Environmental Smoking and Smoking Onset in Adolescence: The Role of Dopamine-Related Genes. Findings from Two Longitudinal Studies

Although environmental smoking (i.e., paternal and maternal smoking, sibling smoking, and peer smoking) is one of the most important factors for explaining adolescent smoking behavior, not all adolescents are similarly affected. The extent to which individuals are vulnerable to smoking in their environment might depend on genetic factors. The aim of this study was to examine the interplay between environmental smoking and genes encoding components of the dopaminergic system (i.e., dopamine receptor D2, D4, and dopamine transporter DAT1) in adolescent smoking onset. Data from two longitudinal studies were used. Study 1 consisted of 991 non-smoking early adolescents (mean age = 12.52, SD = .57) whereas study 2 consisted of 365 non-smoking middle to late adolescents (mean age = 14.16, SD = 1.07) who were followed for 16 and 48 months, respectively. Logistic regression analyses were conducted using Mplus. In study 1, we found positive associations between parents'' and friends'' smoking at the first measurement and smoking status 16 months later. In study 2 we found a positive association between friends'' smoking and smoking onset 48 months later. Neither study demonstrated any interaction effects of the DRD2, DRD4, or DAT1 genotypes. In conclusion, the effects of environmental smoking on smoking onset are similar for adolescent carriers and non-carriers of these specific genes related to the dopaminergic system.     

Genetic Variations in COMT and DRD2 Modulate Attentional Bias for Affective Facial Expressions

Studies have revealed that catechol-O-methyltransferase (COMT) and dopaminegic receptor2 (DRD2) modulate human attention bias for palatable food or tobacco. However, the existing evidence about the modulations of COMT and DRD2 on attentional bias for facial expressions was still limited. In the study, 650 college students were genotyped with regard to COMT Val158Met and DRD2 TaqI A polymorphisms, and the attentional bias for facial expressions was assessed using the spatial cueing task. The results indicated that COMT Val158Met underpinned the individual difference in attentional bias for negative emotional expressions (P = 0.03) and the Met carriers showed more engagement bias for negative expressions than the Val/Val homozygote. On the contrary, DRD2 TaqIA underpinned the individual difference in attentional bias for positive expressions (P = 0.003) and individuals with TT genotype showed much more engagement bias for positive expressions than the individuals with CC genotype. Moreover, the two genes exerted significant interactions on the engagements for negative and positive expressions (P = 0.046, P = 0.005). These findings suggest that the individual differences in the attentional bias for emotional expressions are partially underpinned by the genetic polymorphisms in COMT and DRD2.     

Dopamine Genetic Risk Score Predicts Depressive Symptoms in Healthy Adults and Adults with Depression

Background

Depression is a common source of human disability for which etiologic insights remain limited. Although abnormalities of monoamine neurotransmission, including dopamine, are theorized to contribute to the pathophysiology of depression, evidence linking dopamine-related genes to depression has been mixed. The current study sought to address this knowledge-gap by examining whether the combined effect of dopamine polymorphisms was associated with depressive symptomatology in both healthy individuals and individuals with depression.

Methods

Data were drawn from three independent samples: (1) a discovery sample of healthy adult participants (n = 273); (2) a replication sample of adults with depression (n = 1,267); and (3) a replication sample of healthy adult participants (n = 382). A genetic risk score was created by combining functional polymorphisms from five genes involved in synaptic dopamine availability (COMT and DAT) and dopamine receptor binding (DRD1, DRD2, DRD3).

Results

In the discovery sample, the genetic risk score was associated with depressive symptomatology (β = −0.80, p = 0.003), with lower dopamine genetic risk scores (indicating lower dopaminergic neurotransmission) predicting higher levels of depression. This result was replicated with a similar genetic risk score based on imputed genetic data from adults with depression (β = −0.51, p = 0.04). Results were of similar magnitude and in the expected direction in a cohort of healthy adult participants (β = −0.86, p = 0.15).

