Assessment of the Genetic Characteristics of a Generation Born during a Long-Term Socioeconomic Crisis.

BACKGROUND: A socioeconomic crisis in Russia lasted from 1991 to 1998 and was accompanied by a sharp drop in the birth rate. The main factor that influenced the refusal to have children during this period is thought to be prolonged social stress. METHODS: comparing frequencies of common gene variants associated with stress-induced diseases among generations born before, after, and during this crisis may show which genes may be preferred under the pressure of natural selection during periods of increased social stress in urban populations. RESULTS: In the "crisis" group, a statistically significant difference from the other two groups was found in rs6557168 frequency (p = 0.001); rs4522666 was not in the Hardy-Weinberg equilibrium in this group, although its frequency did not show a significant difference from the other groups (p = 0.118). Frequencies of VNTRs in SLC6A3 and MAOA as well as common variants rs17689918 in CRHR1, rs1360780 in FKBP5, rs53576 in OXTR, rs12720071 and rs806377 in CNR1, rs4311 in ACE, rs1800497 in ANKK1, and rs7412 and rs429358 in APOE did not differ among the groups. CONCLUSIONS: a generation born during a period of prolonged destructive events may differ from the rest of the gene pool of the population in some variants associated with personality traits or stress-related disorders.

Athletic performance, sports experience, and exercise addiction: an association study on ANKK1 gene polymorphism rs1800497.

Introduction: Exercise addiction is a phenomenon being able to affecting the athletic performance. The gene, ANKK1 and the polymorphism NM_178510.2:c.2137G > A (rs1800497) has been linked to the exercise addiction. However, further studies on diverse populations and sport branches are needed to totally explore the possible association of this polymorphism with the athletic performance. Thus, the present study aims to decipher any possible relations of the rs1800497 polymorphism with the athletic performance/personal best (PB) and sport experience of elite athletes. Methods: Sixty volunteer elite athletes (31 sprint/power and 29 endurance) and 20 control/sedentary participated in the study. The polymorphism was genotyped using whole exome sequencing approach and PB were determined according to the International Association of Athletics Federations (IAAF) score. Results: Our results underlined that there were not any significance differences for both allele and genotype frequencies between the groups in terms of athletic performance, although the frequency of allele G was higher (p > 0.05). Nevertheless, sport experience significantly associated with the rs1800496 polymorphism (p < 0.05). Discussion: In conclusion, genotype G/G could be inferred to be linked to the higher sport experience and athletic performance. Still, further studies with higher number of participants are needed to conclude the association of this polymorphism with athletic parameters.

Associated and intermediate factors between genetic variants of the dopaminergic D2 receptor gene and harmful alcohol use in young adults.

Dopamine receptor D2 (DRD2) and ankyrin repeat and kinase domain-containing protein 1 (ANKK1) genes have received considerable attention for their involvement in alcohol use disorder (AUD), but many questions remain on their exact role. We conducted a population-based case-control and genetic association study in a large sample of young adults. Our aim was to assess the association between DRD2 and ANKK1 single nucleotide polymorphisms (SNPs) and harmful alcohol use, disentangling associated and possible intermediate factors. A total of 1841 college students from the French region Champagne-Ardennes, aged between 18 and 21 years and who reported at least one lifetime alcohol consumption, were included in this study. Allele frequencies were analysed according to harmful alcohol use (assessed through the Alcohol Use Disorder Identification Test [AUDIT] questionnaire). Different substance use disorders, including nicotine and cannabis dependences, were also assessed through questionnaires, as was a list of potential associated factors (e.g., major depressive episode, conduct disorder, attention-deficit/hyperactivity disorder [ADHD], school failure, sugar consumption, sexual trauma, parents' use of alcohol, tobacco or cannabis). We found that DRD2 rs1800498 was associated with harmful alcohol use. Many factors were detected, but a global path analysis revealed that DRD2 rs1800498 had a significant direct effect on harmful alcohol use and that early age at first alcohol consumption and depressive symptoms moderated this effect. This study suggests an interplay between harmful alcohol use, DRD2 genotypes and other risk factors that, with a full understanding, could be useful for preventive purposes.

