Co-occurrences of substance use and other potentially addictive behaviors: epidemiological results from the Psychological and Genetic Factors of the Addictive Behaviors (PGA) Study

Background and aims: Changes in the nomenclature of addictions suggest a significant shift in the conceptualization of addictions, where non-substance related behaviors can also be classified as addictions. A large amount of data provides empirical evidence that there are overlaps of different types of addictive behaviors in etiology, phenomenology, and in the underlying psychological and biological mechanisms. Our aim was to investigate the co-occurrences of a wide range of substance use and behavioral addictions. Methods: The present epidemiological analysis was carried out as part of the Psychological and Genetic Factors of the Addictive Behaviors (PGA) Study, where data were collected from 3,003 adolescents and young adults (42.6% males; mean age 21 years). Addictions to psychoactive substances and behaviors were rigorously assessed. Results: Data is provided on lifetime occurrences of the assessed substance uses, their co-occurrences, the prevalence estimates of specific behavioral addictions , and co-occurrences of different substance use and potentially addictive behaviors. Associations were found between (i) smoking and problematic Internet use, exercising, eating disorders, and gambling (ii) alcohol consumption and problematic Internet use, problematic online gaming, gambling, and eating disorders, and (iii) cannabis use and problematic online gaming and gambling. Conclusions: The results suggest a large overlap between the occurrence of these addictions and behaviors and underlies the importance of investigating the possible common psychological, genetic and neural pathways. These data further support concepts such as the Reward Deficiency Syndrome and the component model of addictions that propose a common phenomenological and etiological background of different addictive and related behaviors

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

FOXN3 and GDNF polymorphisms as common genetic factors of substance use and addictive behaviors

Epidemiological and phenomenological studies suggest shared underpinnings between multiple addictive behaviors. The present genetic association study was conducted as part of the Psychological and Genetic Factors of Addictions study (n = 3003) and aimed to investigate genetic overlaps between different substance use, addictive, and other compulsive behaviors. Association analyses targeted 32 single-nucleotide polymorphisms, potentially addictive substances (alcohol, tobacco, cannabis, and other drugs), and potentially addictive or compulsive behaviors (internet use, gaming, social networking site use, gambling, exercise, hair-pulling, and eating). Analyses revealed 29 nominally significant associations, from which, nine survived an FDRbl correction. Four associations were observed between FOXN3 rs759364 and potentially addictive behaviors: rs759364 showed an association with the frequency of alcohol consumption and mean scores of scales assessing internet addiction, gaming disorder, and exercise addiction. Significant associations were found between GDNF rs1549250, rs2973033, CNR1 rs806380, DRD2/ANKK1 rs1800497 variants, and the “lifetime other drugs” variable. These suggested that genetic factors may contribute similarly to specific substance use and addictive behaviors. Specifically, FOXN3 rs759364 and GDNF rs1549250 and rs2973033 may constitute genetic risk factors for multiple addictive behaviors. Due to limitations (e.g., convenience sampling, lack of structured scales for substance use), further studies are needed. Functional correlates and mechanisms underlying these relationships should also be investigated

A common polymorphism of the human cardiac sodium channel alpha subunit (SCN5A) gene is associated with sudden cardiac death in chronic ischemic heart disease

Cardiac death remains one of the leading causes of mortality worldwide. Recent research has shed light on pathophysiological mechanisms underlying cardiac death, and several genetic variants in novel candidate genes have been identified as risk factors. However, the vast majority of studies performed so far investigated genetic associations with specific forms of cardiac death only (sudden, arrhythmogenic, ischemic etc.). The aim of the present investigation was to find a genetic marker that can be used as a general, powerful predictor of cardiac death risk. To this end, a case-control association study was performed on a heterogeneous cohort of cardiac death victims (n=360) and age-matched controls (n=300). Five single nucleotide polymorphisms (SNPs) from five candidate genes (beta2 adrenergic receptor, nitric oxide synthase 1 adaptor protein, ryanodine receptor 2, sodium channel type V alpha subunit and transforming growth factor-beta receptor 2) that had previously been shown to associate with certain forms of cardiac death were genotyped using sequence-specific real-time PCR probes. Logistic regression analysis revealed that the CC genotype of the rs11720524 polymorphism in the SCN5A gene encoding a subunit of the cardiac voltage-gated sodium channel occurred more frequently in the highly heterogeneous cardiac death cohort compared to the control population (p=0.019, odds ratio: 1.351). A detailed subgroup analysis uncovered that this effect was due to an association of this variant with cardiac death in chronic ischemic heart disease (p=0.012, odds ratio =1.455). None of the other investigated polymorphisms showed association with cardiac death in this context. In conclusion, our results shed light on the role of this non-coding polymorphism in cardiac death in ischemic cardiomyopathy. Functional studies are needed to explore the pathophysiological background of this association. © 2015 Marcsa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Association between anxiety and non-coding genetic variants of the galanin neuropeptide

