Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(5), P. 792 - 808

Published: April 18, 2024

Language: Английский

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Genome-wide association study identifies 30 obsessive-compulsive disorder associated loci

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 13, 2024

Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on genetic etiology underlying biological mechanisms disorder. We conducted GWAS meta-analysis combining 53,660 OCD cases 2,044,417 controls from 28 European-ancestry cohorts revealing 30 independent significant SNPs SNP-based heritability 6.7%. Separate for clinical, biobank, comorbid, self-report sub-groups found no evidence sample ascertainment impacting our results. Functional positional QTL gene-based approaches identified 249 candidate risk genes OCD, which 25 were as putatively causal, highlighting WDR6, DALRD3, CTNND1 in MHC region. Tissue single-cell enrichment analyses highlighted hippocampal cortical excitatory neurons, along with D1- D2-type dopamine receptor-containing medium spiny playing role risk. displayed correlations 65 out 112 examined phenotypes. Notably, it showed positive all included psychiatric phenotypes, particular anxiety, depression, anorexia nervosa, Tourette syndrome, negative subset autoimmune disorders, educational attainment, body mass index.. This study marks step toward unraveling its landscape advances understanding genetics, providing foundation future interventions to address this debilitating

Language: Английский

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Systematic dissection of pleiotropic loci and critical regulons in excitatory neurons and microglia relevant to neuropsychiatric and ocular diseases

Translational Psychiatry, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 25, 2025

Advancements in single-cell multimodal techniques have greatly enhanced our understanding of disease-relevant loci identified through genome-wide association studies (GWASs). To investigate the biological connections between eye and brain, we integrated bulk multiomic profiles with GWAS summary statistics for eight neuropsychiatric five ocular diseases. Our analysis uncovered latent factors explaining 61.7% genetic variance across these 13 diseases, revealing diverse correlational patterns among them. We 45 pleiotropic 91 candidate genes that contribute to disease risk. By integrating profiles, implicated excitatory neurons microglia as key contributors eye-brain connections. Polygenic enrichment further 15 regulons 16 were linked comorbid conditions. Functionally, neuron-specific involved axon guidance synaptic activity, while microglia-specific associated immune response cell activation. In sum, findings underscore link psychiatric disorders

Language: Английский

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Immune-developmental processes contribute to schizophrenia risk: insights from a genetic overlap study with height

Biological Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

BackgroundShorter stature has been phenotypically linked to increased prevalence of schizophrenia (SCZ), but the nature this association is unknown.MethodsUsing genome-wide genetic data, we studied SCZ-height relationship on a level. Applying novel methods and tools, analyzed gene-sets, tissue-types, cell-types, local correlation, conditional analyses, fine-mapping effector-genes scrutinize relationship.ResultsWe identified 142 genes statistically associated with both SCZ height found enrichment in 3 functional gene-sets. Genetic annotations implicated pituitary specifically mesenchymal stem cells for thyrotropic SCZ. While global correlation was nonsignificant, 9 genomic regions showed robust correlations (7 negative, 6 MHC-region). The shared signal within MHC-regions partially explained by mutual overlap white blood cell count, particularly lymphocytes. Fine-mapping prioritized (GIGYF2, HLA-C, LIN28B) involved immune response sensitivity development cell-types.ConclusionsOverall, our findings suggest an involvement during height-development contributing towards risk

Language: Английский

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Examining the shared etiology of psychopathology with genome-wide association studies

Physiological Reviews, Journal Year: 2023, Volume and Issue: 103(2), P. 1645 - 1665

Published: Jan. 12, 2023

Genome-wide association studies (GWASs) have ushered in a new era of reproducible discovery psychiatric genetics. The field has now identified hundreds common genetic variants that are associated with mental disorders, and many them influence more than one disorder. By advancing the understanding causal biology underlying psychopathology, GWAS results poised to inform development novel therapeutics, stratification at-risk patients, perhaps even revision top-down classification systems psychiatry. Here, we provide concise review findings an emphasis on elucidated shared etiology summarizing insights at three levels analysis: 1) genome-wide architecture; 2) networks, pathways, gene sets; 3) individual variants/genes. Three themes emerge from these efforts. First, all phenotypes heritable, highly polygenic, influenced by pleiotropic incomplete penetrance. Second, highlight broad etiological roles neuronal biology, system-wide effects over localized effects, early neurodevelopment as critical period. Third, loci robustly multiple forms psychopathology harbor genes involved synaptic structure function. Finally, conclude our discussing implications hold for psychiatry, well expected challenges future directions next stage

Language: Английский

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Precision psychiatry: predicting predictability

Psychological Medicine, Journal Year: 2024, Volume and Issue: 54(8), P. 1500 - 1509

Published: March 18, 2024

Abstract Precision psychiatry is an emerging field that aims to provide individualized approaches mental health care. An important strategy achieve this precision reduce uncertainty about prognosis and treatment response. Multivariate analysis machine learning are used create outcome prediction models based on clinical data such as demographics, symptom assessments, genetic information, brain imaging. While much emphasis has been placed technical innovation, the complex varied nature of presents significant challenges successful implementation these models. From perspective, I review ten in psychiatry, including need for studies real-world populations realistic definitions, consideration treatment-related factors placebo effects non-adherence prescriptions. Fairness, prospective validation comparison current practice other key issues currently understudied. A shift proposed from retrospective linear static concepts disease towards research considers importance contextual dynamic health.

