Psychiatric Genetics最新文献

Introduction: Globally, 80% of the burdenof major depressive disorder (MDD) pertains to low- and middle-income countries. Research into genetic and environmental risk factors has the potential to uncover disease mechanisms that may contribute to better diagnosis and treatment of mental illness, yet has so far been largely limited to participants with European ancestry from high-income countries. The DIVERGE study was established to help overcome this gap and investigate genetic and environmental risk factors for MDD in Pakistan.

Methods: DIVERGE aims to enrol 9000 cases and 4000 controls in hospitals across the country. Here, we provide the rationale for DIVERGE, describe the study protocol and characterise the sample using data from the first 500 cases. Exploratory data analysis is performed to describe demographics, socioeconomic status, environmental risk factors, family history of mental illness and psychopathology.

Results and discussion: Many participants had severe depression with 74% of patients who experienced multiple depressive episodes. It was a common practice to seek help for mental health struggles from faith healers and religious leaders. Socioeconomic variables reflected the local context with a large proportion of women not having access to any education and the majority of participants reporting no savings.

Conclusion: DIVERGE is a carefully designed case-control study of MDD in Pakistan that captures diverse risk factors. As the largest genetic study in Pakistan, DIVERGE helps address the severe underrepresentation of people from South Asian countries in genetic as well as psychiatric research.

Prior studies have indicated the pathological role of brain-derived neurotrophic factor (BDNF) gene polymorphism in panic disorders (PD). A functionally less active BDNF Val66Met mutant was previously detected in PD patients with different ethnic backgrounds. However, the results remain inconclusive or inconsistent. A meta-analysis was used to explore the consistency of the BDNF Val66Met mutant's association with PD irrespective of the subject's ethnicity. Relevant case-controlled full-length clinical and preclinical reports were retrieved by database searching, and 11 articles involving 2203 cases and 2554 controls were systematically selected per the standard inclusion criteria. Eleven articles were finally included that explored the relationship between the Val66Met polymorphism and PD risk susceptibility. Statistical analysis revealed a significant genetic association of the mutation, allele frequencies, and genotype distributions of BDNF with PD onset. Our findings demonstrated that the BDNF Val66Met is a susceptibility factor of PD.

Objectives: In this study designed to investigate the effect of diet and gut microbiome on neuropsychiatric disorders, we explored the mechanisms of the interaction between diet and gut microbiome on the risk of neuroticism.

Methods: First, using the individual genotype data from the UK Biobank cohort (N = 306 165), we calculated the polygenic risk score (PRS) based on 814 dietary habits single nucleotide polymorphisms (SNPs), 21 diet compositions SNPs and 1001 gut microbiome SNPs, respectively. Gut microbiome and diet-associated SNPs were collected from three genome-wide association studies (GWAS), including the gut microbiome (N = 3890), diet compositions (over 235 000 subjects) and dietary habits (N = 449 210). The neuroticism score was calculated by 12 questions from the Eysenck Personality Inventory Neuroticism scale. Then, regression analysis was performed to evaluate the interaction effects between diet and the gut microbiome on the risk of neuroticism.

Results: Our studies demonstrated multiple candidate interactions between diet and gut microbiome, such as protein vs. Bifidobacterium (β = 4.59 × 10-3; P = 9.45 × 10-3) and fat vs. Clostridia (β = 3.67 × 10-3; P = 3.90 × 10-2). In addition, pieces of fresh fruit per day vs. Ruminococcus (β = -5.79 × 10-3, P = 1.10 × 10-3) and pieces of dried fruit per day vs. Clostridiales (β = -5.63 × 10-3, P = 1.49 × 10-3) were found to be negatively associated with neuroticism in fruit types. We also identified several positive interactions, such as tablespoons of raw vegetables per day vs. Veillonella (β = 5.92 × 10-3, P = 9.21 × 10-4) and cooked vegetables per day vs. Acidaminococcaceae (β = 5.69 × 10-3, P = 1.24 × 10-3).

Conclusions: Our results provide novel clues for understanding the roles of diet and gut microbiome in the development of neuroticism.

