Gene discovery and biological insights into anxiety disorders from a large-scale multi-ancestry genome-wide association study

Nature Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 18, 2024

Language: Английский

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Gene Discovery and Biological Insights into Anxiety Disorders from a Multi-Ancestry Genome-wide Association Study of >1.2 Million Participants

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

Published: Feb. 15, 2024

ABSTRACT We leveraged information from more than 1.2 million participants to investigate the genetics of anxiety disorders across five continental ancestral groups. Ancestry-specific and cross-ancestry genome-wide association studies identified 51 anxiety-associated loci, 39 which are novel. Additionally, polygenic risk scores derived individuals European descent were associated with in African, Admixed-American, East Asian The heritability was enriched for genes expressed limbic system, cerebral cortex, cerebellum, metencephalon, entorhinal brain stem. Transcriptome- proteome-wide analyses highlighted 115 through brain-specific cross-tissue regulation. also observed global local genetic correlations depression, schizophrenia, bipolar disorder putative causal relationships several physical health conditions. Overall, this study expands knowledge regarding pathogenesis disorders, highlighting importance investigating diverse populations integrating multi-omics information.

Language: Английский

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Causal relationship between resting-state networks and depression: a bidirectional two-sample mendelian randomization study

BMC Psychiatry, Journal Year: 2024, Volume and Issue: 24(1)

Published: May 29, 2024

Abstract Background Cerebral resting-state networks were suggested to be strongly associated with depressive disorders. However, the causal relationship between cerebral and disorders remains controversial. In this study, we aimed investigate effect of on using a bidirectional Mendelian randomization (MR) design. Methods Updated summary-level genome-wide association study (GWAS) data correlated obtained from meta-analysis European-descent GWAS Complex Trait Genetics Lab. Depression-related FinnGen involving participants European ancestry. Resting-state functional magnetic resonance imaging multiband diffusion brain performed measure structural connectivity in seven well-known networks. Inverse-variance weighting was used as primary estimate, whereas MR-Pleiotropy RESidual Sum Outliers (PRESSO), MR-Egger, weighted median detect heterogeneity, sensitivity, pleiotropy. Results total, 20,928 20,573 well depression-related 48,847 patients 225,483 controls analyzed. Evidence for limbic network found inverse variance–weighted (odds ratio, $$28.21$$ ; 95% confidence interval, $$3.32-239.54$$ $$\text{P}=0.002$$ ), SC LN not found(OR=1.0025; CI,1.0005-1.0046; P =0.012). No significant associations MR study. Conclusions These results suggest that genetically determined has may play critical role its neuropathology.

Language: Английский

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Causal associations between iron levels in subcortical brain regions and psychiatric disorders: a Mendelian randomization study

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

Published: Jan. 22, 2025

Despite observational studies linking brain iron levels to psychiatric disorders, the exact causal relationship remains poorly understood. This study aims examine between in specific subcortical regions and risk of disorders. Utilizing two-sample Mendelian randomization (MR) analysis, this investigates associations level changes 16 nuclei eight major including schizophrenia (SCZ), depressive disorder (MDD), autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder, bipolar anxiety obsessive-compulsive insomnia. The genetic instrumental variables linked were derived from genome-wide association data UK Biobank Brain Imaging Psychiatric Genomics Consortium. Bidirectional estimation was primarily obtained using inverse variance weighting (IVW) method. Iron left substantia nigra showed a negative with MDD (ORIVW = 0.94, 95% CI 0.91–0.97, p < 0.001) trends SCZ 0.90, 0.82–0.98, 0.020). Conversely, putamen positively associated ASD 1.11, 1.04–1.19, 0.002). Additionally, several bidirectional observed for Lower may increase MDD, potentially SCZ, indicating potential shared pathogenic mechanism. Higher lead development ASD. indicate importance underlying biomechanical interactions regulation these

Language: Английский

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Obstructive sleep apnea and structural and functional brain alterations: a brain-wide investigation from clinical association to genetic causality

BMC Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 27, 2025

Obstructive sleep apnea (OSA) is linked to brain alterations, but the specific regions affected and causal associations between these changes remain unclear. We studied 20 pairs of age-, sex-, BMI-, education- matched OSA patients healthy controls using multimodal magnetic resonance imaging (MRI) from August 2019 February 2020. Additionally, large-scale Mendelian randomization analyses were performed genome-wide association study (GWAS) data on 3935 imaging-derived phenotypes (IDPs), assessed in up 33,224 individuals December 2023 March 2024, explore potential genetic causality alterations whole structure function. In cohort study, exhibited significantly lower fractional amplitude low-frequency fluctuation regional homogeneity right posterior cerebellar lobe bilateral superior middle frontal gyrus, while showing higher levels left occipital central gyrus. Decreased anisotropy (FA) increased apparent diffusion coefficient (ADC) was shown longitudinal fasciculus. According results Affiliation file 2: table s6, it ADC value fasciculus a positive correlation with lowest oxygen saturation. analyses, area inferior temporal sulcus (OR: 0.89; 95% CI: 0.82-0.96), rfMRI connectivity ICA100 edge 893 0.88; 951 0.82-0.97), 1213 0.82-0.96) decreased OSA. Conversely, mean thickness G-front-inf-Triangul hemisphere 1.14; 1.05-1.23), orientation dispersion index tapetum 1.13; 1.04-1.23), 258 1.04-1.22) showed opposite results. Nerve fiber damage imbalances neuronal activity across multiple caused by hypoxia, particularly lobe, underlie structural functional impairments