Effect of ANKK1 Polymorphisms on Serum Valproic Acid Concentration in Chinese Han Adult Patients in the Early Postoperative Period.

INTRODUCTION: This study aimed to investigate the relationship between gene polymorphisms and clinical factors with the concentrations of valproic acid (VPA) in adult patients who underwent neurosurgery in China. METHODS: A total of 531 serum concentration samples at steady state were collected from 313 patients to develop a population pharmacokinetic (PPK) model. Data analysis was performed using nonlinear mixed effects modeling. Covariates included demographic parameters, biological characteristics, and genetic polymorphism. Bootstrap evaluation showed that the final model was stable. Sensitive analysis was performed to verify the relationship between gene polymorphisms and concentrations of VPA. Linear regression was used to analyze the relationship between VPA concentration, ANKK1, and daily dosage. RESULTS: In the recruited patients, 17 of 25 single-nucleotide polymorphism distributions were consistent with the Hardy-Weinberg equilibrium. A one-compartment model with first-order absorption and elimination was developed for VPA injections. VPA clearance was significantly influenced by three variables: sex (17.41% higher in male than female patients), body weight, and the ANKK1 gene. Typical values for the elimination clearance and the volume of central compartment were 0.614 L/min and 23.5 L, respectively. The model evaluation indicated the stable and precise performance of the final model. After sensitive analysis using Kruskal-Wallis and Mann-Whitney U tests, we found that patients with AA alleles had higher VPA concentrations than those with GG and AG alleles. Linear regression models showed that gene polymorphisms of ANKK1 had little effects on VPA concentration. CONCLUSION: A PPK model of VPA in Chinese Han patients was successfully established; this can be helpful for model-informed precision-dosing approaches in clinical patient care, and for exploring the mechanism of VPA-induced weight gain.

Association between DRD2/ANKK1 TaqIA Allele Status and Striatal Dopamine D2/3 Receptor Availability in Alcohol Use Disorder.

BACKGROUND: The association between blunted dopaminergic neurotransmission and alcohol use disorder (AUD) is well-known. In particular, the impairment of postsynaptic dopamine 2 and 3 receptors (DRD2/3) in the ventral and dorsal striatum during the development and maintenance of alcohol addiction has been investigated in several positron emission tomography (PET) studies. However, it is unclear whether these changes are the result of adaptation or genetic predisposition. METHODS: Here we investigated the association between DRD2/ankyrin repeat and kinase domain-containing 1 (ANKK1) TaqIA allele (rs1800497) status and striatal DRD2/3 availability measured by 18F-fallypride PET in 12 AUD patients and 17 sex-matched healthy controls. Age and smoking status were included as covariates. RESULTS: Contrary to our expectations, TaqIA allele status was not associated with striatal DRD2/3 availability in either group and there was no significant difference between groups, possibly due to the relatively small sample size (N = 29). CONCLUSIONS: Nonetheless, this is the first in vivo study investigating the relationship between dopamine receptor availability and genetic factors in AUD. The pitfalls of assessing such relationships in a relatively small sample are discussed. CLINICAL TRIAL REGISTRATION: The published analysis is an additional, post hoc analysis to the preregistered trial with clinical trial number NCT01679145 available on https://clinical-trials.gov/ct2/show/NCT01679145.

ANKK1 and TH gene variants in combination with paternal maltreatment increase susceptibility to both cognitive and attentive impulsivity.