Kleefstra syndrome is a rare genetic disorder caused by haploinsufficiency of the euchromatic histone lysine methyltransferase 1 (EHMT1) gene. It is characterized by a variety of dysmorphic features, comorbid medical issues, and developmental delays/intellectual disability. Neuropsychiatric symptoms may also occur, including autistic features and psychosis, and are often accompanied by functional regression. However, the phenomenology of psychotic symptoms in this syndrome has not been well described in the literature. As such, in this brief report, we review the literature with respect to the occurrence of psychosis in Kleefstra syndrome and describe the symptom profile of a 35-year-old affected male with an intellectual disability, autism spectrum disorder, and schizophrenia (in association with manic features). This is the first report of psychotic symptoms fully remitting in response to zuclopenthixol therapy in an individual with Kleefstra syndrome. This case is also unique as it demonstrates that functional regression does not necessarily coincide with the development of schizophrenia-like presentations in affected individuals.

Objective: The alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors significantly regulate the synaptic transmission and functions of various synaptic receptors. This study aimed to identify single nucleotide mutations in the glutamate receptor, ionotropic, AMPA type (GRIA) gene family, which is associated with schizophrenia.

Methods: The exon regions of four genes (GRIA1, GRIA2, GRIA3, and GRIA4) encoding glutamate ionotropic receptor AMPA type proteins were resequenced in 516 patients with schizophrenia. We analyzed the protein function of the identified rare mutants via immunoblotting.

Results: A total of 24 coding variants were detected in the GRIA gene family, including six missense mutations, 17 synonymous mutations, and one frameshift insertion. Notably, three ultra-rare missense mutations (GRIA1p.V182A, GRIA2p.P123Q, and GRIA4p.Y491H) were not documented in the single nucleotide polymorphism database, gnomAD genomes, and 1517 healthy controls available from Taiwan BioBank. Immunoblotting revealed GRIA4p.Y491H mutant with altered protein expressions in cultured cells compared with the wild type.

Conclusion: Our findings suggest that, in some patients affected by schizophrenia, the GRIA gene family harbors rare functional mutations, which support rare coding variants that could contribute to the genetic architecture of this illness. The in-vitro impacts of these rare pathological mutations on the pathophysiology of schizophrenia are worthy of future investigation.

Objective: It was aimed to investigate the role of the forkhead box protein P2 (FOXP2) gene in the cause of specific learning disorder (SLD) with the next-generation sequencing method.

Material and methods: The study included 52 children diagnosed with SLD and 46 children as control between the ages of 6-12 years. Interview Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifelong Version in Turkish, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-Based Screening and Evaluation Scale for Attention Deficit and Disruptive Behavior Disorders, Specific Learning Disability Test Battery were applied to all participants. The FOXP2 gene was screened by the next-generation sequencing (NGS) method in all participants.

Results: A total of 17 variations were detected in the FOXP2 gene in participants. The number and diversity of variations were higher in the patient group. In the patient group, c.1914 + 8A>T heterozygous variation and three different types of heterozygous variation (13insT, 13delT and 4dup) in the c.1770 region were detected. It was found that the detected variations showed significant relationships with the reading phenotypes determined by the test battery.

Conclusion: It was found that FOXP2 variations were seen more frequently in the patient group. Some of the detected variations might be related to the clinical phenotype of SLD and variations found in previous studies from different countries were not seen in Turkish population. Our study is the first to evaluate the role of FOXP2 gene variations in children with SLD in Turkish population, and novel variations in the related gene were detected.

Nonpharmacological antidepressant treatments are effective and well tolerated in selected patients. However, response is heterogeneous and validated biomarkers would be precious to aid treatment choice. We searched Pubmed, Scopus, and Google Scholar until May 2022 for original articles evaluating the association of genetic variables with the efficacy of nonpharmacological treatments for major depressive episodes. Most studies analyzed small sample sizes using the candidate gene approach, leading to poorly replicated findings that need to be interpreted cautiously. The few available methylome-wide and genome-wide association studies (GWASs) considered only electroconvulsive therapy (ECT) and cognitive-behavioral therapy in small samples, providing interesting findings by using polygenic risk scores. A deeper knowledge of the genetic factors implicated in treatment response may lead to a better understanding of the neurobiological mechanisms of nonpharmacological therapies for depression, and depression itself. Future GWAS are going to expand their sample size, thanks to consortia such as the gen-ECT-ic consortium.

