Multi-Polygenic Analysis of Nicotine Dependence in Individuals of European Ancestry

Introduction: Heritability estimates of nicotine dependence (ND) range from 40% to 70%, but discovery GWAS of ND are underpowered and have limited predictive utility. In this work, we leverage genetically correlated traits and diseases to increase the accuracy of polygenic risk prediction. Methods: We employed a multi-trait model using summary statistic-based best linear unbiased predictors (SBLUP) of genetic correlates of DSM-IV diagnosis of ND in 6394 individuals of European Ancestry (prevalence = 45.3%, %female = 46.8%, mu(age) = 40.08 [s.d. = 10.43]) and 3061 individuals from a nationally-representative sample with Fagerstrom Test for Nicotine Dependence symptom count (FTND; 51.32% female, mean age = 28.9 [s.d. = 1.70]). Polygenic predictors were derived from GWASs known to be phenotypically and genetically correlated with ND (i.e., Cigarettes per Day [CPD], the Alcohol Use Disorders Identification Test [AUDIT-Consumption and AUDIT-Problems], Neuroticism, Depression, Schizophrenia, Educational Attainment, Body Mass Index [BMI], and Self-Perceived Risk-Taking); including Height as a negative control. Analyses controlled for age, gender, study site, and the first 10 ancestral principal components. Results: The multi-trait model accounted for 3.6% of the total trait variance in DSM-IV ND. Educational Attainment (beta = -0.125; 95% CI: [-0.149,-0.101]), CPD (0.071 [0.047,0.095]), and Self-Perceived Risk-Taking (0.051 [0.026,0.075]) were the most robust predictors. PGS effects on FTND were limited. Conclusions: Risk for ND is not only polygenic, but also pleiotropic. Polygenic effects on ND that are accessible by these traits are limited in size and act additively to explain risk.Peer reviewe

Evaluation of a multi-disciplinary back pain rehabilitation programme—individual and group perspectives

To evaluate the impact of a multi-disciplinary back pain rehabilitation programme using a combination of individual and group change data. A total of 261 consecutive patients attending an assessment session for the back pain rehabilitation programme completed the SF-36 health survey questionnaire. The patients were requested to complete the questionnaires again at programme completion and at the 6-month follow-up. The Reliable Change Index was used to define 'clinical significance' in terms of the assessment of individual change. Half of those patients considered to be suitable for the programme subsequently completed it. In group terms, non-completers scored lower than completers on all SF-36 scales. Statistically significant improvements were evident for those completing the programme (all scales at P < 0.000), with improvement maintained at follow-up. In individual terms, 'clinical significance' was exceeded most frequently in the Physical Functioning and Role Physical scales. Whilst some participants lost previous improvements between completion and follow-up, others improved over this same time period. The majority of those completing the programme showed improvement in at least one scale. Adding assessment of individual change to traditional group change measures provides greater insight into the impact a rehabilitation programme has upon participants' quality of life. Whilst the programme is clearly effective for those who complete it, work is required to limit post-programme deterioration and improve uptak

Complexes Formed in Solution Between Vanadium(IV)/(V) and the Cyclic Dihydroxamic Acid Putrebactin or Linear Suberodihydroxamic Acid

The ability of microbial siderophores to coordinate metal ions, particularly Fe(III), continues to generate interest in the poten-tial applications of these bioligands in the environment and medicine.13 Siderophores produced by terrestrial and marin

Prediction of function in daily life following multidisciplinary rehabilitation for individuals with chronic musculoskeletal pain; a prospective study

Background: The prevalence of chronic musculoskeletal pain is high, with widespread negative economic, psychological, and social consequences for the individual. It is therefore important to find ways to predict the outcome of rehabilitation programmes in terms of function in daily life. The aims of this study were to investigate the improvements over time from multidisciplinary rehabilitation in terms of pain and function, and analyse the relative impact of individual and psychosocial factors as predictors of function in daily life in individuals with chronic musculoskeletal pain. Methods: A prospective study was conducted among one hundred and forty three (N = 143) musculoskeletal pain patients. Measures of pain, function, and functional health status were obtained at baseline, after 5 weeks of intensive training, at the end of the 57-week rehabilitation programme, and at a 1 year follow-up, using validated self-administrated measures. Linear regression analysis was applied to investigate the relative impact of musculoskeletal pain, individual- , and psychosocial factors in function. Results: The participants studied showed a significant increase in function during the 57 weeks rehabilitation period. There was also a significant increase in function from the end of the rehabilitation period (57th week) to the one year follow-up measures. Pain intensity associated significantly with pain experience over all measurement periods. High levels of pain intensity (β = .42**) and pain experience (β = .37*), and poor psychological capacity (β = -.68*) at baseline, as well as poor physiological capacity (β = -.44**) and high levels of anxiety (β = .48**) and depression (β = .58***) at the end of the rehabilitation program were the most important prognostic factors of variance in functioning over the 4 measurement periods. Conclusion: The data suggest that physical capacity, emotional distress and coping skills should be priority areas in rehabilitation programmes to improve functioning in daily life

Association between Age and the 7 Repeat Allele of the Dopamine D4 Receptor Gene

Longevity is in part (25%) inherited, and genetic studies aim to uncover allelic variants that play an important role in prolonging life span. Results to date confirm only a few gene variants associated with longevity, while others show inconsistent results. However, GWAS studies concentrate on single nucleotide polymorphisms, and there are only a handful of studies investigating variable number of tandem repeat variations related to longevity. Recently, Grady and colleagues (2013) reported a remarkable (66%) accumulation of those carrying the 7 repeat allele of the dopamine D4 receptor gene in a large population of 90-109 years old Californian centenarians, as compared to an ancestry-matched young population. In the present study we demonstrate the same association using continuous age groups in an 18-97 years old Caucasian sample (N = 1801, p = 0.007). We found a continuous pattern of increase from 18-75, however frequency of allele 7 carriers decreased in our oldest age groups. Possible role of gene-environment interaction effects driven by historical events are discussed. In accordance with previous findings, we observed association preferentially in females (p = 0.003). Our results underlie the importance of investigating non-disease related genetic variants as inherited components of longevity, and confirm, that the 7-repeat allele of the dopamine D4 receptor gene is a longevity enabling genetic factor, accumulating in the elderly female population

Influence of Particle Size Distribution on the Performance of Ionic Liquid-based Electrochemical Double Layer Capacitors.

