Association between reduced plasma BDNF concentration and MMSE scores in both chronic schizophrenia and mild cognitive impairment.

Reduced brain derived neurotrophic factor (BDNF) concentration is reported to be associated with a cognitive decline in schizophrenia, depending on the stage of the disease. Aim of the study was to examine the possible association between plasma BDNF and cognitive decline in chronic stable schizophrenia and mild cognitive impairment (MCI). The study included 123 inpatients of both sexes with schizophrenia, 123 patients with MCI and 208 healthy control subjects. Cognitive abilities were assessed using mini mental state examination (MMSE), Clock Drawing test (CDT) and cognitive subscale of the Positive and Negative Syndrome Scale (PANSS). Plasma BDNF concentration was determined using ELISA. BDNF concentration was lower in patients with schizophrenia and MCI compared to age-matched healthy controls and was similar in carriers of different BDNF Val/66Met genotypes. The MMSE and CDT scores were lower in patients with schizophrenia compared to healthy controls and subjects with MCI. Reduced plasma BDNF was significantly associated with lower MMSE scores in all subjects. BDNF concentration in patients with schizophrenia was not affected by clinical and demographic factors. BDNF Val66Met polymorphism was not associated with the MMSE scores in all participants. Further studies should include longitudinal follow-up and other cognitive scales to confirm these results and offer cognition-improving strategies to prevent cognitive decline in chronic schizophrenia.

Whole-exome sequencing of individuals from an isolated population under extreme conditions implicates rare risk variants of schizophrenia.

Schizophrenia (SCZ), which affects approximately 1% of the world's population, is a global public health concern. It is generally considered that the interplay between genes and the environment is important in the onset and/or development of SCZ. Although several whole-exome sequencing studies have revealed rare risk variants of SCZ, no rare coding variants have been strongly replicated. Assessing isolated populations under extreme conditions might lead to the discovery of variants with a recent origin, which are more likely to have a higher frequency than chance to reflect gene-environment interactions. Following this approach, we examined a unique cohort of Tibetans living at an average altitude above 4500 meters. Whole-exome sequencing of 47 SCZ cases and 53 controls revealed 275 potential novel risk variants and two known variants (12:46244485: A/G and 22:18905934: A/G) associated with SCZ that were found in existing databases. Only one gene (C5orf42) in the gene-based statistics surpassed the exome-wide significance in the cohort. Metascape enrichment analysis suggested that novel risk genes were strongly enriched in pathways relevant to hypoxia, neurodevelopment, and neurotransmission. Additionally, 47 new risk genes were followed up in Han sample of 279 patients with SCZ and 95 controls, only BAI2 variant appearing in one case. Our findings suggest that SCZ patients living at high altitudes may have a unique risk gene signature, which may provide additional information on the underlying biology of SCZ, which can be exploited to identify individuals at greater risk of exposure to hypoxia.

The contribution of silencer variants to human diseases.

BACKGROUND: Although disease-causal genetic variants have been found within silencer sequences, we still lack a comprehensive analysis of the association of silencers with diseases. Here, we profiled GWAS variants in 2.8 million candidate silencers across 97 human samples derived from a diverse panel of tissues and developmental time points, using deep learning models. RESULTS: We show that candidate silencers exhibit strong enrichment in disease-associated variants, and several diseases display a much stronger association with silencer variants than enhancer variants. Close to 52% of candidate silencers cluster, forming silencer-rich loci, and, in the loci of Parkinson's-disease-hallmark genes TRIM31 and MAL, the associated SNPs densely populate clustered candidate silencers rather than enhancers displaying an overall twofold enrichment in silencers versus enhancers. The disruption of apoptosis in neuronal cells is associated with both schizophrenia and bipolar disorder and can largely be attributed to variants within candidate silencers. Our model permits a mechanistic explanation of causative SNP effects by identifying altered binding of tissue-specific repressors and activators, validated with a 70% of directional concordance using SNP-SELEX. Narrowing the focus of the analysis to individual silencer variants, experimental data confirms the role of the rs62055708 SNP in Parkinson's disease, rs2535629 in schizophrenia, and rs6207121 in type 1 diabetes. CONCLUSIONS: In summary, our results indicate that advances in deep learning models for the discovery of disease-causal variants within candidate silencers effectively "double" the number of functionally characterized GWAS variants. This provides a basis for explaining mechanisms of action and designing novel diagnostics and therapeutics.

Distinct genetic liability profiles define clinically relevant patient strata across common diseases.

