Genetic correlation and causal associations between psychiatric disorders and lung cancer risk.

BACKGROUND: Patients with certain psychiatric disorders have increased lung cancer incidence. However, establishing a causal relationship through traditional epidemiological methods poses challenges. METHODS: Available summary statistics of genome-wide association studies of cigarette smoking, lung cancer, and eight psychiatric disorders, including attention deficit/hyperactivity disorder (ADHD), autism, depression, major depressive disorder, bipolar disorder, insomnia, neuroticism, and schizophrenia (range N: 46,350-1,331,010) were leveraged to estimate genetic correlations using Linkage Disequilibrium Score Regression and assess causal effect of each psychiatric disorder on lung cancer using two-sample Mendelian randomization (MR) models, comprising inverse-variance weighted (IVW), weighted median, MR-Egger, pleiotropy residual sum and outlier testing (MR-PRESSO), and a constrained maximum likelihood approach (cML-MR). RESULTS: Significant positive correlations were observed between each psychiatric disorder and both smoking and lung cancer (all FDR < 0.05), except for the correlation between autism and lung cancer. Both univariable and the cML-MA MR analyses demonstrated that liability to schizophrenia, depression, ADHD, or insomnia was associated with an increased risk of overall lung cancer. Genetic liability to insomnia was linked specifically to squamous cell carcinoma (SCC), while genetic liability to ADHD was associated with an elevated risk of both SCC and small cell lung cancer (all P < 0.05). The later was further supported by multivariable MR analyses, which accounted for smoking. LIMITATIONS: Participants were constrained to European ancestry populations. Causal estimates from binary psychiatric disorders may be biased. CONCLUSION: Our findings suggest appropriate management of several psychiatric disorders, particularly ADHD, may potentially reduce the risk of developing lung cancer.

Genetic evidence strengthens the bidirectional connection between oral health status and psychiatric disorders: A two-sample Mendelian randomization study.

BACKGROUND: Observational studies cannot accurately infer the causal associations between oral health status and psychiatric disorders. METHODS: We conducted univariate and multivariate Mendelian randomization (MR) analyses using single nucleotide polymorphisms (SNPs) associated with eight oral health statuses (periodontitis, DMFS, Nteeth, toothache, loose teeth, painful gums, bleeding gums, and mouth ulcers) and four psychiatric disorders (Schizophrenia, Major Depressive Disorder (MDD), anxiety and stress-related disorder (ASRD), and Bipolar Disorder (BIP)) as instrumental variables. Genetic data were sourced from the Gene-lifestyle interactions in dental endpoints (GLIDE), UK Biobank, Psychiatric Genomics Consortium (PGC), and Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH). The inverse variance-weighted (IVW) approach, supported by a comprehensive sensitivity analysis, was employed. RESULTS: Genetically predicted mouth ulcers were significantly linked to higher MDD (OR = 2.17, 95 % CI: 1.33--3.54, P< 0.01) and BIP risks (OR = 2.25, 95 % CI: 1.22-4.15, P = 0.01). BIP heightened bleeding gums risk (OR = 1.01, 95 % CI: 1.00-1.01, P < 0.01). These associations were adjusted for smoking status and alcohol consumption. Painful gums were significantly associated with MDD risk (OR = 96.48, 95 % CI: 2.66-3495.28, P = 0.01), while MDD raised periodontitis risk (OR = 2.15, 95 % CI: 1.24-3.75, P = 0.01), both confounded by smoking and alcohol. Relatively small effects between several variables, while others could not withstand correction for multiple tests. LIMITATIONS: The sample size and limitation to European populations limits the study generalizability. CONCLUSIONS: This study provide evidence of possible causal relationships between several oral health conditions and mental illness. Focusing on oral health and valuing mental health are important for each other and overall health.

Association of Chronic Obstructive Pulmonary Disease with Risk of Psychiatric Disorders: A Two-Sample Mendelian Randomization Study.