Language: Английский

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The shared genetic risk architecture of neurological and psychiatric disorders: a genome-wide analysis

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 23, 2023

While neurological and psychiatric disorders have historically been considered to reflect distinct pathogenic entities, recent findings suggest shared pathobiological mechanisms. However, the extent which these heritable share genetic influences remains unclear. Here, we performed a comprehensive analysis of GWAS data, involving nearly 1 million cases across ten diseases disorders, compare their common risk biological underpinnings. Using complementary statistical tools, demonstrate widespread overlap even in absence correlations. This indicates that large set variants impact multiple but with divergent effect sizes. Furthermore, interrogation revealed range processes associated diseases, while consistently implicated neuronal biology. Altogether, study key etiological aspects, has important implications for disease classification, precision medicine, clinical practice.

Language: Английский

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Combining Transdiagnostic and Disorder-Level GWAS Enhances Precision of Psychiatric Genetic Risk Profiles in a Multi-Ancestry Sample

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 10, 2024

Abstract The etiology of substance use disorders (SUDs) and psychiatric reflects a combination both transdiagnostic (i.e., common) disorder-level independent) genetic risk factors. We applied genomic structural equation modeling to examine these factors across SUDs, psychotic, mood, anxiety using genome-wide association studies (GWAS) European-(EUR) African-ancestry (AFR) individuals. In EUR individuals, represented SUDs (143 lead single nucleotide polymorphisms [SNPs]), psychotic (162 SNPs), mood/anxiety (112 SNPs). identified two novel SNPs for that have probable regulatory roles on FOXP1 , NECTIN3 BTLA genes. AFR (1 SNP) (no significant SUD factor SNP, although previously in EUR- cross-ancestry GWAS, is finding Shared variance accounted overlap between their comorbidities, with second-order GWAS identifying up 12 not significantly associated either first-order Finally, common independent effects showed different associations psychiatric, sociodemographic, medical phenotypes. For example, the components schizophrenia bipolar disorder had distinct affective risk-taking behaviors, phenome-wide conditions tobacco broader factor. Thus, combining approaches can improve our understanding co-occurring increase specificity discovery, which critical demonstrate considerable symptom etiological overlap.

Language: Английский

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Pleiotropic contribution of rbfox1 to psychiatric and neurodevelopmental phenotypes in two zebrafish models

Translational Psychiatry, Journal Year: 2024, Volume and Issue: 14(1)

Published: Feb. 19, 2024

Abstract RBFOX1 is a highly pleiotropic gene that contributes to several psychiatric and neurodevelopmental disorders. Both rare common variants in have been associated with conditions, but the mechanisms underlying effects of are not yet understood. Here we found that, zebrafish, rbfox1 expressed spinal cord, mid- hindbrain during developmental stages. In adults, expression restricted specific areas brain, including telencephalic diencephalic regions an important role receiving processing sensory information directing behaviour. To investigate contribution behaviour, used sa15940 , zebrafish mutant line TL background. We mutants present hyperactivity, thigmotaxis, decreased freezing behaviour altered social repeated these behavioural tests second different genetic background (TU), del19 deficiency affects similarly this line, although there were some differences. similar stronger alterations lower levels hyperactivity than fish. Taken together, results suggest mutations lead multiple changes might be modulated by environmental, epigenetic effects, resemble phenotypic Rbfox1 -deficient mice patients conditions. Our study, thus, highlights evolutionary conservation function paves way further pleiotropy on onset

Language: Английский

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GWAShug: a comprehensive platform for decoding the shared genetic basis between complex traits based on summary statistics

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 53(D1), P. D1006 - D1015

Published: Oct. 9, 2024

Abstract The shared genetic basis offers very valuable insights into the etiology, diagnosis and therapy of complex traits. However, a comprehensive resource providing using accessible summary statistics is currently lacking. It challenging to analyze due difficulty in selecting parameters complexity pipeline implementation. To address these issues, we introduce GWAShug, platform featuring standardized best-practice with four trait level methods three molecular methods. Based on stringent quality control, GWAShug module includes 539 high-quality GWAS for European East Asian populations, covering 54 945 pairs between measurement-based disease-based 43 902 two Users can easily search information by name, MeSH term category, access detailed gene across different pairs. facilitates interactive visualization analysis basic results, allowing users explore data dynamically. Results be conveniently downloaded via FTP links. Additionally, offer an online that allows their own statistics, tables, figures analysis. freely at http://www.gwashug.com.

Language: Английский

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