Stratified medicine holds great promise to tailor treatment to the needs of individual patients. While genetics holds great potential to aid patient stratification, it remains a major challenge to operationalize complex genetic risk factor profiles to deconstruct clinical heterogeneity. Contemporary approaches to this problem rely on polygenic risk scores (PRS), which provide only limited clinical utility and lack a clear biological foundation. To overcome these limitations, we develop the CASTom-iGEx approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue specific gene expression levels. The paradigmatic application of this approach to coronary artery disease or schizophrenia patient cohorts identified diverse strata or biotypes. These biotypes are characterized by distinct endophenotype profiles as well as clinical parameters and are fundamentally distinct from PRS based groupings. In stark contrast to the latter, the CASTom-iGEx strategy discovers biologically meaningful and clinically actionable patient subgroups, where complex genetic liabilities are not randomly distributed across individuals but rather converge onto distinct disease relevant biological processes. These results support the notion of different patient biotypes characterized by partially distinct pathomechanisms. Thus, the universally applicable approach presented here has the potential to constitute an important component of future personalized medicine paradigms.

Genomic insights into the shared and distinct genetic architecture of cognitive function and schizophrenia.

Cognitive impairment is a major determinant of functional outcomes in schizophrenia, however, understanding of the biological mechanisms underpinning cognitive dysfunction in the disorder remains incomplete. Here, we apply Genomic Structural Equation Modelling to identify latent cognitive factors capturing genetic liabilities to 12 cognitive traits measured in the UK Biobank. We identified three broad factors that underly the genetic correlations between the cognitive tests. We explore the overlap between latent cognitive factors, schizophrenia, and schizophrenia symptom dimensions using a complementary set of statistical approaches, applied to data from the latest schizophrenia genome-wide association study (Ncase = 53,386, Ncontrol = 77,258) and the Thematically Organised Psychosis study (Ncase = 306, Ncontrol = 1060). Global genetic correlations showed a significant moderate negative genetic correlation between each cognitive factor and schizophrenia. Local genetic correlations implicated unique genomic regions underlying the overlap between schizophrenia and each cognitive factor. We found substantial polygenic overlap between each cognitive factor and schizophrenia and biological annotation of the shared loci implicated gene-sets related to neurodevelopment and neuronal function. Lastly, we show that the common genetic determinants of the latent cognitive factors are not predictive of schizophrenia symptoms in the Norwegian Thematically Organized Psychosis cohort. Overall, these findings inform our understanding of cognitive function in schizophrenia by demonstrating important differences in the shared genetic architecture of schizophrenia and cognitive abilities.

Study of the genetic association between selected 3q29 region genes and schizophrenia and autism spectrum disorder in the Japanese population.

Psychiatric disorders are highly inheritable, and most psychiatric disorders exhibit genetic overlap. Recent studies associated the 3q29 recurrent deletion with schizophrenia (SCZ) and autism spectrum disorder (ASD). In this study, we investigated the association of genes in the 3q29 region with SCZ and ASD. TM4SF19 and PAK2 were chosen as candidate genes for this study based on evidence from previous research. We sequenced TM4SF19 and PAK2 in 437 SCZ cases, 187 ASD cases and 524 controls in the Japanese population. Through targeted sequencing, we identified 6 missense variants among the cases (ASD & SCZ), 3 missense variants among controls, and 1 variant common to both cases and controls; however, no loss-of-function variants were identified. Fisher's exact test showed a significant association of variants in TM4SF19 among cases (p=0.0160). These results suggest TM4SF19 variants affect the etiology of SCZ and ASD in the Japanese population. Further research examining 3q29 region genes and their association with SCZ and ASD is thus needed.

Loss of dysbindin-1 in excitatory neurons in mice impacts NMDAR-dependent behaviors, neuronal morphology and synaptic transmission in the ventral hippocampus.

Dysbindin-1, a protein encoded by the schizophrenia susceptibility gene DTNBP1, is reduced in the hippocampus of schizophrenia patients. It is expressed in various cellular populations of the brain and implicated in dopaminergic and glutamatergic transmission. To investigate the impact of reduced dysbindin-1 in excitatory cells on hippocampal-associated behaviors and synaptic transmission, we developed a conditional knockout mouse model with deletion of dysbindin-1 gene in CaMKIIα expressing cells. We found that dysbindin-1 reduction in CaMKII expressing cells resulted in impaired spatial and social memories, and attenuation of the effects of glutamate N-methyl-d-asparate receptor (NMDAR) antagonist MK801 on locomotor activity and prepulse inhibition of startle (PPI). Dysbindin-1 deficiency in CaMKII expressing cells also resulted in reduced protein levels of NMDAR subunit GluN1 and GluN2B. These changes were associated with increased expression of immature dendritic spines in basiliar dendrites and abnormalities in excitatory synaptic transmission in the ventral hippocampus. These results highlight the functional relevance of dysbindin-1 in excitatory cells and its implication in schizophrenia-related pathologies.