Conclusions

Sequence variation in multiple genes regulating dopamine neurotransmission may influence depressive symptoms, in a manner that appears to be additive. Further studies are required to confirm the role of genetic variation in dopamine metabolism and depression.     

The Association between Vitamin D and Vascular Stiffness in Adolescents with and without Type 1 Diabetes

Objective

Vitamin D deficiency is common and associated with increased cardiovascular disease (CVD) risk. Pulse wave velocity (PWV) is a marker of vascular stiffness associated with CVD. We hypothesized that Vitamin D (25 (OH) D) levels would be inversely associated with PWV in youth with and without type 1 diabetes (T1D).

Study Design

Comparisons were made between adolescents with T1D (n = 211; age = 17.5±2.3 years; diabetes duration = 10.9±3.2 years; A1c = 9.1±1.7%) and non-DM controls (n = 67; age = 16.9±1.9 years). PWV was measured in the carotid-femoral segment (Sphygmocor Vx, AtCor Medical, Lisle, IL).

Results

Vitamin D levels were similar in adolescents with T1D and controls (27.7±0.7 v. 26.0±1.3 ng/ml; p = 0.26). Vitamin D was significantly inversely associated with PWV after adjusting for age, sex, quarter of the year, and race-ethnicity in adolescents with T1D (beta  = −0.01±0.004, p = 0.02) but not in the non-DM adolescents (beta  = −0.008±0.008, p = 0.32). Vitamin D remained significantly associated with PWV after additionally adjusting for hs-CRP in adolescents with T1D (−0.01±0.004, p = 0.01). After adjusting for BMI z-score, lipids, or blood pressure, the relationship of Vitamin D with PWV was not significant.

Conclusions

Vitamin D levels were inversely associated with PWV in adolescents with T1D, but not independently of BMI, lipids, or blood pressure. Our data contrast with other reports and suggest further research is indicated to determine if Vitamin D supplementation would be beneficial to lower CVD risk in adolescents with T1D with vitamin D insufficiency or deficiency.     

Quality of Life and Costs in Parkinson's Disease: A Cross Sectional Study in Hungary

Background

Patient reported outcomes and costs of illness are useful to capture some of the multiple effects of a disease and its treatments. Our aim was to assess quality of life (QoL) and costs of Parkinson''s disease (PD) in Hungary, and to analyze their associations.

Methods

A cross-sectional questionnaire survey was conducted in one neurology university clinic. Clinical characteristics, PD related resource utilizations and productivity loss in the past 12 months were recorded; the Hoehn&Yahr (HY) scale, PDQ-39 and EQ-5D questionnaires were applied. Cost calculation was performed from the societal perspective.

Results

110 patients (34.5% female) were involved with mean age of 63.3 (SD = 11.3) and disease duration of 8.2 (SD = 5.8) years. PDQ-39 summary score was 48.1 (SD = 13.4). The average EQ-5D score was 0.59 (SD = 0.28), and was significantly lower than the population norm in age-groups 45–74. The correlation was significant between EQ-5D and PDQ-39 (−0.47, p = 0.000), the HY scale and EQ-5D (−0.3416, p = 0.0008) and PDQ-39 (0.3419, p = 0.0006) scores. The total mean cost was €6030.2 (SD = 6163.0)/patient/year (direct medical 35.7%, direct non-medical 29.4%, indirect cost 34.9%). A one year increase in disease duration and 0.1 decrease of the EQ-5D utility score increase the yearly costs by 8 to 10%, and 7.8%, respectively. The effect of the PDQ-39 score on total cost was not significant.

Conclusions

Disease severity and public health importance of PD are clearly demonstrated by the magnitude of QoL loss. PD-related costs are substantial, but are much lower in Hungary than in Western European countries. Disease duration and EQ-5D score are significant proxy of costs.     

