Signature of Altered Retinal Microstructures and Electrophysiology in Schizophrenia Spectrum Disorders Is Associated With Disease Severity and Polygenic Risk

Biological Psychiatry, Journal Year: 2024, Volume and Issue: 96(10), P. 792 - 803

Published: April 27, 2024

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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Genetic susceptibility to schizophrenia through neuroinflammatory pathways is associated with retinal thinning: Findings from the UK-Biobank

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

Published: April 6, 2024

The human retina is part of the central nervous system and can be easily non-invasively imaged with optical coherence tomography. While imaging may provide insights on system-related disorders such as schizophrenia, a typical challenge are confounders often present in schizophrenia which negatively impact retinal health. Here, we therefore aimed to investigate changes context common genetic variations conveying risk measured by polygenic scores. We used population data from UK Biobank, including White British Irish individuals without diagnosed estimated score for based newest genome-wide association study (PGC release 2022). hypothesized that greater susceptibility associated thinning, especially within macula. To gain additional mechanistic insights, conducted pathway-specific associations analyses, focusing gene pathways related schizophrenia. Of 65484 recruited, 48208 participants available matching imaging-genetic were included analysis whom 22427 (53.48%) female 25781 (46.52%) male. Our robust principal component regression results showed scores thinning while controlling confounding factors (b = −0.03, p 0.007, pFWER 0.01). Similarly, found specific neuroinflammation sets revealed significant self-contained 0.041 (reflecting level association), competitive 0.05 enrichment)). These go beyond previous studies suggesting relationship between manifested phenotypes. They indicate mirror reflecting complexities alterations observed connected an inherent predisposition neurodegenerative aspects condition. also suggest potential involvement neuroinflammatory pathway, indications overlap findings further this pathway high could contribute through acute-phase proteins structural retina.

Language: Английский

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Genetic Analysis of Retinal Cell Types in Neuropsychiatric Disorders

JAMA Psychiatry, Journal Year: 2025, Volume and Issue: 82(3), P. 285 - 285

Published: Jan. 8, 2025

Importance As an accessible part of the central nervous system, retina provides a unique window to study pathophysiological mechanisms brain disorders in humans. Imaging and electrophysiological studies have revealed retinal alterations across several neuropsychiatric neurological disorders, but it remains largely unclear which specific cell types biological are involved. Objective To determine whether affected by genomic risk for explore through converges these types. Design, Setting, Participants This genetic association combined findings from genome-wide schizophrenia, bipolar disorder, major depressive multiple sclerosis, Parkinson disease, Alzheimer stroke with single-cell transcriptomic datasets humans, macaques, mice. identify susceptible types, Multi-Marker Analysis Genomic Annotation (MAGMA) cell-type enrichment analyses were applied subsequent pathway performed. The cellular top hits translated structural level using optical coherence tomography (acquired between 2009 2010) genotyping data large population-based UK Biobank cohort study. Data analysis was conducted 2022 2024. Main Outcomes Measures Cell type–specific loading disorder traits gene expression profiles cells. Results Expression amacrine cells (interneurons within retina) robustly enriched schizophrenia mammalian species different developmental stages. primarily driven genes involved synapse biology. Moreover, immune populations sclerosis risk. No consistent associations found or stroke. On level, higher polygenic associated thinning ganglion inner plexiform layer, contains dendrites synaptic connections (B, −0.09; 95% CI, −0.16 −0.03; P = .007; n 36 349; mean [SD] age, 57.50 [8.00] years; 19 859 female [54.63%]). Higher increased thickness nerve fiber layer 0.06; 0.02 0.10; 371; 57.51 843 [54.56%]). Conclusions Relevance novel insights into underpinnings highlights as potential proxy pathology schizophrenia.

Language: Английский

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PennPRS: a centralized cloud computing platform for efficient polygenic risk score training in precision medicine

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 10, 2025

Polygenic risk scores (PRS) are becoming increasingly vital for prediction and stratification in precision medicine. However, PRS model training presents significant challenges broader adoption of PRS, including limited access to computational resources, difficulties implementing advanced methods, availability privacy concerns over individual-level genetic data. Cloud computing provides a promising solution with centralized data resources. Here we introduce PennPRS ( https://pennprs.org ), scalable cloud platform online We developed novel pseudo-training algorithms multiple methods ensemble approaches, enabling without requiring These were rigorously validated through extensive simulations large-scale real analyses involving 6,000 phenotypes across various sources. supports single- multi-ancestry seven allowing users upload their own or query from more than 27,000 datasets the GWAS Catalog, submit jobs, download trained models. Additionally, applied our pipeline train models 8,000 made weights publicly accessible. In summary, improve accessibility applications reduce disparities resources global research community.

