BACKGROUND/AIM:Colorectal cancer (CRC) remains one of the leading causes of cancer-related death in Hungary, with both incidence and mortality rates being among the highest in Europe. Genetic variants that influence inflammation, vascular development, or alcohol metabolism may contribute to CRC susceptibility. This pilot study aimed to investigate, using a candidate gene approach, whether specific polymorphisms in the ALDH2, TNF-α, and VEGF genes are associated with colorectal cancer risk in a Hungarian population. MATERIALS AND METHODS:We conducted a case-control study involving 89 Hungarian participants, including 36 patients with CRC and 53 cancer-free controls. Genotyping of four single nucleotide polymorphisms (rs886205, rs1800629, rs2010963 and rs699947) were performed using TaqMan-based qPCR. Statistical analyses included logistic regression under additive, dominant, and recessive genetic models, adjusted for sex and with sex-stratification. Further exploratory analyses examined genotype distributions by diagnosis subtype. RESULTS:Two variants in the VEGF gene showed possible associations with CRC. The rs699947 AA genotype under a recessive model showed nominal significance for increased CRC risk (adjusted OR=2.97, 95% CI=1.02-8.69, p=0.047), while the rs2010963 C allele under a dominant model suggested a possible protective effect, particularly in males (unadjusted OR=0.23, 95% CI=0.06-0.95, p=0.041). No associations were observed for ALDH2 rs886205 or TNF-α rs1800629, possibly due to the low representation of certain genotypes. None of the nominally significant associations remained statistically significant after applying the Bonferroni correction. CONCLUSION:Although limited by sample size, our findings suggest that two VEGF polymorphisms may act as possible modulators of CRC risk in the Hungarian population, supporting further investigation in larger, independent cohorts.

The PRIME (Prevention and Remediation of Insulin Multimorbidity in Europe) project aims to investigate the correlation between insulin-related somatic disorders and brain disorders. Previous research within the project has demonstrated shared genetic factors among these disorders. Besides genetic factors, environmental factors may also contribute to their development. Cells can respond and adapt to environmental changes by modifying their gene expression, a process influenced by epigenetic mechanisms like chromatin remodeling. We utilized the H-MAGMA software to conduct gene-based analysis incorporating chromatin interaction profiles (Hi-C data) from human brain tissues. This approach allowed us to extract valuable biological insights from genome-wide association study (GWAS) summary statistics. Epigenetic analyses were performed on 21 pairs of three insulin-related somatic diseases and seven neuropsychiatric disorders using cross-disorder GWAS summary statistics and chromatin interaction profiles from human brain tissues. Our analysis revealed significant gene-based associations for all pairs of disorders. We identified several genes that were shared across multiple disorders, which are known to have relevant neurobiological functions and have previously been associated with the investigated disorders. Notable genes among the frequently overlapping ones include RHOA, IHO1, NDUFAF3, PKHD1, CCDC71, TMEM219, AMT, ARIH2, NPIPB11, QRICH1, TAOK2, and BANK1, showing significant associations across various disorder pairs. RHOA, CCDC71, and TAOK2 have previously been linked to both somatic insulin-related disorders and neurodevelopmental disorders. Subsequently, we performed a Gene Ontology analysis on genes that were significant in at least three disorder pairs in our cross-disorder analyses (n=420 genes). The Gene Ontology analysis indicated enrichment in three major biological process domains ("epigenetics," immune system, and mitochondrial organization), as well as a few minor domains. These findings suggest the potential involvement of these processes in the multimorbidity between somatic and brain insulin-related disorders. In the ``epigenetics'' domain specifically, we identified genes associated with covalent chromatin modifications, histone modifications, lysine acetylation, and various protein modifications. Importantly, the enrichment of genes in the epigenetics-related domain is independent of the original use of the H-MAGMA method. Our findings provide valuable insights into the intricate relationship between somatic and brain insulin-related disorders, emphasizing the significance of epigenetic factors. The results support previous findings within the PRIME project and contribute to the understanding of shared genetic and environmental factors underlying these disorders. Further research is necessary to validate these findings and explore the mechanisms behind the comorbidity observed between somatic and brain insulin-related disorders. The insights gained from this study have the potential to aid in the development of targeted interventions and personalized medicine approaches for individuals with co-occurring somatic and psychiatric disorders.