Characterization of a Subtropical Hawksbill Sea Turtle (Eretmocheyles imbricata) Assemblage Utilizing Shallow Water Natural and Artificial Habitats in the Florida Keys

In order to provide information to better inform management decisions and direct further research, vessel-based visual transects, snorkel transects, and in-water capture techniques were used to characterize hawksbill sea turtles in the shallow marine habitats of a Marine Protected Area (MPA), the Key West National Wildlife Refuge in the Florida Keys. Hawksbills were found in hardbottom and seagrass dominated habitats throughout the Refuge, and on man-made rubble structures in the Northwest Channel near Cottrell Key. Hawksbills captured (N = 82) were exclusively juveniles and subadults with a straight standard carapace length (SSCL) ranging from 21.4 to 69.0cm with a mean of 44.1 cm (SD = 10.8). Somatic growth rates were calculated from 15 recaptured turtles with periods at large ranging from 51 to 1188 days. Mean SSCL growth rate was 7.7 cm/year (SD = 4.6). Juvenile hawksbills (<50 cm SSCL) showed a significantly higher growth rate (9.2 cm/year, SD = 4.5, N = 11) than subadult hawksbills (50–70 cm SSCL, 3.6 cm/year, SD = 0.9, N = 4). Analysis of 740 base pair mitochondrial control region sequences from 50 sampled turtles yielded 12 haplotypes. Haplotype frequencies were significantly different compared to four other Caribbean juvenile foraging aggregations, including one off the Atlantic coast of Florida. Many-to-one mixed stock analysis indicated Mexico as the primary source of juveniles in the region and also suggested that the Refuge may serve as important developmental habitat for the Cuban nesting aggregation. Serum testosterone radioimmunoassay results from 33 individuals indicated a female biased sex ratio of 3.3 females: 1 male for hawksbills in the Refuge. This assemblage of hawksbills is near the northern limit of the species range, and is one of only two such assemblages described in the waters of the continental United States. Since this assemblage resides in an MPA with intensive human use, basic information on the assemblage is vital to resource managers charged with conservation and species protection in the MPA.     

Joint analysis of the DRD5 marker concludes association with attention-deficit/hyperactivity disorder confined to the predominantly inattentive and combined subtypes

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable, heterogeneous disorder of early onset, consisting of a triad of symptoms: inattention, hyperactivity, and impulsivity. The disorder has a significant genetic component, and theories of etiology include abnormalities in the dopaminergic system, with DRD4, DAT1, SNAP25, and DRD5 being implicated as major susceptibility genes. An initial report of association between ADHD and the common 148-bp allele of a microsatellite marker located 18.5 kb from the DRD5 gene has been followed by several studies showing nonsignificant trends toward association with the same allele. To establish the postulated association of the (CA)(n) repeat with ADHD, we collected genotypic information from 14 independent samples of probands and their parents, analyzed them individually and, in the absence of heterogeneity, analyzed them as a joint sample. The joint analysis showed association with the DRD5 locus (P=.00005; odds ratio 1.24; 95% confidence interval 1.12-1.38). This association appears to be confined to the predominantly inattentive and combined clinical subtypes.     

Dopamine transporter (DAT1) and dopamine receptor D4 (DRD4) genotypes differentially impact on electrophysiological correlates of error processing

Recent studies as well as theoretical models of error processing assign fundamental importance to the brain's dopaminergic system. Research about how the electrophysiological correlates of error processing--the error-related negativity (ERN) and the error positivity (Pe)--are influenced by variations of common dopaminergic genes, however, is still relatively scarce. In the present study, we therefore investigated whether polymorphisms in the DAT1 gene and in the DRD4 gene, respectively, lead to interindividual differences in these error processing correlates. One hundred sixty participants completed a version of the Eriksen Flanker Task while a 26-channel EEG was recorded. The task was slightly modified in order to increase error rates. During data analysis, participants were split into two groups depending on their DAT1 and their DRD4 genotypes, respectively. ERN and Pe amplitudes after correct responses and after errors as well as difference amplitudes between errors and correct responses were analyzed. We found a differential effect of DAT1 genotype on the Pe difference amplitude but not on the ERN difference amplitude, while the reverse was true for DRD4 genotype. These findings are in line with predictions from theoretical models of dopaminergic transmission in the brain. They furthermore tie results from clinical investigations of disorders impacting on the dopamine system to genetic variations known to be at-risk genotypes.     