Recent scientific findings suggest that dopamine exerts a central role on impulsivity, as well as that aversive life experiences may promote the high levels of impulsivity that often underlie violent behavior. To deepen our understanding of the complex gene by environment interplay on impulsive behavior, we genotyped six dopaminergic allelic variants (ANKK1-rs1800497, TH-rs6356, DRD4-rs1800955, DRD4-exonIII-VNTR, SLC6A3-VNTR and COMT-rs4680) in 655 US White male inmates convicted for violent crimes, whose impulsivity was assessed by BIS-11 (Barratt Impulsiveness Scale). Furthermore, in a subsample of 216 inmates from the whole group, we also explored the potential interplay between the genotyped dopaminergic variants and parental maltreatment measured by MOPS (Measure of Parental Style) in promoting impulsivity. We found a significant interaction among paternal MOPS scores, ANKK1-rs1800497-T allele and TH-rs6356-A allele, which increased the variance of BIS-11 cognitive/attentive scores explained by paternal maltreatment from 1.8 up to 20.5%. No direct association between any of the individual genetic variants and impulsivity was observed. Our data suggest that paternal maltreatment increases the risk of attentive/cognitive impulsivity and that this risk is higher in carriers of specific dopaminergic alleles that potentiate the dopaminergic neurotransmission. These findings add further evidence to the mutual role that genetics and early environmental factors exert in modulating human behavior and highlight the importance of childhood care interventions.

Association Between DRD2 and DRD4 Polymorphisms and Eating Disorders in an Italian Population.

Anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED) are the three most common eating disorders (EDs). Their etiopathogenesis is multifactorial where both the environmental and genetic factors contribute to the disease outcome and severity. Several polymorphisms in genes involved in the dopaminergic pathways seem to be relevant in the susceptibility to EDs, but their role has not been fully elucidated yet. In this study, we have analyzed the association between selected common polymorphisms in the DRD2 and DRD4 genes in a large cohort of Italian patients affected by AN (n = 332), BN (n = 122), and BED (n = 132) compared to healthy controls (CTRs) (n = 172). Allelic and genotypic frequencies have been also correlated with the main psychopathological and clinical comorbidities often observed in patients. Our results showed significant associations of the DRD2-rs6277 single nucleotide polymorphism (SNP) with AN and BN, of the DRD4-rs936461 SNP with BN and BED and of DRD4 120-bp tandem repeat (TR) polymorphism (SS plus LS genotypes) with BED susceptibility. Moreover, genotyping of DRD4 48-bp variable number TR (VNTR) identified the presence of ≥7R alleles as risk factors to develop each type of EDs. The study also showed that ED subjects with a history of drugs abuse were characterized by a significantly higher frequency of the DRD4 rs1800955 TT genotype and DRD4 120-bp TR short-allele. Our findings suggest that specific combinations of variants in the DRD2 and DRD4 genes are predisposing factors not only for EDs but also for some psychopathological features often coupled specifically to AN, BN, and BED. Further functional research studies are needed to better clarify the complex role of these proteins and to develop novel therapeutic compounds based on dopamine modulation.

Ankk1 Loss of Function Disrupts Dopaminergic Pathways in Zebrafish.

Ankyrin repeat and kinase domain containing 1 (ANKK1) is a member of the receptor-interacting protein serine/threonine kinase family, known to be involved in cell proliferation, differentiation and activation of transcription factors. Genetic variation within the ANKK1 locus is suggested to play a role in vulnerability to addictions. However, ANKK1 mechanism of action is still poorly understood. It has been suggested that ANKK1 may affect the development and/or functioning of dopaminergic pathways. To test this hypothesis, we generated a CRISPR-Cas9 loss of function ankk1 zebrafish line causing a 27 bp insertion that disrupts the ankk1 sequence introducing an early stop codon. We found that ankk1 transcript levels were significantly lower in ankk1 mutant (ankk127ins ) fish compared to their wild type (ankk1 +/+) siblings. In ankk1 +/+ adult zebrafish brain, ankk1 protein was detected in isocortex, hippocampus, basolateral amygdala, mesencephalon, and cerebellum, resembling the mammalian distribution pattern. In contrast, ankk1 protein was reduced in the brain of ankk127ins/27ins fish. Quantitative polymerase chain reaction analysis revealed an increase in expression of drd2b mRNA in ankk127ins at both larval and adult stages. In ankk1 +/+ adult zebrafish brain, drd2 protein was detected in cerebral cortex, cerebellum, hippocampus, and caudate homolog regions, resembling the pattern in humans. In contrast, drd2 expression was reduced in cortical regions of ankk127ins/27ins being predominantly found in the hindbrain. No differences in the number of cell bodies or axonal projections detected by anti-tyrosine hydroxylase immunostaining on 3 days post fertilization (dpf) larvae were found. Behavioral analysis revealed altered sensitivity to effects of both amisulpride and apomorphine on locomotion and startle habituation, consistent with a broad loss of both pre and post synaptic receptors. Ankk127ins mutants showed reduced sensitivity to the effect of the selective dopamine receptor antagonist amisulpride on locomotor responses to acoustic startle and were differentially sensitive to the effects of the non-selective dopamine agonist apomorphine on both locomotion and habituation. Taken together, our findings strengthen the hypothesis of a functional relationship between ANKK1 and DRD2, supporting a role for ANKK1 in the maintenance and/or functioning of dopaminergic pathways. Further work is needed to disentangle ANKK1's role at different developmental stages.