Background: Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disorder often accompanied by comorbidities. Although the past few years have witnessed significant scientific progress, the potential relationship between COPD and mental illness remains a subject of debate. Materials and Methods: We retrieved COPD data from the genome-wide association studies (GWAS) directory and data on mental illnesses, including Alzheimer's disease, schizophrenia, panic disorder, attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, multiple disabilities, obsessive-compulsive disorder, post-traumatic stress disorder, and schizophrenia, from the Psychiatric Genomics Consortium. A two-sample Mendelian randomization (MR) approach was applied to explore the association between COPD and mental illnesses, with subgroup analyses based on smoking history. Results: Our two-sample MR analysis revealed no causal link between overall COPD and the development of common psychiatric disorders. Subgroup analyses based on smoking history showed no causal association between never-smokers with COPD and the occurrence of psychiatric disorders. However, ever-smokers with COPD were associated with a significantly increased risk of ADHD (OR: 2.303, 95% CI: 1.558-3.403, P = 0.001) and a modestly reduced risk of Alzheimer's disease (OR: 0.994, 95% CI: 0.988-0.999, P = 0.034). Conclusion: COPD patients with a history of smoking face a higher risk of developing ADHD but may experience a slight reduction in the risk of Alzheimer's disease. Conversely, there was no observed causal association between COPD and psychiatric disorders among patients who never smoked.

Epigenetics of Ageing and Psychiatric Disorders.

Both classic epigenetic modifications and microRNAs can impact a range of bodily processes, from metabolism to brain function, and may contribute to the development of diseases such as cancer, cardiovascular disorders, and psychiatric disorders. Numerous studies suggest a connection between epigenetic changes and mood disorders. In this study, we performed a comprehensive search using PubMed and Google for the terms "epigenetics", "ageing", "miRNA", "schizophrenia", and "mood disorders" in the titles and abstracts of articles. Epigenetic changes during early life may play a crucial role in triggering severe mental disorders and shaping their clinical trajectory. Although these alterations can take place at any age, their impact may not be immediately evident or observable until later in life. Epigenetic modifications play a crucial role in the ageing process and challenge the prevailing belief that mutations are the primary driver of ageing. However, it is plausible that these epigenetic changes are a consequence of the disorder rather than its root cause. Moreover, both the disorder and the epigenetic alterations may be influenced by shared environmental or genetic factors. In the near future, we might be able to replace chronological age with biological age, based on the epigenetic clock, with the promise of providing greater therapeutic benefits. A wide range of epigenetic drugs are currently under development at various stages. Although their full effectiveness is yet to be realized, they show great potential in the treatment of cancer, psychiatric disorders, and other complex diseases.

Genetic correlations between suicide attempts and psychiatric and intermediate phenotypes adjusting for mental disorders.

BACKGROUND: Suicide attempts are a moderately heritable trait, and genetic correlations with psychiatric and related intermediate phenotypes have been reported. However, as several mental disorders as well as major depressive disorder (MDD) are strongly associated with suicide attempts, these genetic correlations could be mediated by psychiatric disorders. Here, we investigated genetic correlations of suicide attempts with psychiatric and related intermediate phenotypes, with and without adjusting for mental disorders. METHODS: To investigate the genetic correlations, we utilized large-scale genome-wide association study summary statistics for suicide attempts (with and without adjusting for mental disorders), nine psychiatric disorders, and 15 intermediate phenotypes. RESULTS: Without adjusting for mental disorders, suicide attempts had significant positive genetic correlations with risks of attention-deficit/hyperactivity disorder, schizophrenia, bipolar disorder, MDD, anxiety disorders and posttraumatic stress disorder; higher risk tolerance; earlier age at first sexual intercourse, at first birth and at menopause; higher parity; lower childhood IQ, educational attainment and cognitive ability; and lower smoking cessation. After adjusting for mental disorders, suicide attempts had significant positive genetic correlations with the risk of MDD; earlier age at first sexual intercourse, at first birth and at menopause; and lower educational attainment. After adjusting for mental disorders, most of the genetic correlations with psychiatric disorders were decreased, while several genetic correlations with intermediate phenotypes were increased. CONCLUSIONS: These findings highlight the importance of considering mental disorders in the analysis of genetic correlations related to suicide attempts and suggest that susceptibility to MDD, reproductive behaviors, and lower educational levels share a genetic basis with suicide attempts after adjusting for mental disorders.

Metabolome subtyping reveals multi-omics characteristics and biological heterogeneity in major psychiatric disorders.