Language: Английский

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Prevalence and network structure of depression, anxiety and adverse doctor-patient relationship risks among patients with physical diseases: A cross-sectional study

Journal of Affective Disorders, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Brain-wide pleiotropy investigation of alcohol drinking and tobacco smoking behaviors

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

Published: Feb. 20, 2025

To investigate the pleiotropic mechanisms linking brain structure and function to alcohol drinking tobacco smoking, we integrated genome-wide data generated by GWAS Sequencing Consortium of Alcohol Nicotine use (GSCAN; up 805,431 participants) with information related 3935 imaging-derived phenotypes (IDPs) available from UK Biobank (N = 33,224). We observed global genetic correlation smoking behaviors white matter hyperintensities, morphology superior longitudinal fasciculus, mean thickness pole-occipital. With respect latter IDP, identified a local age at which individual began regularly (hg38 chr2:35,895,678-36,640,246: rho 1, p 1.01 × 10-5). This region has been previously associated initiation, educational attainment, chronotype, cortical thickness. Our genetically informed causal inference analysis using both latent variable approach Mendelian randomization linked activity prefrontal premotor cortex that inferior precentral sulci, cingulate sulci number alcoholic drinks per week (genetic causality proportion, gcp 0.38, 8.9 10-4, -0.18 ± 0.07; inverse variance weighting, IVW beta -0.04, 95%CI -0.07--0.01). relationship could be role these regions in modulation reward-seeking motivation processing social cues. Overall, our brain-wide investigation highlighted different likely contribute suggesting decision-making activities chemosensory as modulators propensity towards consumption.

Language: Английский

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Temporomandibular disorders and mental health: shared etiologies and treatment approaches

The Journal of Headache and Pain, Journal Year: 2025, Volume and Issue: 26(1)

Published: March 12, 2025

The biopsychosocial model suggests that temporomandibular disorders (TMDs) often coexist with mental health disorders, particularly depression and anxiety, affecting a significant portion of the global population. interplay between TMDs contributes to complex comorbidity, perpetuating cycle mutual influence reinforcement. This review investigates neurobiological mechanisms epidemiological evidence supporting shared etiology exploring potential vulnerabilities bidirectional causal relationships. Shared may stem from genetic epigenetic predispositions, psychosocial factors, behavioral aspects. Inflammatory cytokines, neurotransmitters, neurotrophins, neuropeptides play pivotal roles in both peripheral central sensitization as well neuroinflammation. Brain imaging studies suggest exhibit overlapping brain regions indicative reward processing deficits anomalies within triple network model. Future research efforts are crucial for developing comprehensive understanding underlying confirming reciprocal effects disorders. provides valuable insights oral healthcare professionals, stressing importance optimizing treatment strategies individuals dealing concurrent issues through personalized, holistic, multidisciplinary approach.

Language: Английский

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Integration of metabolomic and brain-imaging data highlights pleiotropy among posttraumatic stress disorder, glycoprotein acetyls, and pallidum structure

Biological Psychiatry Global Open Science, Journal Year: 2025, Volume and Issue: unknown, P. 100482 - 100482

Published: March 1, 2025

The development of posttraumatic stress disorder (PTSD) is attributable to the interplay between exposure severe traumatic events, environmental factors, and biological characteristics. Blood brain imaging markers have been associated with PTSD. However, our knowledge, no study has systematically investigated genetic relationship PTSD, metabolic biomarkers, brainwide imaging. We integrated genome-wide data informative 233 3935 imaging-derived phenotypes (IDPs). Pleiotropy was assessed by applying global local correlation, colocalization, genetically inferred causality. observed significant overlap PTSD glycoprotein acetyls (GlycA) (a stable inflammatory biomarker) in 2 independent cohorts (discovery r g = 0.26, p 1.00 × 10-4; replication 0.23, 5.99 10-19). Interestingly, there correlation anxiety GlycA (p .33). were both correlated median T2∗ left pallidum (IDP-1444: 0.14, 1.39 10-5; -0.38, 2.50 10-3, respectively). Local 7 regions < 2.0 10-5), mapping genes related immune response, inflammation, processes. Furthermore, we identified 1 variant, rs12048743, evidence horizontal pleiotropy linking IDP-1444 (z 17.14, z -6.07, theta 2.06 10-8). Regional colocalization among GlycA, IDP-1444, tissue-specific transcriptomic regulation for frontal cortex testis (rs12048743-chr1q32.1; posterior probability > 0.8). While also tested causality metabolomic IDPs, these not consistent across different informed causal inference methods. Our findings highlight a new putative pleiotropic mechanism that links systemic inflammation structure

Language: Английский

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Estimating the direct effects of the genetic liabilities to bipolar disorder, schizophrenia, and behavioral traits on suicide attempt using a multivariable Mendelian randomization approach

Neuropsychopharmacology, Journal Year: 2024, Volume and Issue: 49(9), P. 1383 - 1391

Published: Feb. 23, 2024

Language: Английский

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