Interaction between visual impairment and genetic risk of dementia and psychosis in older adults.

BACKGROUND: Visual impairment (VI) is associated with dementia and other neuropsychiatric outcomes, but previous studies have not considered genetic sources of confounding or effect modification. METHODS: We analysed data from the Health and Retirement Study, an ongoing nationally representative survey of older US adults, a subset of whom underwent genetic testing from 2006 to 2012 (n = 13 465). Using discrete time proportional hazards models and generalised estimating equations, we measured the association between VI and dementia, depression and hallucinations adjusting for demographics and comorbidities, ancestry-specific principal components and polygenic risk scores (PRS) for Alzheimer's disease, major depressive disorder or schizophrenia. Effect modification was assessed using VI-PRS interaction terms and stratified analyses. RESULTS: VI was associated with dementia, depression and hallucinations after adjusting polygenic risk and other confounders. There was no VI-PRS interaction for dementia or depression. However, the association between VI and hallucinations varied by genetic risk of schizophrenia. Within the bottom four quintiles of schizophrenia PRS, VI was not associated with hallucinations among White (OR 1.16, 95% CI: 0.87-1.55) or Black participants (OR 0.96, 95% CI: 0.49-1.89). In contrast, VI was strongly associated with hallucinations among White (OR 2.08, 95% CI: 1.17-3.71) and Black (OR 10.63, 95% CI: 1.74-65.03) participants in the top quintile of schizophrenia PRS. CONCLUSIONS: The association between VI and neuropsychiatric outcomes is not explained by shared genetic risk factors, and there is a significant interaction between VI and polygenic risk of hallucinations in older adults.

The Role of microRNA in Schizophrenia: A Scoping Review.

Schizophrenia is a serious mental disease that is regulated by multiple genes and influenced by multiple factors. Due to the complexity of its etiology, the pathogenesis is still unclear. MicroRNAs belong to a class of small non-coding RNAs that are highly conserved in endogenous evolution and play critical roles in multiple biological pathways. In recent years, aberrant miRNA expression has been implicated in schizophrenia, with certain miRNAs emerging as potential diagnostic and prognostic biomarkers for this disorder. In this review, our objective is to investigate the differential expression of miRNAs in schizophrenia, elucidate their potential mechanisms of action, and assess their feasibility as biomarkers. The PubMed electronic database and Google Scholar were searched for the years 2003 to 2024. The study focused on schizophrenia and miRNA as the research topic, encompassing articles related to biomarkers, etiology, action mechanisms, and differentially expressed genes associated with schizophrenia and miRNA. A total of 1488 articles were retrieved, out of which 49 were included in this scope review. This study reviewed 49 articles and identified abnormal expression of miRNA in different tissues of both schizophrenia patients and healthy controls, suggesting its potential role in the pathogenesis and progression of schizophrenia. Notably, several specific miRNAs, including miR-34a, miR-130b, miR-193-3p, miR-675-3p, miR-1262, and miR-218-5p, may serve as promising biological markers for diagnosing schizophrenia. Furthermore, this study summarized potential mechanisms through which miRNAs may contribute to the development of schizophrenia. The studies within the field of miRNA's role in schizophrenia encompass a broad spectrum of focus. Several selected studies have identified dysregulated miRNAs associated with schizophrenia across various tissues, thereby highlighting the potential utility of specific miRNAs as diagnostic biomarkers for this disorder. Various mechanisms underlying dysregulated miRNAs in schizophrenia have been explored; however, further investigations are needed to determine the exact mechanisms by which these dysregulated miRNAs contribute to the pathogenesis of this condition. The exploration of miRNA's involvement in the etiology and identification of biomarkers for schizophrenia holds significant promise in informing future clinical trials and advancing our understanding in this area.

Whole genome sequencing study of identical twins discordant for psychosis.