Dopamine D1 Receptor Gene Variation Modulates Opioid Dependence Risk by Affecting Transition to Addiction

Dopamine D1 receptor (DRD1) modulates opioid reinforcement, reward, and opioid-induced neuroadaptation. We propose that DRD1 polymorphism affects susceptibility to opioid dependence (OD), the efficiency of transition to OD, and opioid-induced pleasure response. We analyzed potential association between seven DRD1 polymorphisms with the following traits: duration of transition from the first use to dependence (DTFUD), subjective pleasure responses to opioid on first use and post-dependence use, and OD risk in 425 Chinese with OD and 514 healthy controls. DTFUD and level of pleasure responses were examined using a semi-structured interview. The DTFUD of opioid addicts ranged from 5 days to 11 years. Most addicts (64.0%) reported non-comfortable response upon first opioid use, while after dependence, most addicts (53.0%) felt strong opioid-induced pleasure. Survival analysis revealed a correlation of prolonged DTFUD with the minor allele-carrying genotypes of DRD1 rs4532 (hazard ratios (HR) = 0.694; p = 0.001) and rs686 (HR = 0.681, p = 0.0003). Binary logistic regression indicated that rs10063995 GT genotype (vs. GG+TT, OR = 0.261) could predict decreased pleasure response to first-time use and the minor alleles of rs686 (OR = 0.535) and rs4532 (OR = 0.537) could predict decreased post-dependence pleasure. Moreover, rs686 minor allele was associated with a decreased risk for rapid transition from initial use to dependence (DTFUD≤30 days; OR = 0.603) or post-dependence euphoria (OR = 0.603) relative to major allele. In conclusion, DRD1 rs686 minor allele decreases the OD risk by prolonging the transition to dependence and attenuating opioid-induced pleasure in Chinese.     

E-Cigarette Use among Smokers with Serious Mental Illness

Background

We examined electronic cigarette (EC) use, correlates of use, and associated changes in smoking behavior among smokers with serious mental illness in a clinical trial.

Methods

Adult smokers were recruited during acute psychiatric hospitalization (N = 956, 73% enrollment among approached smokers) in the San Francisco Bay Area between 2009–2013. At baseline, participants averaged 17 (SD = 10) cigarettes per day for 19 (SD = 14) years; 24% intended to quit smoking in the next month. Analyses examined frequency and correlates of EC use reported over the 18-month trial and changes in smoking behavior by EC use status.

Findings

EC use was 11% overall, and by year of enrollment, increased from 0% in 2009 to 25% in 2013. In multiple logistic regression, the likelihood of EC use was significantly greater with each additional year of recruitment, for those aged 18–26, and for those in the preparation versus precontemplation stage of change, and unlikely among Hispanic participants. EC use was unrelated to gender, psychiatric diagnosis, and measures of tobacco dependence at baseline. Further, over the 18-month trial, EC use was not associated with changes in smoking status or, among continued smokers, with reductions in cigarettes per day.

Interpretation

Within a clinical trial with smokers with serious mental illness, EC use increased over time, particularly among younger adults and those intending to quit tobacco. EC use was unrelated to changes in smoking. The findings are of clinical interest and warrant further study.     

Management of Deep Brain Stimulator Battery Failure: Battery Estimators,Charge Density,and Importance of Clinical Symptoms

Objective

We aimed in this investigation to study deep brain stimulation (DBS) battery drain with special attention directed toward patient symptoms prior to and following battery replacement.