GABAA subunit single nucleotide polymorphisms show sex-specific association to alcohol consumption and mental distress in a Norwegian population-based sample.

Little is known about genetic influences on the relationship between alcohol consumption and mental distress in the general population, where the majority report consumption and distress far below diagnostic thresholds. This study investigated single nucleotide polymorphisms (SNPs) from candidate gene studies on alcohol use disorder and depressive disorders, for association with alcohol consumption and with mental distress in a population-based sample from the Cohort of Norway (n = 1978, 49% women). The relationship between alcohol consumption and mental distress was further examined for genotype modification. There was a positive correlation between mental distress and alcohol consumption in men, as well as an association between SNPs and mental distress in men (GABRG1, GABRA2, DRD2, ANKK1, MTHFR) and women (CHRM2, MTHFR) and between SNPs and alcohol consumption in women (GABRA2, MTHFR). No modification by SNP genotype was found on the relationship between alcohol consumption and mental distress. The association between mental distress and GABRG1 in men remained significant after correcting for multiple comparisons. The results indicate that alcohol consumption and mental distress are associated in the general population even at levels below clinical thresholds and point to SNPs in genes related to GABAergic signalling for level of mental distress in men.

Genotypes of ANKK1 and DRD2 genes and risk of metabolic syndrome and its components: A cross-sectional study on Iranian women.

We aimed to investigate the association between polymorphism of DRD2/ANKK1 gene with MetS and its components. Women (n = 531, aged 19-50 years) from the North-west of Iran were included by cluster sampling method. Polymorphisms of ANKK1 and DRD2 genes were defined in the study population. D/D (OR: 3.16; 95%CI: 1.31-7.60) and I/D (OR: 1.76; 95%CI: 1.12-2.78) genotypes of DRD2 (rs1799732) increased risk of MetS compared to I/I genotype. The D/D genotype of DRD2 (rs1799732) increased odds of hypertriglyceridemia in the study population. T/T (OR: 6.72; 95%CI: 1.99-22.71) and C/T (OR: 4.42; 95%CI: 2.79-7.01) genotypes of ANKK1 (rs1800497) increased risk of MetS compared to C/C genotype. Also, C/T genotype increased the odds of HTN, high FBS, high TG and low HDL-C levels compared to C/C genotype. These polymorphisms can affect the MetS components via their relation to the signaling of dopaminergic pathways and eating behaviors.

Analysis of Selected Variants of DRD2 and ANKK1 Genes in Combat Athletes.

The level of physical activity is conditioned by many different factors, including, among others, the personality traits of a person. Important is the fact that personality traits are a moderately heritable factor and on the basis of the analysis of several genes, various lifetime outcomes can be predicted. One of the most important pathways influencing personality traits is connected to the dopaminergic system; hence, we decided to analyze the DRD2 PROM. rs1799732, DRD2 rs1076560, DRD2 Tag1D rs1800498, DRD2 Ex8 rs6276, DRD2Tag1B rs1079597 and ANKK1 Tag1A rs180049. The research group included 258 male athletes (mean age = 26.02; SD = 8.30), whereas the control group was 284 healthy male volunteers matched for age (mean age = 22.89; SD = 4.78), both of Caucasian origin and without history of substance dependency or psychosis. Genomic DNA was extracted from venous blood using standard procedures. Genotyping was conducted with the real-time PCR method. Differences in the frequency of the DRD2Tag1B rs1079597 gene polymorphism were found between people practicing combat sports and the control group, and the DRD2 PROM. rs1799732, DRD2 rs1076560, DRD2 Tag1D rs1800498, DRD2 Ex8 rs6276, DRD2Tag1B rs1079597 and ANKK1 Tag1A rs1800497 genotypes and allele frequencies in the studied sample did not differ between the analyzed groups. Hence, we considered these polymorphic places as an interesting area for the further search for unambiguous associations between personality traits and attitude towards physical effort.