The Prevention and Remediation of Insulin Multimorbidity in Europe (PRIME) project aims to investigate the comorbidity of brain and somatic disorders, with a particular focus on metabolic conditions. Previous studies carried out as part of this project have provided evidence of genetic factors common to these disorders. This study delves into the cellular aspects of these disorders and their shared biological underpinnings using single-cell data and multi-omics. In this study, we leveraged the sc-linker framework to integrate single-cell RNA-sequencing (scRNA-seq) data, epigenomic SNP-to-gene maps, and genome-wide association study (GWAS) summary statistics to identify relevant cell types and processes associated with comorbid brain and metabolic disorders, emphasizing insulin multimorbidity. We examined type 2 diabetes (T2D) and several brain disorders in brain tissue, as well as in the liver, which plays a critical role in metabolism, and the colon to explore the association between these tissues and brain/metabolic disorders using single-cell data. The analysis revealed intriguing associations between type 2 diabetes (T2D) and γ-aminobutyric acid-ergic (GABAergic) inhibitory neurons within the brain. GABAergic neurons, known for their role in neural signaling and inhibitory control, were associated with T2D, suggesting the involvement of neural circuitry dysregulation in insulin-related metabolic disorders. Furthermore, the investigation of liver scRNA-seq data shed light on a specific association between major depressive disorder (MDD) and T2D with dendritic cells in the liver. Dendritic cells are involved in immune response modulation, highlighting the connection between immune dysregulation and T2D multimorbidity. Additionally, the analysis of colon tissue provided evidence linking colonel adipocytes to MDD and T2D, indicating potential shared molecular signatures and underlying biological mechanisms in adipose tissue. The findings contribute to understanding the cellular mechanisms underlying brain-metabolic disorder comorbidity, particularly in T2D. By integrating scRNA-seq, epigenomic information, and GWAS summary statistics, GABAergic inhibitory neurons were identified as potential cellular components of T2D within the brain. Furthermore, the study suggests a disease-specific involvement of dendritic cells in both MDD and T2D in the liver, emphasizing the contribution of immune-related processes to metabolic dysfunction. Additionally, the adipose-related results highlight the significance of lipid metabolism in the shared biology of T2D and brain disorders. The integration of multi-omics data through the sc-linker framework provides valuable insights into the shared biology of brain and metabolic disorders, paving the way for targeted therapeutic interventions. The results highlight the potential importance of neural circuitry dysregulation, immune-related processes, and lipid metabolism in the pathogenesis and comorbidity of brain and metabolic disorders. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 847879.

A common genetic basis of various substance and behavioral addictions has long been suggested considering the rate of co-occurrences and the overlaps in psychological and molecular mechanisms. The goal of the current study is to investigate possible genetic overlaps between different types of substance-related, addictive and compulsive behaviors conducted as part of the Psychological and Genetic Factors of Addictions (PGA) study. The genetic analysis of both substance and behavioral addictions was conducted within the same cohort of 3003 Hungarian young adults. Participants were assessed for a wide range of potentially addictive substances (nicotine, alcohol, cannabis, and other drugs) and potentially addictive behaviors (internet use, gaming, social networking site use, gambling, exercising, hair-pulling and eating) in order to investigate possible shared genetic factors utilizing the large sample of the PGA study. A Genetic Addiction Risk Score (GARS) was also calculated for the participants based on a set of 11 genetic polymorphisms in order to estimate addiction vulnerability risk scores for possible future prevention strategy as well as personalized pharmacological and non-pharmacological therapy. The genetic association analysis included 32 single-nucleotide polymorphisms (SNPs) selected from earlier GWAS and candidate gene association studies in the literature in order to best represent the expected distribution pattern of the various phenotypes assessed in the sample. The genotyping was carried out by the The QuantStudio™ 12K Flex OpenArray® System, fluorescent intensities were evaluated by the QuantStudio 12K Flex Software and the Thermo Fisher Cloud service. The genetic association analysis was conducted applying an allele-wise design. The phenotype measures were assessed using multiple questionnaires. The GARS score was calculated based on the risk scores of 11 genetic variants (SNPs and VNTRs). The statistical analyses revealed 29 nominally significant genetic associations, from which nine survived FDRbl correction for multiple testing. Four of the nine significant associations were observed between the FOXN3 rs759364 SNP and certain potentially addictive behavioral traits: 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 and DRD2/ANKK1 rs1800497 variants and the 'lifetime other drugs' variable. The GARS score was calculated for each participants and significant score differences have been identified between different subgroups of the cohort. The results indicate a pleiotropic effect, ie. that certain genetic factors may contribute to multiple forms of addiction. Based on the presented results, rs759364 of FOXN3 is shown to constitute genetic risk for increased alcohol consumption, internet use, gaming and exercise, while rs1549250, rs2973033 of GDNF may be non-specific genetic risk factors for various types of addictive behaviors. The GARS scoring is a useful tool to evaluate the individual susceptibility for substance use disorders. Future studies should examine functional correlates and potential mechanisms underlying these relationships.

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.

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.