Background

Previously our group developed web-based calculators and smart phone applications to estimate DBS battery life (http://mdc.mbi.ufl.edu/surgery/dbs-battery-estimator).

Methods

A cohort of 320 patients undergoing DBS battery replacement from 2002–2012 were included in an IRB approved study. Statistical analysis was performed using SPSS 20.0 (IBM, Armonk, NY).

Results

The mean charge density for treatment of Parkinson’s disease was 7.2 µC/cm²/phase (SD = 3.82), for dystonia was 17.5 µC/cm²/phase (SD = 8.53), for essential tremor was 8.3 µC/cm²/phase (SD = 4.85), and for OCD was 18.0 µC/cm²/phase (SD = 4.35). There was a significant relationship between charge density and battery life (r = −.59, p<.001), as well as total power and battery life (r = −.64, p<.001). The UF estimator (r = .67, p<.001) and the Medtronic helpline (r = .74, p<.001) predictions of battery life were significantly positively associated with actual battery life. Battery status indicators on Soletra and Kinetra were poor predictors of battery life. In 38 cases, the symptoms improved following a battery change, suggesting that the neurostimulator was likely responsible for symptom worsening. For these cases, both the UF estimator and the Medtronic helpline were significantly correlated with battery life (r = .65 and r = .70, respectively, both p<.001).

Conclusions

Battery estimations, charge density, total power and clinical symptoms were important factors. The observation of clinical worsening that was rescued following neurostimulator replacement reinforces the notion that changes in clinical symptoms can be associated with battery drain.     

Associations between Family-Related Factors,Breakfast Consumption and BMI among 10- to 12-Year-Old European Children: The Cross-Sectional ENERGY-Study

Objective

To investigate associations of family-related factors with children’s breakfast consumption and BMI-z-score and to examine whether children’s breakfast consumption mediates associations between family-related factors and children’s BMI-z-score.

Subjects

Ten- to twelve-year-old children (n = 6374; mean age = 11.6±0.7 years, 53.2% girls, mean BMI-z-score = 0.4±1.2) and one of their parents (n = 6374; mean age = 41.4±5.3 years, 82.7% female, mean BMI = 24.5±4.2 kg/m²) were recruited from schools in eight European countries (Belgium, Greece, Hungary, the Netherlands, Norway, Slovenia, Spain, and Switzerland). The children self-reported their breakfast frequency per week. The body weight and height of the children were objectively measured. The parents responded to items on family factors related to breakfast (automaticity, availability, encouragement, paying attention, permissiveness, negotiating, communicating health beliefs, parental self-efficacy to address children’s nagging, praising, and family breakfast frequency). Mediation analyses were performed using multi-level regression analyses (child-school-country).

Results

Three of the eleven family-related variables were significantly associated with children’s BMI-z-score. The family breakfast frequency was negatively associated with the BMI-z-score; permissiveness concerning skipping breakfast and negotiating about breakfast were positively associated with the BMI-z-score. Children’s breakfast consumption was found to be a mediator of the two associations. All family-related variables except for negotiating, praising and communicating health beliefs, were significantly associated with children’s breakfast consumption.

Conclusions

Future breakfast promotion and obesity prevention interventions should focus on family-related factors including the physical home environment and parenting practices. Nevertheless, more longitudinal research and intervention studies to support these findings between family-related factors and both children’s breakfast consumption and BMI-z-score are needed.     