Growing evidence suggests that major psychiatric disorders (MPDs) share common etiologies and pathological processes. However, the diagnosis is currently based on descriptive symptoms, which ignores the underlying pathogenesis and hinders the development of clinical treatments. This highlights the urgency of characterizing molecular biomarkers and establishing objective diagnoses of MPDs. Here, we collected untargeted metabolomics, proteomics and DNA methylation data of 327 patients with MPDs, 131 individuals with genetic high risk and 146 healthy controls to explore the multi-omics characteristics of MPDs. First, differential metabolites (DMs) were identified and we classified MPD patients into 3 subtypes based on DMs. The subtypes showed distinct metabolomics, proteomics and DNA methylation signatures. Specifically, one subtype showed dysregulation of complement and coagulation proteins, while the DNA methylation showed abnormalities in chemical synapses and autophagy. Integrative analysis in metabolic pathways identified the important roles of the citrate cycle, sphingolipid metabolism and amino acid metabolism. Finally, we constructed prediction models based on the metabolites and proteomics that successfully captured the risks of MPD patients. Our study established molecular subtypes of MPDs and elucidated their biological heterogeneity through a multi-omics investigation. These results facilitate the understanding of pathological mechanisms and promote the diagnosis and prevention of MPDs.

Genomic data resources of the Brain Somatic Mosaicism Network for neuropsychiatric diseases.

Somatic mosaicism is defined as an occurrence of two or more populations of cells having genomic sequences differing at given loci in an individual who is derived from a single zygote. It is a characteristic of multicellular organisms that plays a crucial role in normal development and disease. To study the nature and extent of somatic mosaicism in autism spectrum disorder, bipolar disorder, focal cortical dysplasia, schizophrenia, and Tourette syndrome, a multi-institutional consortium called the Brain Somatic Mosaicism Network (BSMN) was formed through the National Institute of Mental Health (NIMH). In addition to genomic data of affected and neurotypical brains, the BSMN also developed and validated a best practices somatic single nucleotide variant calling workflow through the analysis of reference brain tissue. These resources, which include >400 terabytes of data from 1087 subjects, are now available to the research community via the NIMH Data Archive (NDA) and are described here.

Causal atlas between inflammatory bowel disease and mental disorders: a bi-directional 2-sample Mendelian randomization study.

Background: The brain-gut axis link has attracted increasing attention, with observational studies suggesting that the relationship between common mental disorders and inflammatory bowel disease (IBD) may run in both directions. However, so far, it is not clear whether there is causality and in which direction. Methods: We conducted a bidirectional 2-sample Mendelian randomization study to investigate the relationship between IBD, including Crohn's disease (CD) and ulcerative colitis (UC), and mental disorders, using summary-level GWAS data. The main analysis was the inverse variance weighted method. IBD (including CD and UC), and nine mental disorders were used as both exposures and outcomes. Results: We found that UC could significantly lead to obsessive-compulsive disorder, attention deficit hyperactivity disorder, and autism spectrum disorder, with odds ratio (OR) of 1.245 (95% confidence intervals [CI]: 1.069-1.450; P=0.008), 1.050 (95%CI: 1.023-1.077; P=2.42×10-4), and 1.041 (95%CI: 1.015-1.068; P=0.002) respectively. In addition, we found that bipolar disorder and schizophrenia could increase the odds of IBD, with OR values of 1.138 (95%CI: 1.084-1.194; P=1.9×10-7), and 1.115 (95%CI: 1.071-1.161; P=1.12×10-7), respectively. Our results also indicate that obsessive-compulsive disorder could lead to IBD, especially for UC, with OR values of 1.091 (95%CI: 1.024-1.162; P=0.009), and 1.124 (95%CI: 1.041-1.214; P=0.004), respectively. Conclusions: Our findings indicate that the brain-gut axis involves the association between IBD, especially UC, and some mental disorders, which guides the targeted prevention, management, and mechanism exploration of these diseases.

Interindividual variation in human cortical cell type abundance and expression.

