The ANKK1/DRD2 gene TaqIA polymorphism (rs1800497) is associated with the severity of extrapyramidal side effects of haloperidol treatment in CYP2D6 extensive metabolizers with schizophrenia spectrum disorders.

OBJECTIVES: Extrapyramidal symptoms (EPS) are one of the most prominent side effects of haloperidol. Variability of EPS severity may be associated with the genetic factors, affecting both haloperidol pharmacokinetics (e.g., CYP2D6) and pharmacodynamics (e.g., DRD2, ANKK1). We conducted a 3-week prospective study to investigate the associations of ANKK1/DRD2 TaqIA (rs1800497), DRD2 -141C Ins/Del (rs1799732) polymorphisms and CYP2D6 metabolic phenotype on the efficacy of haloperidol treatment and severity of EPS in patients with schizophrenia spectrum disorders. METHODS: In total, 57 inpatients with schizophrenia spectrum disorders (24 (42.1%)) females; age -46.7 (11.8) years (M(SD)) of European ancestry were enrolled. BARS and SAS scales were used to assess EPS. PANSS and CGI scales - to assess the efficacy of haloperidol treatment. Genotyping was performed by real-time PCR. CYP2D6 metabolic phenotype was predicted by the CYP2D6 *3, *4, *5, *6, *9, *10, *41 and xN genotypes. RESULTS: Minor C allele of TaqIA was associated with higher scores of BARS (p=0.029) and SAS (p=0.024) on day 21 and minor Del allele of -141C Ins/Del - with more prominent clinical improvement by CGI scale (p=0.007) but not by PANSS. These differences were observed only in extensive CYP2D6 metabolizers, although no associations with the metabolic type itself were found. General linear model showed that the combination of TaqIA genotype and metabolic type was significantly associated with BARS score on day 21 (p=0.013). CONCLUSIONS: Our results highlight the importance of using both pharmacokinetic and pharmacodynamic genetic markers for predicting haloperidol treatment response to personalize schizophrenia spectrum disorders treatment.

A Genome-Wide Association Study Reveals a BDNF-Centered Molecular Network Associated with Alcohol Dependence and Related Clinical Measures.

At least 50% of factors predisposing to alcohol dependence (AD) are genetic and women affected with this disorder present with more psychiatric comorbidities, probably indicating different genetic factors involved. We aimed to run a genome-wide association study (GWAS) followed by a bioinformatic functional annotation of associated genomic regions in patients with AD and eight related clinical measures. A genome-wide significant association of rs220677 with AD (p-value = 1.33 × 10-8 calculated with the Yates-corrected χ2 test under the assumption of dominant inheritance) was discovered in female patients. Associations of AD and related clinical measures with seven other single nucleotide polymorphisms listed in previous GWASs of psychiatric and addiction traits were differently replicated in male and female patients. The bioinformatic analysis showed that regulatory elements in the eight associated linkage disequilibrium blocks define the expression of 80 protein-coding genes. Nearly 68% of these and of 120 previously published coding genes associated with alcohol phenotypes directly interact in a single network, where BDNF is the most significant hub gene. This study indicates that several genes behind the pathogenesis of AD are different in male and female patients, but implicated molecular mechanisms are functionally connected. The study also reveals a central role of BDNF in the pathogenesis of AD.

GWAS of depression in 4,520 individuals from the Russian population highlights the role of MAGI2 (S-SCAM) in the gut-brain axis.

We present the results of the depression Genome-wide association studies study performed on a cohort of Russian-descent individuals, which identified a novel association at chromosome 7q21 locus. Gene prioritization analysis based on already known depression risk genes indicated MAGI2 (S-SCAM) as the most probable gene from the locus and potential susceptibility gene for the disease. Brain and gut expression patterns were the main features highlighting functional relatedness of MAGI2 to the previously known depression risk genes. Local genetic covariance analysis, analysis of gene expression, provided initial suggestive evidence of hospital anxiety and depression scale and diagnostic and statistical manual of mental disorders scales having a different relationship with gut-brain axis disturbance. It should be noted, that while several independent methods successfully in silico validate the role of MAGI2, we were unable to replicate genetic association for the leading variant in the MAGI2 locus, therefore the role of rs521851 in depression should be interpreted with caution.

The association of obesity with eating disorders risk: online survey of a large cohort of Russian-speaking individuals seeking medical weight correction assistance.