Monozygotic (MZ) twins are often thought to have identical genomes, but recent work has shown that early post-zygotic events can result in a spectrum of DNA variants that are different between MZ twins. Such variants may explain phenotypic discordance and contribute to disease etiology. Here we performed whole genome sequencing in 17 pairs of MZ twins discordant for a psychotic disorder (schizophrenia, schizoaffective disorder or bipolar disorder). We examined various classes of rare variants that are discordant within a twin pair. We identified four genes harboring rare, predicted deleterious missense variants that were private to an affected individual in the cohort. Variants in FOXN1 and FLOT2 would have been categorized as damaging from recent schizophrenia and bipolar exome sequencing studies. Additionally, we identified four rare genic copy number variants (CNVs) private to an affected sample, two of which overlapped genes that have shown evidence for association with schizophrenia or bipolar disorder. One such CNV was a 3q29 duplication previously implicated in autism and developmental delay. We have performed the largest MZ twin study for discordant psychotic phenotypes to date. These findings warrant further investigation using other analytical approaches.

Investigating copy number variants in schizophrenia pedigrees using a new consensus pipeline called PECAN.

Copy number variants (CNVs) have been implicated in many human diseases, including psychiatric disorders. Whole genome sequencing offers advantages in CNV calling compared to previous array-based methods. Here we present a robust and transparent CNV calling pipeline, PECAN (PEdigree Copy number vAriaNt calling), for short-read, whole genome sequencing data, comprised of a novel combination of four calling methods and structural variant genotyping. This method is scalable and can incorporate pedigree information to retain lower-confidence CNVs that would otherwise be discarded. We have robustly benchmarked PECAN using gold-standard CNV calls for two well-established evaluation samples, NA12878 and HG002, showing that PECAN performs with high precision and recall on both datasets, outperforming another pedigree-based CNV calling pipeline. As part of this work, we provide a list of high-confidence gold standard CNVs for the NA12878 reference sample, curated from multiple studies. We applied PECAN to a collection of pedigrees multiply affected with schizophrenia and identified a rare deletion that perfectly co-segregates with schizophrenia in one of the pedigrees. The CNV overlaps the gene PITRM1, which has been implicated in a complex phenotype including ataxia, developmental delay, and schizophrenia-like episodes in affected adults.

Association between periodontal disease and schizophrenia: a bidirectional two-sample Mendelian randomization study.

The connection between periodontal disease (PD) and schizophrenia (SCZ) has been reported in observational studies, but it remains unclear. This research aims to examine the bidirectional causal impacts between PD and SCZ. The FinnGen consortium supplied summarized data on PD for 346,731 individuals (87,497 cases and 259,234 controls) of Finnish ancestry, and information on SCZ was acquired from the OpenGWAS repository, encompassing 127,906 individuals (52,017 cases and 75,889 controls) of European ancestry. Next, we conducted Mendelian randomization (MR) analysis to establish a causal inference relationship between PD and SCZ. The inverse variance weighted (IVW) method was utilized as the primary analysis. Additionally, some sensitivity analyses were utilized to verify the stability of the results. The analysis of IVW results indicated no impact of PD on SCZ (IVW OR = 1.10, 95% CI 0.97-1.24, P = 0.14). Nevertheless, the inverse relationship between PD and SCZ was identified through reverse MR analysis (IVW OR = 1.03, 95% CI 1.01-1.05, P = 0.002). The findings from MR-Egger, weighted median, simple mode, and weighted mode approaches aligned with the outcomes of the IVW method. Based on sensitivity analyses, horizontal pleiotropy is unlikely to distort causal estimates. This study presented the initial proof of a genetic causal relationship between SCZ and PD, albeit with a minimal impact. Further exploration is needed to gain a deeper understanding of this relationship. Furthermore, no genetic causal relationship between PD and SCZ was identified.

Genetic components of microdeletion syndromes and their role in determining schizophrenia traits.

Schizophrenia is a neuropsychiatric disorder characterized by various symptoms such as hallucinations, delusions, and disordered thinking. The etiology of this disease is unknown; however, it has been linked to many microdeletion syndromes that are likely to contribute to the pathology of schizophrenia. In this review we have comprehensively analyzed the role of various microdeletion syndromes, like 3q29, 15q13.3, and 22q11.2, which are known to be involved with schizophrenia. A variety of factors lead to schizophrenia phenotypes, but copy number variants that disrupt gene regulation and impair brain function and cognition are one of the causes that have been identified. Multiple case studies have shown that loss of one or more genes in the microdeletion regions lead to brain activity defects. In this article, we present a coherent paradigm that connects copy number variations (CNVs) to numerous neurological and behavioral abnormalities associated with schizophrenia. It would be helpful in understanding the different aspects of the microdeletions and how they contribute in the pathophysiology of schizophrenia.