Single-cell transcriptomic studies have identified a conserved set of neocortical cell types from small postmortem cohorts. We extended these efforts by assessing cell type variation across 75 adult individuals undergoing epilepsy and tumor surgeries. Nearly all nuclei map to one of 125 robust cell types identified in the middle temporal gyrus. However, we found interindividual variance in abundances and gene expression signatures, particularly in deep-layer glutamatergic neurons and microglia. A minority of donor variance is explainable by age, sex, ancestry, disease state, and cell state. Genomic variation was associated with expression of 150 to 250 genes for most cell types. This characterization of cellular variation provides a baseline for cell typing in health and disease.

Molecular programs of regional specification and neural stem cell fate progression in macaque telencephalon.

During early telencephalic development, intricate processes of regional patterning and neural stem cell (NSC) fate specification take place. However, our understanding of these processes in primates, including both conserved and species-specific features, remains limited. Here, we profiled 761,529 single-cell transcriptomes from multiple regions of the prenatal macaque telencephalon. We deciphered the molecular programs of the early organizing centers and their cross-talk with NSCs, revealing primate-biased galanin-like peptide (GALP) signaling in the anteroventral telencephalon. Regional transcriptomic variations were observed along the frontotemporal axis during early stages of neocortical NSC progression and in neurons and astrocytes. Additionally, we found that genes associated with neuropsychiatric disorders and brain cancer risk might play critical roles in the early telencephalic organizers and during NSC progression.

Severe mental illness and the risk of breast cancer: A two-sample, two-step multivariable Mendelian randomization study.

BACKGROUND: Based on epidemiological reports, severe mental illness (SMI) and breast cancer (BC) risk are linked positively. However, it is susceptible to clinical confounding factors, such as smoking, alcohol consumption, etc. Here, we performed a two-sample, two-step multivariable Mendelian randomization (MR) research to explore how the SMI etiologically influences BC risk and to quantify mediating effects of known modifiable risk factors. METHODS: Data concerning the single nucleotide polymorphism (SNP)-associated with schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), and BC were obtained from two large consortia: the Breast Cancer Association Consortium (BCAC) and the Psychiatric Genomics Consortium (PGC). Then, the correlations of the previous SMI with the BC prevalence and the potential impact of mediators were explored through the two-sample and two-step MR analyses. RESULTS: In two-sample MR, schizophrenia increased BC incidence (odds ratio (OR) 1.06, 95% confidence interval (CI) 1.02-1.10, P = 0.001). In subgroup analysis, schizophrenia increased ER+ BC (OR 1.06, 95% CI 1.03-1.10, P = 0.0009) and ER-BC (OR 1.06, 95% CI 1.01-1.11, P = 0.0123) incidences. Neither MDD nor BD elevated the BC risk. In two-step MR, smoking explained 11.29% of the schizophrenia-all BC risk association. CONCLUSIONS: Our study indicates that schizophrenia increases susceptibility to breast cancer, with smoking playing a certain mediating role. Therefore, BC screening and smoking should be incorporated into the health management of individuals with schizophrenia.

Phosphodiesterase and psychiatric disorders: a two-sample Mendelian randomization study.

BACKGROUND: Phosphodiesterases (PDEs) have been associated with psychiatric disorders in observational studies; however, the causality of associations remains unestablished. METHODS: Specifically, cyclic nucleotide PDEs were collected from genome-wide association studies (GWASs), including PDEs obtained by hydrolyzing both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) (PDE1A, PDE2A, and PDE3A), specific to cGMP (PDE5A, PDE6D, and PDE9A) and cAMP (PDE4D and PDE7A). We performed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the relationship between PDEs and nine psychiatric disorders. The inverse-variance-weighted (IVW) method, MR-Egger, and weighted median were used to estimate causal effects. The Cochran's Q test, MR-Egger intercept test, MR Steiger test, leave-one-out analyses, funnel plot, and MR pleiotropy residual sum and outlier (MR-PRESSO) were used for sensitivity analyses. RESULTS: The PDEs specific to cAMP were associated with higher-odds psychiatric disorders. For example, PDE4D and schizophrenia (SCZ) (odds ratios (OR) = 1.0531, PIVW = 0.0414), as well as major depressive disorder (MDD) (OR = 1.0329, PIVW = 0.0011). Similarly, PDE7A was associated with higher odds of attention-deficit/hyperactivity disorder (ADHD) (OR = 1.0861, PIVW = 0.0038). Exploring specific PDE subtypes and increase intracellular cAMP levels can inform the development of targeted interventions. We also observed PDEs (which hydrolyzes both cAMP and cGMP) was associated with psychiatric disorders [OR of PDE1A was 1.0836 for autism spectrum disorder; OR of PDE2A was 0.8968 for Tourette syndrome (TS) and 0.9449 for SCZ; and OR of PDE3A was 0.9796 for MDD; P < 0.05]. Furthermore, psychiatric disorders also had some causal effects on PDEs [obsessive-compulsive disorder on increased PDE6D and decreased PDE2A and PDE4D; anorexia nervosa on decreased PDE9A]. The results of MR were found to be robust using multiple sensitivity analysis. CONCLUSIONS: In this study, potential causal relationships between plasma PDE proteins and psychiatric disorders were established. Exploring other PDE subtypes not included in this study could provide a more comprehensive understanding of the role of PDEs in psychiatric disorders. The development of specific medications targeting PDE subtypes may be a promising therapeutic approach for treating psychiatric disorders.

