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.

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.

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.