COMT and Neuregulin 1 Markers for Personalized Treatment of Schizophrenia Spectrum Disorders Treated with Risperidone Monotherapy.

Pharmacogenetic markers are current targets for the personalized treatment of psychosis. Limited data exist on COMT and NRG1 polymorphisms in relation to risperidone treatment. This study focuses on the impact of COMT rs4680 and NRG1 (rs35753505, rs3924999) polymorphisms on risperidone treatment in schizophrenia spectrum disorders (SSDs). This study included 103 subjects with SSD treated with risperidone monotherapy. COMT rs4680, NRG1 rs35753505, and rs3924999 were analyzed by RT-PCR. Participants were evaluated via the Positive and Negative Syndrome Scale (PANSS) after six weeks. Socio-demographic and clinical characteristics were collected. COMT rs4680 genotypes significantly differed in PANSS N scores at admission: AG>AA genotypes (p = 0.03). After six weeks of risperidone, PANSS G improvement was AA>GG (p = 0.05). The PANSS total score was as follows: AA>AG (p = 0.04), AA>GG (p = 0.02). NRG1 rs35753504 genotypes significantly differed across educational levels, with CC>CT (p = 0.02), and regarding the number of episodes, TT>CC, CT>CC (p = 0.01). The PANSS total score after six weeks of treatment showed a better improvement for TT

The impact of sex on gene expression in the brain of schizophrenic patients: a systematic review and meta-analysis of transcriptomic studies.

BACKGROUND: Schizophrenia is a severe neuropsychiatric disorder characterized by altered perception, mood, and behavior that profoundly impacts patients and society despite its relatively low prevalence. Sex-based differences have been described in schizophrenia epidemiology, symptomatology and outcomes. Different studies explored the impact of schizophrenia in the brain transcriptome, however we lack a consensus transcriptomic profile that considers sex and differentiates specific cerebral regions. METHODS: We performed a systematic review on bulk RNA-sequencing studies of post-mortem brain samples. Then, we fulfilled differential expression analysis on each study and summarized their results with regions-specific meta-analyses (prefrontal cortex and hippocampus) and a global all-studies meta-analysis. Finally, we used the consensus transcriptomic profiles to functionally characterize the impact of schizophrenia in males and females by protein-protein interaction networks, enriched biological processes and dysregulated transcription factors. RESULTS: We discovered the sex-based dysregulation of 265 genes in the prefrontal cortex, 1.414 genes in the hippocampus and 66 genes in the all-studies meta-analyses. The functional characterization of these gene sets unveiled increased processes related to immune response functions in the prefrontal cortex in male and the hippocampus in female schizophrenia patients and the overexpression of genes related to neurotransmission and synapses in the prefrontal cortex of female schizophrenia patients. Considering a meta-analysis of all brain regions available, we encountered the relative overexpression of genes related to synaptic plasticity and transmission in females and the overexpression of genes involved in organizing genetic information and protein folding in male schizophrenia patients. The protein-protein interaction networks and transcription factors activity analyses supported these sex-based profiles. CONCLUSIONS: Our results report multiple sex-based transcriptomic alterations in specific brain regions of schizophrenia patients, which provides new insight into the role of sex in schizophrenia. Moreover, we unveil a partial overlapping of inflammatory processes in the prefrontal cortex of males and the hippocampus of females.

Schizophrenia is a serious illness characterised by changes in perception, mood and behaviour that profoundly affect patients and society. The frequency, symptoms and progression of schizophrenia are different in women and men, but the biological reason for this is not understood. The identification of disease mechanisms specific in men and women, is relevant because it would allow a better understanding of this pathology, as well as improving the personalisation of diagnoses and treatments for patients. To achieve this goal, in this work we reviewed all available RNA sequencing studies of post-mortem brain samples from women and men affected by schizophrenia. Then, we compared gene expression in each study by sex, and integrated all study results in different brain regions: prefrontal cortex, hippocampus and all-studies. We discovered significant changes between men and women: 265 genes differentially expressed in the prefrontal cortex, 1414 genes in the hippocampus and 66 genes in meta-analyses of all-studies. The study of these genes revealed increased immune response functions in the prefrontal cortex of men and in the hippocampus of women with schizophrenia, as well as increased neurotransmission and synapses in the prefrontal cortex of women with schizophrenia. Our results report multiple gene expression changes in specific brain regions of patients with schizophrenia, providing new insights into the role of sex in schizophrenia.