Genetic diversity of the North African population revealed by the typing of SNPs in the DRD2/ANKK1 genomic region.

The dopamine - related genes, like dopamine D2 receptor (DRD2) gene and ankyrin repeat and kinase domain containing 1 (ANKK1) gene are implicated in neurological functions. Some polymorphisms of the DRD2/ANKK1 locus (TaqIA, TaqIB, TaqID) have been used to study genetic diversity and the evolution of human populations. The present investigation aims to assess the genetic diversity in seven North African populations in order to explore their genetic structure and to compare them to others worldwide populations studied for the same locus. Nine single nucleotide polymorphisms (SNPs) from the DRD2/ANKK1 locus (rs1800497 TaqIA, rs2242592, rs1124492, rs6277, rs6275, rs1079727, rs2002453, rs2234690 and rs1079597 TaqIB) were typed in 366 individuals from seven North African populations: six from Tunisia (Sousse, Smar, Kesra, Kairouan, Mehdia and Kerkennah) and one from Libya. The allelic frequencies of rs2002453 and rs2234690 were higher in the Smar population than in the other North African populations. More, the Smar population showed the lowest average heterozygosity (0.313). The principal component analysis (PCA) showed that the Smar population was clearly separated from others. Furthermore, linkage disequilibrium analysis shown a high linkage disequilibrium in the North African population and essentially in Smar population. Comparison with other world populations has shown that the heterozygosity of North African population was very close to that of the African and European populations. The PCA and the haplotypic analysis suggested the presence of an important Eurasian genetic component for the North African population. These results suggested that the Smar population was isolated from the others North Africans ones by its peculiar genetic structure because of isolation, endogamy and genetic drift. On the other hand, the North African population is characterized by a multi ancestral gene pool from Eurasia and sub-Saharan Africa due to human migration since prehistoric times.

Associations of the ANKK1 and DRD2 gene polymorphisms with overweight, obesity and hedonic hunger among women from the Northwest of Iran.

BACKGROUND: Pleasure from palatable foods can stimulate hedonic eating and, therefore, might be a major culprit for obesity. Dopamine receptor polymorphisms, especially variants in the genes regulating the D2 receptor, including ANKK1 and DRD2, are the prime candidates for assessing the individual differences in hedonic eating. This study was carried out to investigate the possible associations of the T (rs1800497) and Del (rs1799732) alleles with body mass index (BMI) and hedonic hunger among Iranian Azeri women. METHODS: A total of 372 healthy overweight/obese subjects (BMI ≥ 25 kg/m2) and 159 normal weight individuals (BMI 18.5-24.9 kg/m2) were genotyped for the polymorphisms of ANNK1 and DRD2 genes using PCR-RFLP. BMI and hedonic hunger were also evaluated. RESULTS: Three hundred and sixty-three (68.36%), 152 (28.63%), and 16 (3.01%) of the participants had CC, CT, and TT genotypes for ANNK1 gene, respectively. Of 515 samples genotyped for DRD2 gene, 315 (60.51%), 173 (33.59%), and 27 (5.24%) had Ins/Ins, Ins/Del, and Del/Del genotypes, respectively. The genotype and genotype frequencies were significantly different between the groups (p = 0.04). Significant differences were observed between the T+ genotype (TT + TC) and the T- genotype (CC) regarding the BMI and hedonic hunger scores (p < 0.05). In addition, Del+ group (Del/Del + Ins/Del) had higher BMI and hedonic hunger scores compared to Del- group (Ins/Ins) (p < 0.05). CONCLUSIONS: Our findings showed that the frequencies of T and Del alleles were greater in the overweight/obese individuals. Also, the polymorphism of ANKK1 (rs1800497) and polymorphism of the DRD2 gene (rs1799732) showed significant associations with BMI and hedonic hunger. LEVEL OF EVIDENCE: Level III, case-control study.