Background:Tourette Syndrome (TS) is a neurodevelopmental disorder that presents with motor and vocal tics early in childhood. The aim of this study was to investigate genetic variants in the 3' untranslated region (3'UTR) of TS candidate genes with a putative link to microRNA (miRNA) mediated regulation or gene expression. Methods:We used anin silicoapproach to identify 32 variants in the 3'UTR of 18 candidate genes putatively changing the binding site for miRNAs. In a sample composed of TS cases and controls (n= 290), as well as TS family trios (n= 148), we performed transmission disequilibrium test (TDT) and meta-analysis. Results:We found positive association of rs3750486 in the LIM homeobox 6 (LHX6) gene (p= 0.021) and rs7795011 in the inner mitochondrial membrane peptidase subunit 2 (IMMP2L) gene (p= 0.029) with TS in our meta-analysis. The TDT showed an over-transmission of the A allele of rs1042201 in the arylacetamide deacetylase (AADAC) gene in TS patients (p= 0.029). Conclusion:This preliminary study provides further support for the involvement of LHX6, IMMP2L, and AADAC genes, as well as epigenetic mechanisms, such as altered miRNA mediated gene expression regulation in the etiology of TS.

Abstract: Introduction and aim: Earlier results in the literature suggest that overweight subjects show weaker performance in executive function tasks as compared to normal weight people. Dopaminergic system is strongly linked to executive functions, body mass regulation and ingestion. The aim of the present study was to examine the possible relationship between DRD4 VNTR 7-repeat allele, body mass index and Stroop performance in a healthy adult population, and to draw psychogenetic conclusions. Method: 152 subjects without diabetic or psychiatric history participated in the study. Along with non-invasive DNA sampling, demographic, weight and height data were collected. The participants also solved the computerized Stroop task. 11 subjects belonged to the underweight (mean body mass index = 17.9 kg/m2), 98 subjects to the normal (mean body mass index = 21.8 kg/m2), and 43 subjects to the overweight (mean body mass index = 28.9 kg/m2) category. After grouping participants according to their body mass index and DRD4 VNTR genotype, we compared their mean performance to investigate the possible psychogenetic associations. Results: Body mass index and stimuli type showed significant interaction on error number (p = 0.045): subjects with normal body mass index made significantly less error as compared to under- and overweight subjects in incongruent trials. The 7-repeat allele carriers made tendentiously more errors than non-carriers. Normal weight people made less error – independently from their genotype –, while subjects with either low or high BMI carrying the 7-repeat allele made more errors compared to non-carriers. Conclusion: Under- and overweight subjects perform weaker where inhibition is necessary in the task. This may reflect their reactions to food-related situations. Orv Hetil. 2019; 160(39): 1554–1562.

Twin studies provide evidence for the heritability of social attitudes, e.g. competitiveness, however, there are no psychogenetic association results linking competitive attitudes to genetic polymorphisms. Candidate gene studies report association with competitiveness-related phenotypes, risk taking for example was linked with the 7-repeat allele of the dopamine D4 receptor gene. This polymorphism has been studied extensively with novelty seeking and certain psychiatric disorders, as it plays a crucial role in molecular genetic mechanisms driving behavioral responses to the environment, especially modulating behavior through the reward circuitry. In the present study, we examined association of the DRD4 48-bp VNTR and competitiveness using self-report data from 399 non-related Caucasians. We found an interesting gene-sex interaction: 7-carrier males were more hypercompetitive as compared to non-carriers, while 7-carrier females were less hypercompetitive as compared to non-carriers. This finding remained significant after Bonferroni correction for multiple testing. Interestingly, among females we observed a significant positive correlation between hypercompetitiveness and mood characteristic variables, however, no such relationship could be detected in males. In 7-carrier females the association of hypercompetitiveness and anxiety or depression was more robust as compared to non-carrier females. These results highlight the importance of cultural influences in interpreting gene-sex interaction effects. Our results underlies interaction between genes and the environment; suggesting that the 7-repeat allele plays an important role in adaptivity, enabling sex-specific behavior to social expectations.