Transcriptome-Wide Structural Equation Modeling of 13 Major Psychiatric Disorders for Cross-Disorder Risk and Drug Repurposing.

Importance: Psychiatric disorders display high levels of comorbidity and genetic overlap, necessitating multivariate approaches for parsing convergent and divergent psychiatric risk pathways. Identifying gene expression patterns underlying cross-disorder risk also stands to propel drug discovery and repurposing in the face of rising levels of polypharmacy. Objective: To identify gene expression patterns underlying genetic convergence and divergence across psychiatric disorders along with existing pharmacological interventions that target these genes. Design, Setting, and Participants: This genomic study applied a multivariate transcriptomic method, transcriptome-wide structural equation modeling (T-SEM), to investigate gene expression patterns associated with 5 genomic factors indexing shared risk across 13 major psychiatric disorders. Follow-up tests, including overlap with gene sets for other outcomes and phenome-wide association studies, were conducted to better characterize T-SEM results. The Broad Institute Connectivity Map Drug Repurposing Database and Drug-Gene Interaction Database public databases of drug-gene pairs were used to identify drugs that could be repurposed to target genes found to be associated with cross-disorder risk. Data were collected from database inception up to February 20, 2023. Main Outcomes and Measures: Gene expression patterns associated with genomic factors or disorder-specific risk and existing drugs that target these genes. Results: In total, T-SEM identified 466 genes whose expression was significantly associated (z ≥ 5.02) with genomic factors and 36 genes with disorder-specific effects. Most associated genes were found for a thought disorders factor, defined by bipolar disorder and schizophrenia. Several existing pharmacological interventions were identified that could be repurposed to target genes whose expression was associated with the thought disorders factor or a transdiagnostic p factor defined by all 13 disorders. Conclusions and Relevance: The findings from this study shed light on patterns of gene expression associated with genetic overlap and uniqueness across psychiatric disorders. Future versions of the multivariate drug repurposing framework outlined here have the potential to identify novel pharmacological interventions for increasingly common, comorbid psychiatric presentations.

The shared genetic architecture of smoking behaviours and psychiatric disorders: evidence from a population-based longitudinal study in England.

BACKGROUND: Considering the co-morbidity of major psychiatric disorders and intelligence with smoking, to increase our understanding of why some people take up smoking or continue to smoke, while others stop smoking without progressing to nicotine dependence, we investigated the genetic propensities to psychiatric disorders and intelligence as determinants of smoking initiation, heaviness of smoking and smoking cessation in older adults from the general population. RESULTS: Having utilised data from the English Longitudinal Study of Ageing (ELSA), our results showed that one standard deviation increase in MDD-PGS was associated with increased odds of being a moderate-heavy smoker (odds ratio [OR] = 1.11, SE = 0.04, 95%CI = 1.00-1.24, p = 0.028). There were no other significant associations between SZ-PGS, BD-PGS, or IQ-PGS and smoking initiation, heaviness of smoking and smoking cessation in older adults from the general population in the UK. CONCLUSIONS: Smoking is a behaviour that does not appear to share common genetic ground with schizophrenia, bipolar disorders, and intelligence in older adults, which may suggest that it is more likely to be modifiable by smoking cessation interventions. Once started to smoke, older adults with a higher polygenic predisposition to major depressive disorders are more likely to be moderate to heavy smokers, implying that these adults may require targeted smoking cessation services.