Objective: Schizophrenia is a debilitating disease that is associated with higher rates of death by unnatural causes including suicide. Exposure to stressful events is an important risk factor for suicidal ideation (SI); however, the mechanisms that link stress, SI, and suicide remain unclear. Epigenetic processes are involved in both vulnerability to suicidal behavior and stress. Therefore, we sought to study the relationship between epigenetic modifications and suicidal behavior and stress.

Methods: This pilot study was conducted on 39 patients diagnosed with schizophrenia (54% men and age 45.5 ± 12.7). We analyzed the effects of (a) stress exposure and (b) the mediation of DNA methylation [via an epigenetic wide association study (EWAS) of more than 450 000 CpG sites across the genome] on SI severity.

Results: The top CpG site mediating the effect of global stress exposure on SI was cg27660192 located in an intergenic region on chromosome 11, exerting a facilitating effect on worsening SI through DNA hypomethylation.

Conclusion: These preliminary results indicate that DNA methylation in peripheral tissues can shed light on the complex relationship between stress and SI in schizophrenia.

Psychiatric diseases exact a heavy socioeconomic toll, and it is particularly difficult to identify their risk factors and causative mechanisms due to their multifactorial nature, the limited physiopathological insight, the many confounding factors, and the potential reverse causality between the risk factors and psychiatric diseases. These characteristics make Mendelian randomization (MR) a precious tool for studying these disorders. MR is an analytical method that employs genetic variants linked to a certain risk factor, to assess if an observational association between that risk factor and a health outcome is compatible with a causal relationship. We report the first systematic review of all existing applications and findings of MR in psychiatric disorders, aiming at facilitating the identification of risk factors that may be common to different psychiatric diseases, and paving the way to transdiagnostic MR studies in psychiatry, which are currently lacking. We searched Web of Knowledge, Scopus, and Pubmed databases (until 3 May 2022) for articles on MR in psychiatry. The protocol was preregistered in PROSPERO (CRD42021285647). We included methodological details and results from 50 articles, mainly on schizophrenia, major depression, autism spectrum disorders, and bipolar disorder. While this review shows how MR can offer unique opportunities for unraveling causal links in risk factors and etiological elements of specific psychiatric diseases and transdiagnostically, some methodological flaws in the existing literature limit reliability of results and probably underlie their heterogeneity. We highlight perspectives and recommendations for future works on MR in psychiatry.

Objective: Previous observational studies have shown that the levels of tumor necrosis factor (TNF) increased in patients with schizophrenia. The present two-sample Mendelian randomization (MR) study aims to identify the causal link between TNF and schizophrenia.

Methods: To date, the largest genome-wide association study (GWAS) for TNF (n = 23 141) and for schizophrenia (53 386 cases and 77 258 controls) was used. All participants were of European ancestry. The MR-egger_intercept test and Cochran's Q statistic were used to determine the pleiotropy and heterogeneity, respectively. Weighted median and inverse variance weighted (IVW) were used to evaluate the causal association of TNF with schizophrenia.

Results: We found no significant pleiotropy or heterogeneity of all three selected plasma TNF genetic instrumental variants in breast cancer GWAS. Interestingly, the odds ratio (OR) = 1.517 with 95% confidence interval (CI), 1.006-2.288 and P = 0.047 of schizophrenia correspond to one unit increase in natural log-transformed TNF levels using IVW method. The increased trend was further proven using weighted median (OR = 1.585; 95% CI, 1.017-2.469; P = 0.042). Reverse MR analysis shows no causal effect of schizophrenia on plasma TNF levels.

Conclusions: Our analysis suggested a causal association between genetically increased TNF signaling and increased risk of schizophrenia in the European population. Thus, TNF may be a potential risk for schizophrenia.