Musical Aptitude Is Associated with AVPR1A-Haplotypes

Artistic creativity forms the basis of music culture and music industry. Composing, improvising and arranging music are complex creative functions of the human brain, which biological value remains unknown. We hypothesized that practicing music is social communication that needs musical aptitude and even creativity in music. In order to understand the neurobiological basis of music in human evolution and communication we analyzed polymorphisms of the arginine vasopressin receptor 1A (AVPR1A), serotonin transporter (SLC6A4), catecol-O-methyltranferase (COMT), dopamin receptor D2 (DRD2) and tyrosine hydroxylase 1 (TPH1), genes associated with social bonding and cognitive functions in 19 Finnish families (n = 343 members) with professional musicians and/or active amateurs. All family members were tested for musical aptitude using the auditory structuring ability test (Karma Music test; KMT) and Carl Seashores tests for pitch (SP) and for time (ST). Data on creativity in music (composing, improvising and/or arranging music) was surveyed using a web-based questionnaire. Here we show for the first time that creative functions in music have a strong genetic component (h² = .84; composing h² = .40; arranging h² = .46; improvising h² = .62) in Finnish multigenerational families. We also show that high music test scores are significantly associated with creative functions in music (p<.0001). We discovered an overall haplotype association with AVPR1A gene (markers RS1 and RS3) and KMT (p = 0.0008; corrected p = 0.00002), SP (p = 0.0261; corrected p = 0.0072) and combined music test scores (COMB) (p = 0.0056; corrected p = 0.0006). AVPR1A haplotype AVR+RS1 further suggested a positive association with ST (p = 0.0038; corrected p = 0.00184) and COMB (p = 0.0083; corrected p = 0.0040) using haplotype-based association test HBAT. The results suggest that the neurobiology of music perception and production is likely to be related to the pathways affecting intrinsic attachment behavior.     

Dopamine Genes (DRD2/ANKK1-TaqA1 and DRD4-7R) and Executive Function: Their Interaction with Obesity

Obesity is a multifactorial disease caused by the interaction between genotype and environment, and it is considered to be a type of addictive alteration. The A1 allele of the DRD2/ANKK1-TaqIA gene has been associated with addictive disorders, with obesity and with the performance in executive functions. The 7 repeat allele of the DRD4 gene has likewise been associated with the performance in executive functions, as well as with addictive behaviors and impulsivity. Participants were included in the obesity group (N = 42) if their body mass index (BMI) was equal to or above 30, and in the lean group (N = 42) if their BMI was below 25. The DRD2/ANKK1-TaqIA and DRD4 VNTR polymorphisms were obtained. All subjects underwent neuropsychological assessment. Eating behavior traits were evaluated. The ‘DRD2/ANKK1-TaqIA A1-allele status’ had a significant effect on almost all the executive variables, but no significant ‘DRD4 7R-allele status’ effects were observed for any of the executive variables analyzed. There was a significant ‘group’ x ‘DRD2/ANKK1-TaqIA A1-allele status’ interaction effect on LN and ‘group’ x ‘DRD4 7R-allele status’ interaction effect on TMT B-A score. Being obese and a carrier of the A1 allele of DRD2/ANKK1-TaqIA or the 7R allele of DRD4 VNTR polymorphisms could confer a weakness as regards the performance of executive functions.     

Path Analysis to Identify Factors Influencing Health Skills and Behaviors in Adolescents: A Cross-Sectional Survey

Background

Studies conducted in the past mostly rely on models of functional health literacy in adult populations. However, such models do not satisfy the need for health intervention in adolescents. The identification of key factors influencing adolescents'' health literacy is essential in developing effective prevention and intervention measures. This study aimed to test a theoretical model of predictors on health skills and health behaviors in adolescents.

Methods

A cross-sectional survey was conducted in Guangdong using a multi-stage stratified cluster sample design. A representative random sample of 3821 students aged 13–25 years was selected using multi-stage stratified cluster sampling. The path analysis was used to test a hypothesized model of health literacy.

Results

The path analysis showed that knowledge of infectious disease (β = 0.26), health skills (β = 0.22), health concept (β = 0.20), general health knowledge (β = 0.15), gender (β = 0.12), and school performance (β = 0.06) had positive direct effect on health behaviors in adolescents. The explanatory variables accounted for 43% of the variance in explaining health behaviors. Knowledge of infectious disease (β = 0.30), health concept (β = 0.17), general health knowledge (β = 0.13), and school performance (β = 0.05) had positive indirect effect on health behaviors through the impacts on health skills.