Epistatic effect of Ankyrin repeat and kinase domain containing 1 - Dopamine receptor D2 and catechol-o-methyltransferase single nucleotide polymorphisms on the risk for hazardous use of alcohol in Lithuanian population.

AIM: The Lithuanian population has outstanding rates of alcohol consumption and alcohol related mortality. Alteration of brain dopaminergic system play a role in the risk for addiction disorders. We evaluated the association of one single nucleotide polymorphism rs1800497 in the Ankyrin Repeat and Kinase Domain Containing 1 - Dopamine Receptor D2 complex (ANKK1-DRD2) and a catechol-o-methyltransferase (COMT) rs4680 single nucleotide polymorphism with the risk for alcohol use disorder and impulsiveness in Lithuanian population. Both genetic polymorphisms are known to alter brain dopaminergic activity, thus we also investigated the possible interaction effect of these polymorphisms. METHODS: The study included 329 participants recruited from the local community. Hazardous alcohol use was evaluated using the Alcohol Use Disorder Identification Test (AUDIT). Impulsiveness was measured using the Barratt Impulsiveness Scale - 11 (BIS-11). Between group differences of AUDIT and BIS-11 scores were examined stratified by genetic polymorphisms and their combinations. The independent effect of each polymorphism and their interaction for hazardous alcohol use were evaluated using adjusted logistic regression analyses. RESULTS: The ANKK1-DRD2 rs1800497 polymorphism was associated with total AUDIT score, but not with the hazardous use of alcohol, as indicated by the AUDIT test cut-off of 8. The COMT rs4680 GG genotype was associated with the hazardous use of alcohol (adjusted OR = 2.094, p = 0.029), but this association was not statistically significant after adjustment for multiple comparisons. Presence of both COMT rs4680 and ANKK1-DRD2 rs1800497 GGxCT/TT polymorphisms was associated with significantly increased risk for hazardous use of alcohol (adjusted OR = 5.016, p = 0.005). The COMT rs4680 and ANKK1-DRD2 rs1800497 genetic polymorphisms, and their combination were not associated with impulsiveness. CONCLUSIONS: Our study demonstrated that the interaction of COMT rs4680 and ANKK1-DRD2 rs1800497 genetic polymorphisms is associated with a hazardous use of alcohol.

Suicidal ideation and aggression in childhood, genetic variation and young adult depression.

BACKGROUND: Suicidal thoughts and behaviors have been studied in association with a variety of risk factors. The aim of the present study was to determine if levels of child/adolescent aggression and/or variation in candidate genes previously associated with suicidal behaviors in adults would influence the presence of suicidal ideation in childhood/adolescence, and to determine if ideation was associated with young adult depression. METHODS: A longitudinal study of children, adolescents and young adults who were at high or low risk for alcohol and other substance use disorders by familial background were assessed. The Child Behavior Checklist (CBCL) aggression scale scores with derived subtypes (physical and relational) and genetic variation (ANKK1, DRD2, COMT, SLC6A4, HTR2C) were used as predictors of the presence and onset of suicidal ideation in childhood using survival analysis. Structural equation models (SEM) were fit to determine the relative importance of the predictors controlling for background variables. RESULTS: CBCL aggression was significantly associated with child/adolescent suicidal ideation. One SNP in the ANKK1 gene (rs1800497), one in the HTR2C gene (rs6318), and two haplotypes, AAAC in the ANKK1-DRD2 complex and the CCC haplotype of the HTR2C gene, were significantly associated with the presence and onset of child/adolescent suicidal ideation. Follow up in young adulthood showed a significant relationship between suicidal ideation in childhood/adolescence and young adult depression. CONCLUSIONS: Genetic variation and presence of elevated aggression scores from the childhood CBCL are significant predictors of childhood suicidal ideation. Suicidal ideation in childhood and being female are predictors of young adult depression.