Galanin, an inhibitory neuropeptide and cotransmitter has long been known to co-localize with noradrenaline and serotonin in the central nervous system. Several human studies demonstrated altered galanin expression levels in major depressive disorder and anxiety. Pharmacological modulation of galanin signaling and transgenic strategies provide further proof for the involvement of the galanin system in the pathophysiology of mood disorders. Little is known, however, on the dynamic regulation of galanin expression at the transcriptional level. The aim of the present study was to seek genetic association of non-coding single nucleotide variations in the galanin gene with anxiety and depression.Six single nucleotide polymorphisms (SNP) occurring either in the regulatory 5' or 3' flanking regions or within intronic sequences of the galanin gene have been genotyped with a high-throughput TaqMan OpenArray qPCR system in 526 healthy students (40% males). Depression and anxiety scores were obtained by filling in the Hospital Anxiety and Depression Scale (HADS) questionnaire. Data were analyzed by ANCOVA and Bonferroni correction was applied for multiple testing. Linkage disequilibrium (LD) analysis was used to map two haploblocks in the analyzed region.A single-locus and a haplotype genetic association proved to be statistically significant. In single-marker analysis, the T allele of the rs1042577 SNP within the 3' untranslated region of the galanin gene associated with greater levels of anxiety (HADS scores were 7.05±4.0 vs 6.15±.15; p = 0.000407). Haplotype analysis revealed an association of the rs948854 C_rs4432027_C allele combination with anxiety [F(1,1046) = 4.140, p = 0.042141, η2 = 0.004, power = 0.529]. Neither of these associations turned out to be gender-specific. These promoter polymorphisms are supposed to participate in epigenetic regulation of galanin expression by creating potentially methylatable CpG dinucleotides. The functional importance of the rs1042577_T allele remains to be elucidated

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

Glial Cell Line-Derived Neurotrophic Factor (GDNF) as a Novel Candidate Gene of Anxiety.

Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor for dopaminergic neurons with promising therapeutic potential in Parkinson's disease. A few association analyses between GDNF gene polymorphisms and psychiatric disorders such as schizophrenia, attention deficit hyperactivity disorder and drug abuse have also been published but little is known about any effects of these polymorphisms on mood characteristics such as anxiety and depression. Here we present an association study between eight (rs1981844, rs3812047, rs3096140, rs2973041, rs2910702, rs1549250, rs2973050 and rs11111) GDNF single nucleotide polymorphisms (SNPs) and anxiety and depression scores measured by the Hospital Anxiety and Depression Scale (HADS) on 708 Caucasian young adults with no psychiatric history. Results of the allele-wise single marker association analyses provided significant effects of two single nucleotide polymorphisms on anxiety scores following the Bonferroni correction for multiple testing (p = 0.00070 and p = 0.00138 for rs3812047 and rs3096140, respectively), while no such result was obtained on depression scores. Haplotype analysis confirmed the role of these SNPs; mean anxiety scores raised according to the number of risk alleles present in the haplotypes (p = 0.00029). A significant sex-gene interaction was also observed since the effect of the rs3812047 A allele as a risk factor of anxiety was more pronounced in males. In conclusion, this is the first demonstration of a significant association between the GDNF gene and mood characteristics demonstrated by the association of two SNPs of the GDNF gene (rs3812047 and rs3096140) and individual variability of anxiety using self-report data from a non-clinical sample

Severity of behavioral addiction symptoms among young adults using non-prescribed sedatives/hypnotics

Introduction: Young adulthood is considered a critical period in terms of non-medical use of sedatives/hypnotics (NMUSH) as well as different types of behavioral addictions (BAs). However, the relationship between these behaviors has received scarce attention among young adult samples. Therefore, the aim of the present study was to investigate the association between NMUSH and symptoms of distinct BAs among young adults. Materials and methods: Analyses were conducted based on the data of two large sample studies (including a representative sample) carried out with young adult samples. The following BAs were assessed: problematic internet use, problematic video gaming, problematic social media use, problem gambling, exercise addiction, eating disorders, compulsive buying behavior, problematic mobile phone use, work addiction, and hair pulling. Symptoms of distinct BAs were analyzed in three groups formed based on the NMUSH: non-users, lifetime users, and current users. Results: The symptoms of problematic internet use, problematic social media use, problem gambling, exercise addiction, eating disorders, compulsive buying behavior and work addiction were significantly more severe among lifetime and/or current non-medical sedative and hypnotic users, compared to the non-user participants. The symptoms of problematic mobile phone use were the most severe in the non-user group. Conclusions: The results suggest co-occurrence between NMUSH and distinct BAs among young adults. These findings draw attention to the need for preventive interventions for this high-risk population

From genomes to diaries: a 3-year prospective, real-life study of ragweed-specific sublingual immunotherapy

During the last decades, the prevalence of allergy has dramatically increased. Allergen-specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease, but there are still many questions and unmet needs hindering its widespread use to fulfill its treatment potential and maximize its benefits for the society. To provide a comprehensive phenome-wide overview in sublingual immunotherapy, using ragweed allergy as a target, we planned and carried out a longitudinal, prospective, observational, open-label study (DesensIT). In this paper we present challenges of using deep and comprehensive phenotypes embracing biological, clinical and patient-reported outcomes in allergen-specific immunotherapy and show how we designed the DesensIT project to optimize data collection, processing and evaluation