Language: Английский

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Retinal ganglion cell vulnerability to pathogenic tau in Alzheimer’s disease

Acta Neuropathologica Communications, Journal Year: 2025, Volume and Issue: 13(1)

Published: Feb. 15, 2025

Abstract Pathological tau isoforms, including hyperphosphorylated at serine 396 (pS396-tau) and oligomers (Oligo-tau), are elevated in the retinas of patients with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) AD dementia. These exhibit significant retinal ganglion cell (RGC) loss, however presence isoforms RGCs their impact on RGC integrity, particularly early AD, have not been studied. Here, we analyzed superior temporal cross-sections from 25 MCI or 16 age- sex-matched cognitively normal controls. Using marker ribonucleic acid binding protein multiple splicing (RBPMS) Nissl staining, found a 46–56% reduction RBPMS + neurons layer (GCL) ( P < 0.05–0.001). loss was accompanied by soma hypertrophy (10–50% enlargement, 0.05–0.0001), nuclear displacement, apoptosis (30–50% increase, 0.05–0.01), prominent expression granulovacuolar degeneration (GVD) bodies GVD-necroptotic markers. Both pS396-tau Oligo-tau were identified RGCs, hypertrophic cells. PS396-tau counts significantly increased 2.1–3.5-fold versus control 0.05–0.0001). Tauopathy-laden strongly inter-correlated r =0.85, 0.0001) tauopathy associated =-0.40–(-0.64), 0.05–0.01). Their abundance correlated brain pathology deficits, higher tauopathy-laden Braak stages (V–VI), clinical dementia ratings (CDR = 3), mini-mental state examination (MMSE ≤ 26) scores. central mid-periphery showed closest associations status, while exhibited strongest correlations (NFTs, stages, ABC scores; S =0.78–0.81, 0.001–0.0001) decline (MMSE; =-0.79, 0.0019). Overall, these findings identify link between pathogenic involving apoptotic death pathways. Future research should validate results larger more diverse cohorts develop as potential noninvasive biomarker for detection monitoring progression.

Language: Английский

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Leveraging multimodal neuroimaging and GWAS for identifying modality-level causal pathways to Alzheimer's disease

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Abstract The UK Biobank study has produced thousands of brain imaging-driven phenotypes (IDPs) collected from more than 40,000 genotyped individuals so far, facilitating the investigation genetic and imaging biomarkers for disorders. Motivated by efforts in genetics to integrate gene expression levels with genome-wide association studies (GWASs), recent methods adopted an instrumental variable (IV) approach identify causal IDPs However, several methodological challenges arise existing achieving causality genetics, including horizontal pleiotropy high dimensionality candidate IVs. In this work, we propose testing each modality (i.e., structural, functional, diffusion MRI) as a useful alternative, which offers enhanced understanding roles variants features on behavior controlling pleiotropic effects other modalities. We demonstrate utility proposed method using Alzheimer’s GWAS data International Genomics Project (IGAP) study. Our is implemented summary statistics, available GitHub.

Language: Английский

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Genetic susceptibility to schizophrenia through neuroinflammatory pathways associated with retinal thinness

Nature Mental Health, Journal Year: 2025, Volume and Issue: unknown

Published: April 21, 2025

Language: Английский

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Retinal ganglion cell vulnerability to pathogenic tau in Alzheimer's disease

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

Published: Sept. 21, 2024

Abstract Accumulation of pathological tau isoforms, especially hyperphosphorylated at serine 396 (pS396-tau) and oligomers, has been demonstrated in the retinas patients with mild cognitive impairment (MCI) Alzheimer’s disease (AD). Previous studies have noted a decrease retinal ganglion cells (RGCs) AD patients, but presence impact isoforms RGCs RGC integrity, particularly early stages, not explored. To investigate this, we examined superior temporal cross-sections from 25 MCI (due to AD) or dementia 16 cognitively normal (CN) controls, matched for age gender. We utilized marker ribonucleic acid binding protein multiple splicing (RBPMS) Nissl staining assess neuronal density cell layer (GCL). Our study found that hypertrophic containing pS396-tau T22-positive oligomers were more frequently observed compared CN subjects. Quantitative analyses indicated decline 46-55% 55-56% reductions RBPMS + (P<0.01) GCL neurons (P<0.01-0.001), respectively, patients. This count was accompanied by increases necroptotic-like morphology cleaved caspase-3 apoptotic Furthermore, there 2.1 3.1-fold increase (P<0.05-0.0001) pS396-tau-laden greater abundance individuals higher Braak stages (V-VI), severe clinical ratings (CDR=3), lower mini-mental state examination (MMSE) scores. Strong correlations between total amount RGCs, counts correlating significantly brain neurofibrillary tangle scores ( r = 0.71, P= 0.0001), stage 0.65, 0.0009), MMSE -0.76, 0.0004). These findings suggest tauopathy, characterized oligomeric is associated may contribute degeneration AD. Future research should validate these larger cohorts explore noninvasive imaging techniques target pathology improve detection monitor progression.

Language: Английский

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Multi-organ imaging-derived polygenic indexes for brain and body health

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

Published: April 20, 2023

The UK Biobank (UKB) imaging project is a crucial resource for biomedical research, but limited to 100,000 participants due cost and accessibility barriers. Here we used genetic data predict heritable imaging-derived phenotypes (IDPs) larger cohort. We developed evaluated 4,375 IDP scores (IGS) derived from UKB brain body images. When applied who were not imaged, IGS revealed links numerous stratified at increased risk both somatic diseases. For example, identified individuals higher Alzheimer's disease multiple sclerosis, offering additional insights beyond traditional polygenic of these independent external cohorts, also those high in the All Us Research Program Disease Neuroimaging Initiative study. Our results demonstrate that, while cohort largely healthy may be most enriched management, it holds immense potential stratifying various diseases broader cohorts.

Language: Английский

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