering hidden variance: pair-wise SNP analysis accounts for additional variance in nicotine dependence.
Authors: Culverhouse RC, Saccone NL, Stitzel JA, Wang JC, Steinbach JH, Goate AM, Schwantes-An TH, Grucza RA, Stevens VL, Bierut LJ
Source: Hum Genet, 2011 Feb;129(2), p. 177-88.
EPub date: 2010 Nov 16.
The restricted partition method.
Authors: Culverhouse R
Source: Adv Genet, 2010;72, p. 117-39.
Peer smoking and the nicotinic receptor genes: an examination of genetic and environmental risks for nicotine dependence.
Authors: Johnson EO, Chen LS, Breslau N, Hatsukami D, Robbins T, Saccone NL, Grucza RA, Bierut LJ
Source: Addiction, 2010 Nov;105(11), p. 2014-22.
EPub date: 2010 Sep 15.
Genetics of addictions.
Authors: Hartz SM, Bierut LJ
Source: Clin Lab Med, 2010 Dec;30(4), p. 847-64.
Nicotinic ?5 receptor subunit mRNA expression is associated with distant 5' upstream polymorphisms.
Authors: Smith RM, Alachkar H, Papp AC, Wang D, Mash DC, Wang JC, Bierut LJ, Sadee W
Source: Eur J Hum Genet, 2011 Jan;19(1), p. 76-83.
EPub date: 2010 Aug 11.
Genetics of addictions.
Authors: Hartz SM, Bierut LJ
Source: Psychiatr Clin North Am, 2010 Mar;33(1), p. 107-24.
Parental monitoring at age 11 and smoking initiation up to age 17 among Blacks and Whites: a prospective investigation.
Authors: Bohnert KM, Ríos-Bedoya CF, Breslau N
Source: Nicotine Tob Res, 2009 Dec;11(12), p. 1474-8.
EPub date: 2009 Nov 6.
Association of CHRN genes with "dizziness" to tobacco.
Authors: Ehringer MA, McQueen MB, Hoft NR, Saccone NL, Stitzel JA, Wang JC, Bierut LJ
Source: Am J Med Genet B Neuropsychiatr Genet, 2010 Mar 5;153B(2), p. 600-9.
The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans.
Authors: Saccone NL, Wang JC, Breslau N, Johnson EO, Hatsukami D, Saccone SF, Grucza RA, Sun L, Duan W, Budde J, Culverhouse RC, Fox L, Hinrichs AL, Steinbach JH, Wu M, Rice JP, Goate AM, Bierut LJ
Source: Cancer Res, 2009 Sep 1;69(17), p. 6848-56.
EPub date: 2009 Aug 25.
Risky sexual behaviors and sexually transmitted diseases: a comparison study of cocaine-dependent individuals in treatment versus a community-matched sample.
Authors: Cavazos-Rehg PA, Spitznagel EL, Schootman M, Strickland JR, Afful SE, Cottler LB, Bierut LJ
Source: AIDS Patient Care STDS, 2009 Sep;23(9), p. 727-34.
Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5.
Authors: Wang JC, Cruchaga C, Saccone NL, Bertelsen S, Liu P, Budde JP, Duan W, Fox L, Grucza RA, Kern J, Mayo K, Reyes O, Rice J, Saccone SF, Spiegel N, Steinbach JH, Stitzel JA, Anderson MW, You M, Stevens VL, Bierut LJ, Goate AM, COGEND collaborators and GELCC collaborators
Source: Hum Mol Genet, 2009 Aug 15;18(16), p. 3125-35.
EPub date: 2009 May 14.
Multiple distinct risk loci for nicotine dependence identified by dense coverage of the complete family of nicotinic receptor subunit (CHRN) genes.
Authors: Saccone NL, Saccone SF, Hinrichs AL, Stitzel JA, Duan W, Pergadia ML, Agrawal A, Breslau N, Grucza RA, Hatsukami D, Johnson EO, Madden PA, Swan GE, Wang JC, Goate AM, Rice JP, Bierut LJ
Source: Am J Med Genet B Neuropsychiatr Genet, 2009 Jun 5;150B(4), p. 453-66.