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1.  Dopamine genes and nicotine dependence in treatment seeking and community smokers 
We utilized a cohort of 828 treatment seeking self-identified white cigarette smokers (50% female) to rank candidate gene single nucleotide polymorphisms (SNPs) associated with the Fagerström Test for Nicotine Dependence (FTND), a measure of nicotine dependence which assesses quantity of cigarettes smoked and time- and place-dependent characteristics of the respondent’s smoking behavior. 1123 SNPs at 55 autosomal candidate genes, nicotinic acetylcholine receptors and genes involved in dopaminergic function, were tested for association to baseline FTND scores adjusted for age, depression, education, sex and study site. SNP P values were adjusted for the number of transmission models, the number of SNPs tested per candidate gene, and their intragenic correlation. DRD2, SLC6A3 and NR4A2 SNPs with adjusted P values < 0.10 were considered sufficiently noteworthy to justify further genetic, bioinformatic and literature analyses. Each independent signal among the top-ranked SNPs accounted for ~1% of the FTND variance in this sample. The DRD2 SNP appears to represent a novel association with nicotine dependence. The SLC6A3 SNPs have previously been shown to be associated with SLC6A3 transcription or dopamine transporter density in vitro, in vivo and ex vivo. Analysis of SLC6A3 and NR4A2 SNPs identified a statistically significant gene-gene interaction (P=0.001), consistent with in vitro evidence that the NR4A2 protein product (NURR1) regulates SLC6A3 transcription. A community cohort of N=175 multiplex ever smoking pedigrees (N=423 ever smokers) provided nominal evidence for association with the FTND at these top ranked SNPs, uncorrected for multiple comparisons.
doi:10.1038/npp.2009.52
PMCID: PMC3558036  PMID: 19494806
dopamine transporter; Fagerström Test for Nicotine Dependence; single nucleotide polymorphism; candidate gene association scan; gene-gene interaction
2.  Nicotine withdrawal sensitivity, linkage to chr6q26, and association of OPRM1 SNPs in the SMOking in FAMilies (SMOFAM) sample 
Background
Nicotine withdrawal symptoms are related to smoking cessation. A Rasch model has been used to develop a unidimensional sensitivity score representing multiple correlated measures of nicotine withdrawal. A previous autosome-wide screen identified a nonparametric linkage (NPL) log-likelihood ratio (LOD) score of 2.7 on chromosome 6q26 for the sum of nine withdrawal symptoms.
Methods
The objectives of these analyses are: a) to assess the influence of nicotine withdrawal sensitivity on relapse, b) conduct autosome-wide NPL analysis of nicotine withdrawal sensitivity among 158 pedigrees with 432 individuals with microsatellite genotypes and nicotine withdrawal scores, and c) explore family-based association of single nucleotide polymorphism (SNPs) at the mu opioid receptor (MOR) candidate gene (OPRM1) to nicotine withdrawal sensitivity in 172 nuclear pedigrees with 419 individuals with both SNP genotypes and nicotine withdrawal scores.
Results
An increased risk for relapse was associated with nicotine withdrawal sensitivity score (odds ratio, OR=1.25, 95% confidence interval, 95%CI=1.10,1.42). A maximal NPL LOD score of 3.15, suggestive of significant linkage, was identified at chr6q26 for nicotine withdrawal sensitivity. Evaluation of 18 OPRM1 SNPs via the family based association test (FBAT) with the nicotine withdrawal sensitivity score identified eight tagging SNPs with global P-values<0.05 and false discovery rate Q-values<0.06.
Conclusion
An increased risk of relapse, suggestive linkage at chr6q26, and nominally significant association with multiple OPRM1 SNPs was found with Rasch modeled nicotine withdrawal sensitivity score in a multiplex smoking pedigree sample. Future studies should attempt to replicate these findings and investigate the relationship between nicotine withdrawal symptoms and variation at OPRM1.
doi:10.1158/1055-9965.EPI-09-0960
PMCID: PMC3536862  PMID: 19959688
3.  Parenting and Trajectories of Children’s Maladaptive Behaviors: A 12-year Prospective Community Study 
This study investigated how parenting accounted for inter-individual differences in developmental trajectories of different child behaviors across childhood and adolescence. In a cohort sequential community sample of 1,049 children, latent class growth analysis was applied to three parent-reported dimensions (monitoring, positive parenting, inconsistent discipline) across 12 annual assessments (ages 6–18). Four longitudinal parenting styles (authoritative, authoritarian, indulgent, uninvolved) were differentiated on the basis of levels and rates of change in the constituent parenting dimensions. Multi-group analyses demonstrated that these parenting styles were differentially related to changes in parent- and child-reported measures of children’s alcohol and cigarette use, antisocial behavior, and internalizing symptoms, with the authoritative parenting class being related to the most optimal long-term development. Practical implications and future research suggestions are discussed.