Association between DRD2 and ANKK1 polymorphisms with the deficit syndrome in schizophrenia.

BACKGROUND: The clinical course of schizophrenia varies among patients and is difficult to predict. Some patient populations present persistent negative symptoms, referred to as the deficit syndrome. Compared to relatives of non-deficit schizophrenia patients, family members of this patient population are at an increased risk of developing schizophrenia. Therefore, the aim of this study was to search for genetic underpinnings of the deficit syndrome in schizophrenia. METHODS: Three SNPs, i.e., rs1799732 and rs6276 located within DRD2, and rs1800497 within ANKK1, were identified in the DNA samples of 198 schizophrenia probands, including 103 patients with deficit (DS) and 95 patients with non-deficit schizophrenia (NDS). Results: No significant differences concerning any of the analyzed polymorphisms were found between DS and NDS patients. However, significant links were observed between family history of schizophrenia and the deficit syndrome, G/G genotype and rs6276 G allele. In a separate analysis, we identified significant differences in frequencies of rs6276 G allele between DS and NDS patients with family history of schizophrenia. No significant associations were found between DRD2 and ANKK1 SNPs and the age of onset or schizophrenia symptom severity. CONCLUSIONS: The results of our preliminary study fail to provide evidence of associations between DRD2 and ANKK1 polymorphisms with the deficit syndrome or schizophrenia symptom severity, but suggest potential links between rs6276 in DRD2 and the deficit syndrome in patients with hereditary susceptibility to schizophrenia. However, further studies are necessary to confirm this observation.

Association of ANKK1 polymorphism with antipsychotic-induced hyperprolactinemia.

OBJECTIVE: Schizophrenia is a severe highly heritable mental disorder. Genetic polymorphisms of dopaminergic pathways are related to pathogenesis of drug response. Hyperprolactinemia (HPRL), a common adverse effect of antipsychotics, is attributed to blockade of dopamine D2 receptors. Ankyrin Repeat and Kinase Domain containing 1 (ANKK1) gene is closely related to Dopamine Receptor D2 type (DRD2) gene functioning. We examined whether the functional polymorphism rs2734849 in the ANKK1 gene is associated with antipsychotic-induced HPRL. METHODS: We recruited 446 patients with schizophrenia from among the Russian population of the Siberian region. The polymorphism rs2734849 in the ANKK1 gene was genotyped with The MassARRAY® Analyzer 4 by Agena Bioscience™, using the kit SEQUENOM Consumables iPLEXGold 384. Genotype and allele frequencies were compared between groups of schizophrenia patients with and without HPRL using the χ2 test. RESULTS: A comparison between schizophrenia patients with and without HPRL revealed significantly higher frequency of the C allele of the polymorphic variant rs2734849 in the ANKK1 gene in patients with HPRL as compared to the patients without it (χ2 = 3.70; p = .05; odds ratio [OR] = 1.30 [0.99-1.69]). CONCLUSION: The functional polymorphism rs2734849 in the ANKK1 gene was associated with HPRL in patients with schizophrenia.

Ankyrin Repeat and Kinase Domain Containing 1 Gene, and Addiction Vulnerability.

The TaqIA single nucleotide variant (SNV) has been tested for association with addictions in a huge number of studies. TaqIA is located in the ankyrin repeat and kinase domain containing 1 gene (ANKK1) that codes for a receptor interacting protein kinase. ANKK1 maps on the NTAD cluster along with the dopamine receptor D2 (DRD2), the tetratricopeptide repeat domain 12 (TTC12) and the neural cell adhesion molecule 1 (NCAM1) genes. The four genes have been associated with addictions, although TTC12 and ANKK1 showed the strongest associations. In silico and in vitro studies revealed that ANKK1 is functionally related to the dopaminergic system, in particular with DRD2. In antisocial alcoholism, epistasis between ANKK1 TaqIA and DRD2 C957T SNVs has been described. This clinical finding has been supported by the study of ANKK1 expression in peripheral blood mononuclear cells of alcoholic patients and controls. Regarding the ANKK1 protein, there is direct evidence of its location in adult and developing central nervous system. Together, these findings of the ANKK1 gene and its protein suggest that the TaqIA SNV is a marker of brain differences, both in structure and in dopaminergic function, that increase individual risk to addiction development.