BACKGROUND: Eating Disorders pose a serious health risk to individuals. Often, eating disorder symptoms are overlooked when assessing obesity risk. The current cross-sectional study was focused on the search of association between disordered eating behaviors evaluated by Eating Attitudes Test 26 (EAT-26) and obesity in a large cohort of Russian-speaking adults seeking online assistance with medical weight correction. METHODS: The web-based cross-sectional study evaluated the data of online Eating Attitudes Test 26 (EAT-26) completed by 13,341 registered adult visitors of weight loss clinic website. The EAT-26 provides an overall score for potential eating disorders risk, as well as scores for three subscales: Bulimia, dieting, and oral control. Additional self-reported information about sex, weight, height, and age of respondents was used for analysis. The nonparametric analysis of variance and binominal logistic regression modeling were applied to search for an association between obesity and EAT-26 total score and subscales scores. The critical level of the significance was considered as α = 0.05. RESULTS: Women (94%) had lower BMI values but higher EAT-26 total score than men, which was indicated as statistically significant by a Wilcoxon Signed-Ranks Test (Z = - 11.80, p < 0.0001). Logistic regression for the whole cohort revealed that Bulimia subscale score was associated with higher risk of obesity (OR = 1.03, 95% CI 1.02-1.05) whereas higher score of EAT-26 oral control subscale was associated with decreased risk of obesity (OR = 0.93, 95% CI 0.91-0.95). Separate analysis for men and women showed that in men higher obesity risk was associated with higher oral control subscale scores (OR = 1.08, 95% CI 1.06-1.11); while in women both dieting and bulimia subscales scores were associated with higher obesity risk (OR = 1.02, 95% CI 1.01-1.03 and OR = 1.03, 95% CI 1.02-1.05, respectively). Older age was associated with obesity risk for both women and men. CONCLUSIONS: In a large cohort of individuals seeking medical weight correction assistance, the risk of obesity was associated with the higher EAT-26 scores, age, and sex. Moreover, different eating disorder risk profiles were associated with obesity in men and women. Higher oral control subscale score was associated with decreased risk of obesity in women, but with higher risk in men. Older age was a shared obesity risk factor for both sexes. Therefore, the use of EAT-26 would facilitate individual diagnostic assessment for specific eating disorders in different sub-cohorts. Further assessment of separate EAT-26 subscales may be important to predict sex-/age-specific risks of obesity that implies their study in the future. Obesity is a significant health problem. Different factors (e.g. social, biological, and behavioral) are important for their successful treatment. Abnormal eating behaviors may be one of the most likely predictors of increased body weight. This study aims to determine whether there is a significant association between obesity and scores on the eating behavior questionnaire-Eating Attitudes Test-26 (EAT-26)-in a large cohort of adults seeking medical weight correction assistance at a private weight loss clinic web-site. According to the study results, the association was shown for the male sex, older age, and higher Bulimia scores as measured on the EAT-26. Moreover, different EAT-26 scales were associated with obesity risks in women and men subgroups, while older age was a shared risk factor for obesity in both sexes. The findings may suggest sex-/age-specific diagnostic approach and treatment strategies for individuals with obesity.

Screening of Depressive Symptoms in a Russian General Population Sample: A Web-based Cross-sectional Study.

BACKGROUND AND OBJECTIVE: Web-based screening of depressive symptoms in general non-clinical population can provide better insights into actual prevalence of depressive symptoms and associated risk factors. To study the current prevalence of depressive symptoms in Russian non-clinical population we conducted screening using an online survey based on Depression subscale of Hospital Anxiety and Depression Scale (HADS-D). METHODS: The online survey covered 2610 Russian-speaking respondents and included HADS-D, questions about sex, age and presence of cardiovascular diseases (CVD) diagnoses or symptoms in respondents. RESULTS: The proportion of respondents with depressive symptoms, estimated by online HADS-D, was 14.4% (11.5% - at subclinical level, 2.9% - at clinical level). The overall HADS-D score was higher in women (p=0.003), in young individuals under 30 y.o vs. participants over 42 y.o. (p=0.004) and in individuals with self-reported CVD symptoms (p=0.00002). Linear regression analysis showed that self-reported CVD symptoms increase HADS-D score (p<0.001), but male sex (p=0.002) and older age (p<0.001) decrease it. Logistic regression showed that CVD symptoms increase the risk of depressive symptoms by HADS-D (p=0.033, OR=1.29), but older age (p=0.015, OR=0.87) and male sex (as a trend, p=0.052, OR=0.80) decrease this risk. CONCLUSION: Online survey based on HADS-D showed new patterns of depressive symptoms prevalence in Russian non-clinical population. Depressive symptoms prevalence did not differ between men and women and was higher among young people. The reported association between depressive symptoms and CVD was confirmed.

A genome-wide association study identifies a gene network associated with paranoid schizophrenia and antipsychotics-induced tardive dyskinesia.