doi:10.1080/15374416.2011.563470
PMCID: PMC3086657  PMID: 21534057
adolescence; parenting; community sample; internalizing; externalizing; latent class growth analysis; developmental trajectories
4.  The Relation of Change in Hostility and Sociability During Childhood to Substance Use in Mid Adolescence 
In a cohort-sequential longitudinal study (N = 1,075), we related change in children's hostility and sociability assessed from 1st-8th grade to their use of cigarettes, alcohol, and marijuana assessed from 9th-12th grade. Children who were more hostile at 1st grade, and had higher rates of growth of hostility, used more of all three substances at 9th grade, and those with higher initial levels of hostility increased their use of cigarettes and marijuana from 9th to 12th grade. Children who were more sociable at 1st grade used more alcohol at 9th grade. These findings demonstrate the significance of individual differences in the development of personality traits for the prediction of later substance use and have implications for prevention.
doi:10.1016/j.jrp.2009.12.006
PMCID: PMC2854561  PMID: 20401178
trait change; adolescent substance use; hostility; sociability
5.  Validity of Recall of Tobacco Use in Two Prospective Cohorts 
American Journal of Epidemiology  2010;172(7):828-835.
This project studied the convergent validity of current recall of tobacco-related health behaviors, compared with prospective self-report collected earlier at two sites. Cohorts were from the Oregon Research Institute at Eugene (N = 346, collected 19.5 years earlier) and the University of Pittsburgh, Pennsylvania (N = 294, collected 3.9 years earlier). Current recall was examined through computer-assisted interviews with the Lifetime Tobacco Use Questionnaire from 2005 through 2008. Convergent validity estimates demonstrated variability. Validity estimates of some tobacco use measures were significant for Oregon subjects (age at first cigarette, number of cigarettes/day, quit attempts yes/no and number of attempts, and abstinence symptoms at quitting; all P < 0.03). Validity estimates of Pittsburgh subjects’ self-reports of tobacco use and abstinence symptoms were significant (P < 0.001) for all tobacco use and abstinence symptoms and for responses to initial use of tobacco. These findings support the utility of collecting recalled self-report information for reconstructing salient lifetime health behaviors and underscore the need for careful interpretation.
doi:10.1093/aje/kwq179
PMCID: PMC2945825  PMID: 20720099
data collection; mental recall; prospective studies; reproducibility of results; retrospective studies; tobacco use disorder
6.  Genome-wide Linkage of Cotinine Pharmacokinetics Suggests Candidate Regions on Chromosomes 9 and 11 
Characterizing cotinine pharmacokinetics is a useful way to study nicotine metabolism because the same liver enzyme is primarily responsible for the metabolism of both, and the clearances of nicotine and cotinine are highly correlated. We conducted a whole-genome linkage analysis to search for candidate regions influencing quantitative variation in cotinine pharmacokinetics in a large-scale pharmacokinetic study with 61 families containing 224 healthy adult participants. The strongest linkage signal was identified at 135 cM of chromosome 9 with LOD=2.81 and P=0.0002; two other suggestive linkage peaks appear at 31.4 and 73.5 cM of chromosome 11 with LOD=1.96 (P=0.0013) and 1.94 (P=0.0014). The confidence level of the linkage between the three genome regions and cotinine pharmacokinetics is statistically significant with a genome-wide empirical probability of P=0.029.
doi:10.1002/ajmg.b.30859
PMCID: PMC2693302  PMID: 18785207
pharmacokinetics; nicotine; dependence; linkage analysis
7.  The Development of Children’s Intentions to Use Alcohol: Direct and Indirect Effects of Parent Alcohol Use and Parenting Behaviors 
The purpose of this study was to explore the effect of parent alcohol use and parenting behavior on the development of children’s intentions to use alcohol in grades 1 through 8. We hypothesized that the effect of parent alcohol use on children’s intention to use alcohol would be mediated through parenting behavior, specifically monitoring /supervision, positive parenting, and inconsistent discipline. Using cohort-sequential latent growth modeling (LGM), we tested three models examining the effect of the development of parent alcohol use on the development of children’s intentions to use alcohol as mediated by the development of each of the three parenting behaviors. We used multiple group analyses to explore gender differences. The effect of growth in parent alcohol use on the growth in children’s intentions was mediated only by parent monitoring/supervision and was significant only for girls. The effect of inconsistent discipline was directly related to growth in intentions for both boys and girls. Although parent alcohol use was related to less positive parenting, positive parenting was unrelated to children’s intentions to use alcohol.