Electrochemical double layer capacitors (EDLCs) employing ionic liquid electrolytes are the subject of much research as they promise increased operating potentials, and hence energy densities, when compared with currently available devices. Herein we report on the influence of the particle size distribution of activated carbon material on the performance of ionic liquid based EDLCs. Mesoporous activated carbon was ball-milled for increasing durations and the resultant powders characterized physically (using laser diffraction, nitrogen sorption and SEM) and investigated electrochemically in the form of composite EDLC electrodes. A bi-modal particle size distribution was found for all materials demonstrating an increasing fraction of smaller particles with increased milling duration. In general, cell capacitance decreased with increased milling duration over a wide range of rates using CV and galvanostatic cycling. Reduced coulombic efficiency is observed at low rates (<25 mVs(-1)) and the efficiency decreases as the volume fraction of the smaller particles increases. Efficiency loss was attributed to side reactions, particularly electrolyte decomposition, arising from interactions with the smaller particles. The effect of reduced efficiency is confirmed by cycling for over 15,000 cycles, which has the important implication that diminished performance and reduced cycle life is caused by the presence of submicron-sized particles

State Tax Differentials, Cross-Border Commuting, and Commuting Times in Multi-State Metropolitan Areas

We examine the effects of differences in income tax rates on commuting times within multi-state MSAs. Our theoretical model introduces a border into a model of an urban area and shows that differences in average tax rates distort commute times and interstate commutes. Empirically examining multi-state MSAs allows us to exploit tax policy discontinuities while holding fixed other characteristics. We identify large effects on commuting times for affluent households and homeowners in MSAs in which taxes are based on the state of residence. We discuss how the model and empirical design can be used to study other policy differences

Multivariate Analysis of Dopaminergic Gene Variants as Risk Factors of Heroin Dependence

BACKGROUND: Heroin dependence is a debilitating psychiatric disorder with complex inheritance. Since the dopaminergic system has a key role in rewarding mechanism of the brain, which is directly or indirectly targeted by most drugs of abuse, we focus on the effects and interactions among dopaminergic gene variants. OBJECTIVE: To study the potential association between allelic variants of dopamine D2 receptor (DRD2), ANKK1 (ankyrin repeat and kinase domain containing 1), dopamine D4 receptor (DRD4), catechol-O-methyl transferase (COMT) and dopamine transporter (SLC6A3) genes and heroin dependence in Hungarian patients. METHODS: 303 heroin dependent subjects and 555 healthy controls were genotyped for 7 single nucleotide polymorphisms (SNPs) rs4680 of the COMT gene; rs1079597 and rs1800498 of the DRD2 gene; rs1800497 of the ANKK1 gene; rs1800955, rs936462 and rs747302 of the DRD4 gene. Four variable number of tandem repeats (VNTRs) were also genotyped: 120 bp duplication and 48 bp VNTR in exon 3 of DRD4 and 40 bp VNTR and intron 8 VNTR of SLC6A3. We also perform a multivariate analysis of associations using Bayesian networks in Bayesian multilevel analysis (BN-BMLA). FINDINGS AND CONCLUSIONS: In single marker analysis the TaqIA (rs1800497) and TaqIB (rs1079597) variants were associated with heroin dependence. Moreover, -521 C/T SNP (rs1800955) of the DRD4 gene showed nominal association with a possible protective effect of the C allele. After applying the Bonferroni correction TaqIB was still significant suggesting that the minor (A) allele of the TaqIB SNP is a risk component in the genetic background of heroin dependence. The findings of the additional multiple marker analysis are consistent with the results of the single marker analysis, but this method was able to reveal an indirect effect of a promoter polymorphism (rs936462) of the DRD4 gene and this effect is mediated through the -521 C/T (rs1800955) polymorphism in the promoter

DRD4 Polymorphism Moderates the Effect of Alcohol Consumption on Social Bonding

Development of interpersonal relationships is a fundamental human motivation, and behaviors facilitating social bonding are prized. Some individuals experience enhanced reward from alcohol in social contexts and may be at heightened risk for developing and maintaining problematic drinking. We employed a 3 (group beverage condition) ×2 (genotype) design (N = 422) to test the moderating influence of the dopamine D4 receptor gene (DRD4 VNTR) polymorphism on the effects of alcohol on social bonding. A significant gene x environment interaction showed that carriers of at least one copy of the 7-repeat allele reported higher social bonding in the alcohol, relative to placebo or control conditions, whereas alcohol did not affect ratings of 7-absent allele carriers. Carriers of the 7-repeat allele were especially sensitive to alcohol's effects on social bonding. These data converge with other recent gene-environment interaction findings implicating the DRD4 polymorphism in the development of alcohol use disorders, and results suggest a specific pathway by which social factors may increase risk for problematic drinking among 7-repeat carriers. More generally, our findings highlight the potential utility of employing transdisciplinary methods that integrate genetic methodologies, social psychology, and addiction theory to improve theories of alcohol use and abuse