Association of Candidate Single Nucleotide Polymorphisms Related to Candidate Genes in Patients With Schizophrenia.

INTRODUCTION: Schizophrenia is a chronic heterogenic neurodevelopment disorder. Many genes interfere in the development of SCZ. All four genes, NrCAM, PRODH, ANK3, and ANKK1, which were evaluated in this study, were previously reported to be associated with Schizophrenia. The NrCAM contributes to creating cognitive deficiencies through the CAM's signaling pathway. PRODH plays a vital role in creating SCZ negative symptoms through the signaling pathway of glutamatergic and NMDA receptors. ANK3 affects ion channel and molecular adhesion in Ranvier and initial segments of axons, leading to mental retardation, sleep disorder, and SCZ. ANKK1 encodes a protein kinase and was reported to be associated with alcohol addiction, Attention Deficit Hyperactivity Disorder (ADHD), and SCZ. METHODS: The subjects were selected from Schizophrenic patients referring to the Psychiatric Ward of Imam-Hussein Hospital and Schizophrenic Patients Support Institution (AHEBBA). 95 (30 Schizoaffective patients, 57 Paranoid patients, and 8 disorganized) patients were recruited as the subjects in the present case-control association study. 120 healthy subjects were recruited from the Tehran Medical Genetics Laboratory staff and a group of students from the Islamic Azad University of Science and Research in Tehran. The genotypes were determined with molecular genotyping techniques of PCR-RFLP, ARMS-PCR, and Cycle sequencing. Results were analyzed by the Chi-Square test using SPSS V. 24 and R, SNP STATE Package to investigate significant differences between cases and controls. RESULTS: The incidence of schizophrenia was 68% and 32% among men and women, respectively. The evaluation of the allelic association between schizophrenia and all the candidate SNPs showed a significant association between NrCAM's SNP rs10235968 and SCZ (P=0.001). Haplotype T, T, C in rs10235968, rs6967368, rs3763463, respectively, within the NrCAM gene, showed significant association with schizophrenia disorder (P=0.0001). CONCLUSION: No association was found between other candidate SNPs and SCZ among the subjects.

Interactions between DRD2/ANKK1 TaqIA Polymorphism and Dietary Factors Influence Plasma Triglyceride Concentrations in Diabetic Patients from Western Mexico: A Cross-sectional Study.

This study aimed to screen relevant interactions between DRD2/ANKK1 TaqIA polymorphism and dietary intakes with reference to phenotypical features in patients with T2D from western Mexico. In this cross-sectional study, a total of 175 T2D patients were enrolled. Dietary intake was evaluated using 3-day food records and appropriate software. Glycemic and blood lipid profiles were measured by standardized methods. Genotyping of the DRD2/ANKK1 TaqIA polymorphism was performed by the RFLP method. Gene-diet interactions regarding anthropometric and metabolic phenotypes were screened by adjusted multiple linear regression analyses. Genotype frequencies of the DRD2/ANKK1 TaqIA polymorphism were A1A1 (16.0%), A1A2 (52.6%), and A2A2 (31.4%). Statistically significant interactions between the DRD2/ANKK1 TaqIA genotypes and dietary factors in relation to blood triglyceride (TG) levels were found. Carriers of the A1 allele (A1A1 homozygotes plus A1A2 heterozygotes) were protected from TG increases by maltose intake (P int. = 0.023). Instead, A2A2 homozygotes were susceptible to TG rises through consumptions of total fat (P int. = 0.041), monounsaturated fatty acids (P int. = 0.001), and dietary cholesterol (P int. = 0.019). This study suggests that the interactions between DRD2/ANKK1 TaqIA polymorphism and dietary factors (sugar and fats) influence TG levels in diabetic patients.