Evidence for a causal association between psoriasis and psychiatric disorders using a bidirectional Mendelian randomization analysis in up to 902,341 individuals.

BACKGROUND: The causal association between psoriasis and psychiatric disorders remains ambiguous. OBJECTIVES: This study aimed to investigate the causal relationship between psoriasis and common psychiatric disorders using bidirectional Mendelian randomization (MR) analysis. METHODS: Major depressive disorder (MDD) (N = 217,584), bipolar disorder (N = 51,710), schizophrenia (N = 77,096), and anxiety disorder (N = 218,792) were obtained as outcomes, and psoriasis (N = 337,159) were as exposure. Inverse variance weighting (IVW) was used as the main method, with other sensitivity methods as auxiliary methods. Sensitivity analysis and heterogeneity tests were performed to ensure the robustness of the results. We also performed a subgroup analysis of cases with psoriatic arthritis (PsA) (N = 213,879) by using the same testing methods. RESULTS: MR showed that the genetic risk of psoriasis was positively associated with bipolar disorder (odds ratio (OR) = 13.54, 95 % confidence interval (95%CI): 2.43-75.37, P = 0.002) and MDD (OR = 1.08, 95%CI: 1.01-1.15, P = 0.027), which indicated possible causal relationships between psoriasis and these two diseases. Schizophrenia (OR = 3.52, 95%CI: 0.22-55.71, P = 0.372) and anxiety disorders (OR = 0.65, 95%CI: 0.16-2.63, P = 0.546) indicated no significant causal association. No reverse causal effects of psychiatric disorders on psoriasis were found. Subgroup analysis also suggested causal association of PsA with the bipolar affective disorder (OR = 1.05, 95%CI: 1.01-1.08, P = 0.005). LIMITATIONS: Potential pleiotropic effects, restriction to European populations, and differences in diagnostic criteria. CONCLUSIONS: This study has supported the causal association of psoriasis with MDD and bipolar disorder, and the subtype PsA with bipolar disorder, which informed the intervention for mental illnesses in patients with psoriasis.

[Genome-wide studies of comorbidity of somatic and mental diseases]. / Polnogenomnye issledovaniya komorbidnosti somaticheskikh i psikhicheskikh zabolevanii.

Studies of the genomic architecture of complex phenotypes, which include common somatic and mental diseases, have shown that they are characterized by a high degree of polygenicity, i.e. participation of a large number of genes associated with the risk of developing these diseases. In this regard, it is of interest to establish the genetic overlapping between these two groups of diseases. The aim of the review is to analyze genetic studies of the comorbidity of somatic and mental diseases in terms of the universality and specificity of mental disorders in somatic diseases, the reciprocal relationships of these types of pathologies, and the modulating influence of environmental factors on comorbidity. The results of the analysis indicate the existence of a common genetic predisposition to mental and somatic diseases. At the same time, the presence of common genes does not exclude the specificity of the development of mental disorders depending on a specific somatic pathology. It can be assumed that there are genes that are both unique to a particular somatic and comorbid mental illness, and genes that are common to these diseases. Common genes may have varying degrees of specificity, that is, they may be of a universal nature, which, for example, manifests itself in the development of MDD in various somatic diseases, or be specific only for a couple of individual diseases (schizophrenia - breast cancer). At the same time, common genes can have a multidirectional effect, which also contributes to the specificity of comorbidity. In addition, when searching for common genes for somatic and mental diseases, it is necessary to take into account the modulating influence of such confounders as treatment, unhealthy life style, behavioral characteristics, which can also differ in specificity depending on the diseases under consideration.

Nicotinic acetylcholine receptors in neurological and psychiatric diseases.