In the present study we conducted a genome-wide association study (GWAS) in a cohort of 505 patients with paranoid schizophrenia (SCZ), of which 95 had tardive dyskinesia (TD), and 503 healthy controls. Using data generated by the PsychENCODE Consortium (PEC) and other bioinformatic databases, we revealed a gene network, implicated in neurodevelopment and brain function, associated with both these disorders. Almost all these genes are in gene or isoform co-expression PEC network modules important for the functioning of the brain; the activity of these networks is also altered in SCZ, bipolar disorder and autism spectrum disorders. The associated PEC network modules are enriched for gene ontology terms relevant to the brain development and function (CNS development, neuron development, axon ensheathment, synapse, synaptic vesicle cycle, and signaling receptor activity) and to the immune system (inflammatory response). Results of the present study suggest that orofacial and limbtruncal types of TD seem to share the molecular network with SCZ. Paranoid SCZ and abnormal involuntary movements that indicate the orofacial type of TD are associated with the same genomic loci on chromosomes 3p22.2, 8q21.13, and 13q14.2. The limbtruncal type of TD is associated with a locus on chromosome 3p13 where the best functional candidate is FOXP1, a high-confidence SCZ gene. The results of this study shed light on common pathogenic mechanisms for SCZ and TD, and indicate that the pathogenesis of the orofacial and limbtruncal types of TD might be driven by interacting genes implicated in neurodevelopment.

The combined effect of CYP2D6 and DRD2 Taq1A polymorphisms on the antipsychotics daily doses and hospital stay duration in schizophrenia inpatients (observational naturalistic study).

BACKGROUND: To assess the correlation between the antipsychotics (AP) mean daily doses, hospital stay duration and CYP2D6, DRD2 polymorphisms in naturalistic study. SUBJECTS AND METHODS: CYP2D6 polymorphisms *3, *4, *5, *6, *1XN and DRD2/ANKK1 Taq1A polymorphisms were genotyped in a cohort of 226 Caucasian schizophrenic inpatients. AP daily doses, hospital stay duration and AP treatment duration were taken from medical records. To compare mean daily doses of AP among CYP2D6 PMs, EMs, UMs and DRD2/ANKK1 Taq1A carriers the actual AP doses were converted to chlorpromazine (CPZ) equivalents and DDD (defined daily dose). RESULTS: Significant correlation (p=0.004) between CYP2D6 metabolic activity and AP mean daily doses was observed only among DRD2/ANKK1 Taq1A polymorphic allele carriers: 250.53 (95%CI: 154.90-346.17), 473.82 (95%CI: 426.99-520.64) 602.77 (95%CI: 469.65-735.88) CPZ equivalents in PMs, EMs and UMs, consequently. PMs with DRD2/ANKK1 Taq1A CT genotype received significantly lower doses of AP comparing to CC genotype (p=0.02). Mean hospital stay duration of PMs+UMs was significantly higher comparing to EMs (66.4 days (95% CI: 56.9-75.8) vs 50.2 days (95%CI: 45.5-54.7); p=0.047). CONCLUSIONS: In a cohort of schizophrenia inpatients CYP2D6 metabolic activity affects mean AP daily dose only in the presence of DRD2 Taq1A polymorphic allele. CYP2D6 metabolic activity correlates independently from DRD2 Taq1A polymorphism with hospital stay duration. Subpopulation of schizophrenia inpatients with altered CYP2D6 activity (PMs and UMs) carriers of Taq1A polymorphisms needs special attention of clinicians in aligning of AP treatment.

Pharmacodynamic genetic polymorphisms affect adverse drug reactions of haloperidol in patients with alcohol-use disorder.

BACKGROUND: Antipsychotic action of haloperidol is due to blockade of D2 receptors in the mesolimbic dopamine pathway, while the adverse drug reactions are associated with striatal D2 receptor blockade. Contradictory data concerning the effects of genetic polymorphisms of genes encoding these receptors and associated structures (catechol-O-methyltransferase [COMT], glycine transporter and gene encoding the density of D2 receptors on the neuronal membrane) are described. OBJECTIVE: The objectives of this study were to evaluate the correlation between DRD2, SLC6A3 (DAT) and COMT genetic polymorphisms and to investigate their effect on the development of adverse drug reactions in patients with alcohol-use disorder who received haloperidol. PATIENTS AND METHODS: The study included 64 male patients (average age 41.38 ± 10.14 years, median age 40 years, lower quintile [LQ] 35 years, upper quintile [UQ] 49 years). Bio-Rad CFX Manager™ software and "SNP-Screen" sets of "Syntol" (Russia) were used to determine polymorphisms rs4680, rs1800497, rs1124493, rs2242592, rs2298826 and rs2863170. In every "SNP-Screen" set, two allele-specific hybridizations were used, which allowed to determine two alleles of studied polymorphism separately on two fluorescence channels. RESULTS: Results of this study detected a statistically significant difference in the adverse drug reaction intensity in patients receiving haloperidol with genotypes 9/10 and 10/10 of polymorphic marker SLC6A3 rs28363170. In patients receiving haloperidol in tablets, the increases in the UKU Side-Effect Rating Scale (UKU) score of 9.96 ± 2.24 (10/10) versus 13 ± 2.37 (9/10; p < 0.001) and in the Simpson-Angus Scale (SAS) score of 5.04 ± 1.59 (10/10) versus 6.41 ± 1.33 (9/10; p = 0.006) were revealed. CONCLUSION: Polymorphism of the SCL6A3 gene can affect the safety of haloperidol, and this should be taken into account during the choice of drug and its dosage regimen.