Conclusion

This study identified several direct and indirect factors influencing health skills and health behaviors in adolescents. These findings will assist health professionals designing effective health interventions that aim to improve health skills and health behaviors in adolescents.     

On Social and Cognitive Influences: Relating Adolescent Networks,Generalized Expectancies,and Adolescent Smoking

We examine the moderating role of friendship and school network characteristics in relationships between 1) youths’ friends smoking behavior and youths’ own generalized expectancies regarding risk and future orientation and 2) generalized expectancies of youths’ friends and youths’ own generalized expectancies. We then relate these constructs to smoking. Using a longitudinal sample from the National Longitudinal Study of Adolescent Health (N = 15,142), the relationship between friends’ generalized expectancies and youths’ expectancies is stronger for those more central in the network, with more reachability, or stronger network ties, and weaker for those with denser friendship networks. Risk expectancies exhibited an inverted U shaped relationship with smoking at the next time point, whereas future orientation expectancies displayed a nonlinear accelerating negative relationship. There was also a feedback effect in which smoking behavior led to higher risk expectancies and lower future orientation expectancies in instrumental variable analyses.     

Variants in the Dopamine-4-Receptor Gene Promoter Are Not Associated with Sensation Seeking in Skiers

Sensation seeking is a personality trait that has been associated with disinhibited behaviours including substance use and gambling, but also with high-risk sport practices including skydiving, paragliding, and downhill skiing. Twin studies have shown that sensation seeking is moderately heritable, and candidate genes encoding components involved in dopaminergic transmission have been investigated as contributing to this type of behaviour. To determine whether variants in the regulatory regions of the dopamine-4-receptor gene (DRD4) influenced sport-specific sensation seeking, we analyzed five polymorphisms (−1106T/C, −906T/C, −809G/A, −291C/T, 120-bp duplication) in the promoter region of the gene in a cohort of skiers and snowboarders (n = 599) that represented a broad range of sensation seeking behaviours. We grouped subjects by genotype at each of the five loci and compared impulsive sensation seeking and domain-specific (skiing) sensation seeking between groups. There were no significant associations between genotype(s) and general or domain-specific sensation seeking in the skiers and snowboarders, suggesting that while DRD4 has previously been implicated in sensation seeking, the promoter variants investigated in this study do not contribute to sensation seeking in this athlete population.     

Genetic Variants and Early Cigarette Smoking and Nicotine Dependence Phenotypes in Adolescents

Background

While the heritability of cigarette smoking and nicotine dependence (ND) is well-documented, the contribution of specific genetic variants to specific phenotypes has not been closely examined. The objectives of this study were to test the associations between 321 tagging single-nucleotide polymorphisms (SNPs) that capture common genetic variation in 24 genes, and early smoking and ND phenotypes in novice adolescent smokers, and to assess if genetic predictors differ across these phenotypes.

Methods

In a prospective study of 1294 adolescents aged 12–13 years recruited from ten Montreal-area secondary schools, 544 participants who had smoked at least once during the 7–8 year follow-up provided DNA. 321 single-nucleotide polymorphisms (SNPs) in 24 candidate genes were tested for an association with number of cigarettes smoked in the past 3 months, and with five ND phenotypes (a modified version of the Fagerstrom Tolerance Questionnaire, the ICD-10 and three clusters of ND symptoms representing withdrawal symptoms, use of nicotine for self-medication, and a general ND/craving symptom indicator).

Results

The pattern of SNP-gene associations differed across phenotypes. Sixteen SNPs in seven genes (ANKK1, CHRNA7, DDC, DRD2, COMT, OPRM1, SLC6A3 (also known as DAT1)) were associated with at least one phenotype with a p-value <0.01 using linear mixed models. After permutation and FDR adjustment, none of the associations remained statistically significant, although the p-values for the association between rs557748 in OPRM1 and the ND/craving and self-medication phenotypes were both 0.076.