doi:10.1037/0893-164X.22.3.326
PMCID: PMC2596584  PMID: 18778126
Alcohol intentions; children; parent alcohol use; parenting behavior; LGM cohort-sequential modeling
8.  Environmental and Genetic Determinants of Tobacco Use: Methodology for a Multidisciplinary, Longitudinal Family-Based Investigation1 
This article describes the ongoing collaborative effort of six research teams to operationalize and execute an integrative approach to the study of gene × environment interactions in the development of tobacco dependence. At the core of the project is a longitudinal investigation of social and behavioral risk factors for tobacco use in individuals who were, on average, 13 years of age at intake and for whom smoking outcomes extending from early adolescence to young adulthood have been characterized previously (current average age of the cohort is 29 years). The conceptual framework for the integrative approach and the longitudinal investigation on which the study is based is presented. A description is also provided of the methods used to: (a) recruit participants and families to provide DNA samples and information on tobacco use; (b) assess participants for relevant tobacco-related phenotypes including smoking history, current use of tobacco, and nicotine metabolism; (c) assess the quality of the DNA samples collected from participants for genome-wide scanning and candidate gene analysis; (d) examine several research questions concerning the role of genetic and environmental factors in the onset and maintenance of tobacco use; and (e) ensure adherence to local and federal guidelines for ethical and legal investigations of genotypic associations with tobacco-related phenotypes in families. This investigation is unique among ongoing studies of the genetics of tobacco dependence in the extent to which equal importance has been assigned to both phenotypic and genotypic measurements.
PMCID: PMC2587265  PMID: 14578134
9.  A Genome-Wide Screen for Nicotine Dependence Susceptibility Loci 
Genome-wide model free linkage analysis was conducted for nicotine dependence and tobacco use phenotypes in 607 members of 158 nuclear families consisting of at least two ever smokers (100 or more cigarettes smoked in lifetime). DNA from whole blood was genotyped for 739 autosomal microsatellite polymorphisms with an average inter-marker distance of 4.6 cM. A peak LOD score of 2.7 was observed on chromosome 6 for scores for the Fagerström Test for Nicotine Dependence. Exploratory analyses were conducted to determine whether sequence variation at other loci affected other measures of dependence or tobacco use. Four additional loci with LOD scores of 2.7 or more were associated with alternative measures of nicotine dependence, one with current frequency of use, and one with smoking cessation. Several of the corresponding support intervals were near putative loci reported previously (on chromosomes 6, 7, and 8) while others appear to be novel (on chromosomes 5, 16, and 19).
doi:10.1002/ajmg.b.30315
PMCID: PMC2563426  PMID: 16671072
nicotine; dependence; linkage; genetics; smoking
10.  Adolescents’ Relationships with Their Mothers and Fathers: Associations with Depressive Disorder and Subdiagnostic Symptomatology 
Journal of abnormal psychology  2007;116(1):144-154.
This study compared family relationships across three groups of adolescents: a) those with unipolar depressive disorders (n = 82); b) those with subdiagnostic depressive symptoms (n = 78); and c) those without emotional or behavioral difficulties (n = 83). Results based on multi-source, multi-method constructs indicated that depressed adolescents, as well as those with subdiagnostic symptomatology, experience less supportive and more conflictual relationships with each of their parents than do healthy adolescents. These findings are notable in demonstrating that adverse father-adolescent relationships are associated with depressive symptomatology in much the same way as mother-adolescent relationships. As well, they add to the emerging evidence that adolescents with subdiagnostic symptoms experience difficulties in social relationships similar to those experienced by adolescents with depressive disorder.
doi:10.1037/0021-843X.116.1.144
PMCID: PMC2249923  PMID: 17324025
11.  Elementary School Age Children’s Future Intentions and Use of Substances 
This study describes the lifetime prevalence and future intentions related to trying cigarettes, chewing tobacco, alcohol, marijuana, and inhalants of students in the 1st through 7th grade. This article also describes the identification of these substances by children in the 1st through 3rd grade. Participants were 1,075 1st through 5th graders within a school district in western Oregon who were followed for 3 years. Across most substances, prevalence and intentions increased with grade, with a moderate increase between 3rd and 4th grade and a larger increase between 5th and 6th grade. Boys were more likely than girls to identify alcohol and cigarettes and were more likely than girls to report trying chewing tobacco. In addition, 3rd-grade boys were more likely to identify marijuana and, in the early grades, alcohol. Boys were also more likely than girls to intend to use tobacco and drink alcohol when older. For alcohol and cigarettes, intention was related to subsequent trying of the substance, suggesting that intention may be an early warning sign of subsequent substance use.
PMCID: PMC1764642  PMID: 14710464

Results 1-11 (11)