Introduction: The activation of the ATP-gated P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7) produces microglial activation, a process which has been demonstrated in depression, bipolar disorder, and schizophrenia. Emerging data over the last years highlighted the importance of P2X7 cation channel as a potential drug target for these central nervous system disorders. The Gln460Arg (rs2230912) polymorphism of the P2RX7 gene has been widely studied in mood disorders, however the results are still controversial. Therefore, we aimed to investigate the C-terminal region of this gene in major depressive and bipolar disorders (MDD and BD) by studying possibly functional, non-synonymous polymorphisms within a 7 kb long region around the Gln460Arg, including Ala348Thr (rs1718119), Thr357Ser (rs2230911), and Glu496Ala (rs3751143) variants. Since Gln460Arg is located at the 3' end of the P2RX7 gene, we included additional, potentially functional single nucleotide polymorphisms (SNPs) from the 3' untranslated region (UTR), which can be in linkage with Gln460Arg. Based on in silico search, we chose two SNPs in putative microRNA target sites which are located in consecutive positions: rs1653625 and rs1718106. Methods: P2RX7 SNPs from the C-terminal region were selected based on previous functional assays, 3' UTR variants were chosen using PolymiRTS and Patrocles databases. The genotyping of the non-synonymous SNPs was carried out by pre-designed TaqMan (R) kits, while the 3' UTR variants were analyzed by PCR-RFLP method. Case-control analyses were carried out between 315 inpatients with acute major depressive episode (195 MDD, 120 BD) and 406 healthy control subjects. The two subscales of the Hospital Anxiety and Depression Scale (HADS) self-report questionnaire were used for quantitative analyses, including an additional, "at-risk" population of 218 patients with diabetes mellitus. The in vitro reporter gene assays were carried out on HEK and SK-N-FI cells transiently transfected with pMIR vector constructs containing the P2RX7 3' UTR downstream of the luciferase gene. Results: Haplotype analysis indicated a relatively high linkage between the analyzed P2RX7 SNPs. Our casecontrol study did not yield any association between P2RX7 gene variants and depression. However, dimensional analyses showed significant associations of the HADS depression severity scores with Gln460Arg (rs2230912) and Ala348Thr (rs1718119) in the depressed and diabetic patient groups. In the in vitro experiments, the P2RX7 3' UTR constructs with the lowest predicted binding efficiency to their miRNAs showed the highest expression of the gene. The combination of the depression-associated P2RX7 C-terminal and 3' UTR SNPs contributed to the highest depression severity score in the haplotype analysis. Conclusion: Based on our findings, we propose that a P2RX7 haplotype combination of the Gln460Arg and neighboring SNPs contribute to the observed genetic association with depressive symptoms.

Introduction and aim: Earlier results in the literature suggest that overweight subjects show weaker performance in executive function tasks as compared to normal weight people. Dopaminergic system is strongly linked to executive functions, body mass regulation and ingestion. The aim of the present study was to examine the possible relationship between DRD4 VNTR 7-repeat allele, body mass index and Stroop performance in a healthy adult population, and to draw psychogenetic conclusions. Method: 152 subjects without diabetic or psychiatric history participated in the study. Along with non-invasive DNA sampling, demographic, weight and height data were collected. The participants also solved the computerized Stroop task. 11 subjects belonged to the underweight (mean body mass index = 17.9 kg/m2), 98 subjects to the normal (mean body mass index = 21.8 kg/m2), and 43 subjects to the overweight (mean body mass index = 28.9 kg/m2) category. After grouping participants according to their body mass index and DRD4 VNTR genotype, we compared their mean performance to investigate the possible psychogenetic associations. Results: Body mass index and stimuli type showed significant interaction on error number (p = 0.045): subjects with normal body mass index made significantly less error as compared to under- and overweight subjects in incongruent trials. The 7-repeat allele carriers made tendentiously more errors than non-carriers. Normal weight people made less error - independently from their genotype -, while subjects with either low or high BMI carrying the 7-repeat allele made more errors compared to non-carriers. Conclusion: Under- and overweight subjects perform weaker where inhibition is necessary in the task. This may reflect their reactions to food-related situations. Orv Hetil. 2019; 160(39): 1554-1562.

Background and aims Some form of gambling can be observed in nearly every society, as the gratification felt upon winning in uncertain conditions is universal. A culturally distinct form of gambling, associated with a traditional sporting event of archery known as “teer,” is innate to the province of Meghalaya, India. The objective of this study was to find genetic variants underlying this unique form of behavioral addiction. To better understand game-based gambling, we studied genetic variants related to dopaminergic pathways and other genes previously linked to various psychological disorders. Methods This study was carried out on a sample of 196 Indo-Aryan adults from Shillong, Meghalaya. Genotyping of glial cell line-derived neurotrophic factor (GDNF) polymorphisms was carried out using real-time PCR. We further investigated 32 single nucleotide polymorphisms located in the 3′ UTR of additional genes of interest using an OpenArray® real-time PCR platform. Results Case–control analysis revealed a significant association between GDNF variant rs2973033 (p = .00864, χ2 = 13.132, df = 2) and contactin-associated protein-like 2 (CNTNAP2) variant rs2530311 (p = .0448, χ2 = 13.132, df = 2) with gambling. Discussion and conclusions Association of the GDNF gene with gambling could be attributed to its involvement in the development and survival of dopaminergic neurons. Our result is in good agreement with previous data indicating the role of GDNF in certain substance addictions. Several rare variants in the CNTNAP2 gene were also implicated in alcohol addiction in a previous study. This pilot study provides further support for the role of GDNF and CNTNAP2 in addiction behaviors.