Conclusions

Because the genetic predictors differ, specific cigarette smoking and ND phenotypes should be distinguished in genetic studies in adolescents. Fifteen of the 16 top-ranked SNPs identified in this study were from loci involved in dopaminergic pathways (ANKK1/DRD2, DDC, COMT, OPRM1, and SLC6A3).

Impact

Dopaminergic pathways may be salient during early smoking and the development of ND.     

Genetic Variation in the Human Brain Dopamine System Influences Motor Learning and Its Modulation by L-Dopa

Dopamine is important to learning and plasticity. Dopaminergic drugs are the focus of many therapies targeting the motor system, where high inter-individual differences in response are common. The current study examined the hypothesis that genetic variation in the dopamine system is associated with significant differences in motor learning, brain plasticity, and the effects of the dopamine precursor L-Dopa. Skilled motor learning and motor cortex plasticity were assessed using a randomized, double-blind, placebo-controlled, crossover design in 50 healthy adults during two study weeks, one with placebo and one with L-Dopa. The influence of five polymorphisms with established effects on dopamine neurotransmission was summed using a gene score, with higher scores corresponding to higher dopaminergic neurotransmission. Secondary hypotheses examined each polymorphism individually. While training on placebo, higher gene scores were associated with greater motor learning (p = .03). The effect of L-Dopa on learning varied with the gene score (gene score*drug interaction, p = .008): participants with lower gene scores, and thus lower endogenous dopaminergic neurotransmission, showed the largest learning improvement with L-Dopa relative to placebo (p<.0001), while L-Dopa had a detrimental effect in participants with higher gene scores (p = .01). Motor cortex plasticity, assessed via transcranial magnetic stimulation (TMS), also showed a gene score*drug interaction (p = .02). Individually, DRD2/ANKK1 genotype was significantly associated with motor learning (p = .02) and its modulation by L-Dopa (p<.0001), but not with any TMS measures. However, none of the individual polymorphisms explained the full constellation of findings associated with the gene score. These results suggest that genetic variation in the dopamine system influences learning and its modulation by L-Dopa. A polygene score explains differences in L-Dopa effects on learning and plasticity most robustly, thus identifying distinct biological phenotypes with respect to L-Dopa effects on learning and plasticity. These findings may have clinical applications in post-stroke rehabilitation or the treatment of Parkinson''s disease.     

Genetic Variation in the Base Excision Repair Pathway,Environmental Risk Factors,and Colorectal Adenoma Risk

Cigarette smoking, high alcohol intake, and low dietary folate levels are risk factors for colorectal adenomas. Oxidative damage caused by these three factors can be repaired through the base excision repair pathway (BER). We hypothesized that genetic variation in BER might modify colorectal adenoma risk. In a sigmoidoscopy-based study, we examined associations between 182 haplotype tagging SNPs in 14 BER genes, and colorectal adenoma risk, and examined their potential role as modifiers of the effect cigarette smoking, alcohol intake, and dietary folate levels. Among all individuals, no statistically significant associations between BER SNPs and adenoma risk persisted after correction for multiple comparisons. However, among Asian-Pacific Islanders we observed two SNPs in FEN1 and one in NTHL1, and among African-Americans one SNP in APEX1 that were associated with colorectal adenoma risk. Significant associations were also observed between SNPs in the NEIL2 gene and rectal adenoma risk. Three SNPS modified the effect of smoking (MUTYH interaction p = 0.002; OGG1 interaction p = 0.013); FEN1 interaction p = 0.013)), one SNP in LIG3 modified the effect of alcohol consumption (interaction p = 0.024) and two SNPs in LIG3 modified the effect of dietary folate (interaction p = 0.001 and p = 0.08) on colorectal adenoma risk. These findings support a role for genetic variants in the BER pathway as potential modifiers of colorectal adenoma risk. Our findings strengthen the role of oxidative damage induced by key lifestyle and dietary risk factors in colorectal adenoma formation.