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that are widely distributed both pre- and post-synaptically in the mammalian brain. By modulating cation flux across cell membranes, neuronal nAChRs regulate neuronal excitability and the release of a variety of neurotransmitters to influence multiple physiologic and behavioral processes including synaptic plasticity, motor function, attention, learning and memory. Abnormalities of neuronal nAChRs have been implicated in the pathophysiology of neurologic disorders including Alzheimer's disease, Parkinson's disease, epilepsy, and Tourette´s syndrome, as well as psychiatric disorders including schizophrenia, depression, and anxiety. The potential role of nAChRs in a particular illness may be indicated by alterations in the expression of nAChRs in relevant brain regions, genetic variability in the genes encoding for nAChR subunit proteins, and/or clinical or preclinical observations where specific ligands showed a therapeutic effect. Over the past 25 years, extensive preclinical and some early clinical evidence suggested that ligands at nAChRs might have therapeutic potential for neurologic and psychiatric disorders. However, to date the only approved indications for nAChR ligands are smoking cessation and the treatment of dry eye disease. It has been argued that progress in nAChR drug discovery has been limited by translational gaps between the preclinical models and the human disease as well as unresolved questions regarding the pharmacological goal (i.e., agonism, antagonism or receptor desensitization) depending on the disease.

Microdeletions and microduplications linked to severe congenital disorders in infertile men.

Data on the clinical validity of DNA copy number variants (CNVs) in spermatogenic failure (SPGF) is limited. This study analyzed the genome-wide CNV profile in 215 men with idiopathic SPGF and 62 normozoospermic fertile men, recruited at the Andrology Clinic, Tartu University Hospital, Estonia. A two-fold higher representation of > 1 Mb CNVs was observed in men with SPGF (13%, n = 28) compared to controls (6.5%, n = 4). Seven patients with SPGF were identified as carriers of microdeletions (1q21.1; 2.4 Mb) or microduplications (3p26.3, 1.1 Mb; 7p22.3-p22.2, 1.56 Mb; 10q11.22, 1.42 Mb, three cases; Xp22.33; 2.3 Mb) linked to severe congenital conditions. Large autosomal CNV carriers had oligozoospermia, reduced or low-normal bitesticular volume (22-28 ml). The 7p22.3-p22.2 microduplication carrier presented mild intellectual disability, neuropsychiatric problems, and short stature. The Xp22.33 duplication at the PAR1/non-PAR boundary, previously linked to uterine agenesis, was detected in a patient with non-obstructive azoospermia. A novel recurrent intragenic deletion in testis-specific LRRC69 was significantly overrepresented in patients with SPGF compared to the general population (3.3% vs. 0.85%; χ2 test, OR = 3.9 [95% CI 1.8-8.4], P = 0.0001). Assessment of clinically valid CNVs in patients with SPGF will improve their management and counselling for general and reproductive health, including risk of miscarriage and congenital disorders in future offspring.

Precision Medicine Approaches to Mental Health Care.

Developing a more comprehensive understanding of the physiological underpinnings of mental illness, precision medicine has the potential to revolutionize psychiatric care. With recent breakthroughs in next-generation multi-omics technologies and data analytics, it is becoming more feasible to leverage multimodal biomarkers, from genetic variants to neuroimaging biomarkers, to objectify diagnostics and treatment decisions in psychiatry and improve patient outcomes. Ongoing work in precision psychiatry will parallel progress in precision oncology and cardiology to develop an expanded suite of blood- and neuroimaging-based diagnostic tests, empower monitoring of treatment efficacy over time, and reduce patient exposure to ineffective treatments. The emerging model of precision psychiatry has the potential to mitigate some of psychiatry's most pressing issues, including improving disease classification, lengthy treatment duration, and suboptimal treatment outcomes. This narrative-style review summarizes some of the emerging breakthroughs and recurring challenges in the application of precision medicine approaches to mental health care.

Emerging Roles of FTO in Neuropsychiatric Disorders.

FTO (fat mass and obesity associated) is a recently discovered gene related to obesity and expressed in various tissues of the human body, especially with high expression in the brain. Earlier studies have found that FTO is involved in several biological processes, including brain development and function. In particular, recent studies have found that FTO is a demethylase of N6-methyladenosine (m6A) and it can affect neurological function through the m6A modification of mRNA. At present, a number of studies have shown that FTO is associated with many neuropsychiatric disorders. This paper reviews the discovery, structure, function, and tissue expression of FTO followed by discussing the relationship between FTO and neuropsychiatric diseases. In addition, the potential roles of FTO gene in drug addiction, major depression (MDD), and schizophrenia (SCZ) through regulating m6A modification of dopamine related genes were also highlighted.