Increased regional activity of a pro-autophagy pathway in schizophrenia as a contributor to sex differences in the disease pathology.

Based on recent genome-wide association studies, it is theorized that altered regulation of autophagy contributes to the pathophysiology of schizophrenia and bipolar disorder. As activity of autophagy-regulatory pathways is controlled by discrete phosphorylation sites on the relevant proteins, phospho-protein profiling is one of the few approaches available for enabling a quantitative assessment of autophagic activity in the brain. Despite this, a comprehensive phospho-protein assessment in the brains of schizophrenia and bipolar disorder subjects is currently lacking. Using this direction, our broad screening identifies an increase in AMP-activated protein kinase (AMPK)-mediated phospho-activation of the pro-autophagy protein beclin-1 solely in the prefrontal cortex of female, but not male, schizophrenia subjects. Using a reverse translational approach, we surprisingly find that this increase in beclin-1 activity facilitates synapse formation and enhances cognition. These findings are interpreted in the context of human studies demonstrating that female schizophrenia subjects have a lower susceptibility to cognitive dysfunction than males.

Improved functional mapping of complex trait heritability with GSA-MiXeR implicates biologically specific gene sets.

While genome-wide association studies are increasingly successful in discovering genomic loci associated with complex human traits and disorders, the biological interpretation of these findings remains challenging. Here we developed the GSA-MiXeR analytical tool for gene set analysis (GSA), which fits a model for the heritability of individual genes, accounting for linkage disequilibrium across variants and allowing the quantification of partitioned heritability and fold enrichment for small gene sets. We validated the method using extensive simulations and sensitivity analyses. When applied to a diverse selection of complex traits and disorders, including schizophrenia, GSA-MiXeR prioritizes gene sets with greater biological specificity compared to standard GSA approaches, implicating voltage-gated calcium channel function and dopaminergic signaling for schizophrenia. Such biologically relevant gene sets, often with fewer than ten genes, are more likely to provide insights into the pathobiology of complex diseases and highlight potential drug targets.

Shared genetic links between hypothyroidism and psychiatric disorders: evidence from a comprehensive genetic analysis.

Background: Epidemiologic studies have suggested co-morbidity between hypothyroidism and psychiatric disorders. However, the shared genetic etiology and causal relationship between them remain currently unclear. Methods: We assessed the genetic correlations between hypothyroidism and psychiatric disorders [anxiety disorders (ANX), schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP)] using summary association statistics from genome-wide association studies (GWAS). Two disease-associated pleiotropic risk loci and genes were identified, and pathway enrichment, tissue enrichment, and other analyses were performed to determine their specific functions. Furthermore, we explored the causal relationship between them through Mendelian randomization (MR) analysis. Results: We found significant genetic correlations between hypothyroidism with ANX, SCZ, and MDD, both in the Linkage disequilibrium score regression (LDSC) approach and the high-definition likelihood (HDL) approach. Meanwhile, the strongest correlation was observed between hypothyroidism and MDD (LDSC: rg=0.264, P=7.35×10-12; HDL: rg=0.304, P=4.14×10-17). We also determined a significant genetic correlation between MDD with free thyroxine (FT4) and thyroid-stimulating hormone (TSH) levels. A total of 30 pleiotropic risk loci were identified between hypothyroidism and psychiatric disorders, of which the 15q14 locus was identified in both ANX and SCZ (P values are 6.59×10-11 and 2.10×10-12, respectively) and the 6p22.1 locus was identified in both MDD and SCZ (P values are 1.05×10-8 and 5.75×10-14, respectively). Sixteen pleiotropic risk loci were identified between MDD and indicators of thyroid function, of which, four loci associated with MDD (1p32.3, 6p22.1, 10q21.1, 11q13.4) were identified in both FT4 normal level and Hypothyroidism. Further, 79 pleiotropic genes were identified using Magma gene analysis (P<0.05/18776 = 2.66×10-6). Tissue-specific enrichment analysis revealed that these genes were highly enriched into six brain-related tissues. The pathway analysis mainly involved nucleosome assembly and lipoprotein particles. Finally, our two-sample MR analysis showed a significant causal effect of MDD on the increased risk of hypothyroidism, and BIP may reduce TSH normal levels. Conclusions: Our findings not only provided evidence of a shared genetic etiology between hypothyroidism and psychiatric disorders, but also provided insights into the causal relationships and biological mechanisms that underlie their relationship. These findings contribute to a better understanding of the pleiotropy between hypothyroidism and psychiatric disorders, while having important implications for intervention and treatment goals for these disorders.