Temporal changes in brain morphology related to inflammation and schizophrenia: an omnigenic Mendelian randomization study DOI Creative Commons
Yunjia Liu, Hongyan Ren, Yamin Zhang

et al.

Psychological Medicine, Journal Year: 2024, Volume and Issue: 54(9), P. 2054 - 2062

Published: March 6, 2024

Abstract Background Over the past several decades, more research focuses have been made on inflammation/immune hypothesis of schizophrenia. Building upon synaptic plasticity hypothesis, inflammation may contribute underlying pathophysiology Yet, pinpointing specific inflammatory agents responsible for schizophrenia remains a complex challenge, mainly due to medication and metabolic status. Multiple lines evidence point wide-spread genetic association across genome phenotypic variations Method We collected latest genome-wide analysis (GWAS) summary data schizophrenia, cytokines, longitudinal change brain. utilized omnigenic model which takes into account all genomic SNPs included in GWAS trait, instead traditional Mendelian randomization (MR) methods. conducted two round MR investigate triggers resulting changes Results identified seven markers linked onset, passed Bonferroni correction multiple comparisons (bNGF, GROA(CXCL1), IL-8, M-CSF, MCP-3 (CCL7), TNF- β , CRP). Moreover, CRP were found significantly influence linear rate brain morphology changes, predominantly white matter cerebrum cerebellum. Conclusion With an approach, our study sheds light immune pathology Although these findings need confirmation from future studies employing different methodologies, work provides substantial that pervasive, low-level neuroinflammation play pivotal role potentially leading notable morphology.

Language: Английский

CD8+ T cells induce interferon-responsive oligodendrocytes and microglia in white matter aging DOI Creative Commons
Tuğberk Kaya, Nicola Mattugini, Lu Liu

et al.

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(11), P. 1446 - 1457

Published: Oct. 24, 2022

Abstract A hallmark of nervous system aging is a decline white matter volume and function, but the underlying mechanisms leading to pathology are unknown. In present study, we found age-related alterations oligodendrocyte cell state with reduction in total density murine matter. Using single-cell RNA-sequencing, identified interferon (IFN)-responsive oligodendrocytes, which localize proximity CD8 + T cells Absence functional lymphocytes decreased number IFN-responsive oligodendrocytes rescued loss, whereas T-cell checkpoint inhibition worsened response. addition, subpopulation lymphocyte-dependent, microglia vicinity summary, provide evidence that T-cell-induced, important modifiers aging.

Language: Английский

Citations

134
Educational attainment, structural brain reserve and Alzheimer’s disease: a Mendelian randomization analysis DOI Creative Commons
Aida Seyedsalehi, Varun Warrier, Richard A. I. Bethlehem

et al.

Brain, Journal Year: 2022, Volume and Issue: 146(5), P. 2059 - 2074

Published: Oct. 31, 2022

Abstract Higher educational attainment is observationally associated with lower risk of Alzheimer’s disease. However, the biological mechanisms underpinning this association remain unclear. The protective effect education on disease may be mediated via increased brain reserve. We used two-sample Mendelian randomization to explore putative causal relationships between attainment, structural reserve as proxied by MRI phenotypes and Summary statistics were obtained from genome-wide studies (n = 1 131 881), late-onset (35 274 cases, 59 163 controls) 15 measures grey or white matter macro- micro-structure derived diffusion (nmax 33 211). conducted univariable analyses investigate bidirectional associations (i) disease; (ii) imaging-derived phenotypes; (iii) Multivariable was assess whether structure risk. Genetically inversely (odds ratio per standard deviation increase in genetically predicted years schooling 0.70, 95% confidence interval 0.60, 0.80). There positive four cortical metrics (standard units change imaging phenotype one schooling): surface area 0.30 (95% 0.20, 0.40); volume 0.29 0.37); intrinsic curvature 0.18 0.11, 0.25); local gyrification index 0.21 0.31)]; inverse intracellular fraction [−0.09 −0.15, −0.03)] hyperintensities [−0.14 −0.23, −0.05)]. levels area, positively [standard respective phenotype: 0.13 0.10, 0.16); 0.15 0.19) 0.12 0.04, 0.19)]. found no evidence did not attenuate after adjusting for multivariable analyses. Our results provide support a risk, well potential micro-structure. we find that these markers affect other included present study, alternative mechanisms.

Language: Английский

Citations

71
Timing of lifespan influences on brain and cognition DOI Creative Commons
Kristine B. Walhovd, Martin Lövdén, Anders M. Fjell

et al.

Trends in Cognitive Sciences, Journal Year: 2023, Volume and Issue: 27(10), P. 901 - 915

Published: Aug. 8, 2023

Modifiable risk and protective factors for boosting brain cognitive development preventing neurodegeneration decline are embraced in neuroimaging studies. We call sobriety regarding the timing quantity of such influences on cognition. Individual differences level cognition, many which present already at birth early development, appear stable, larger, more pervasive than change across lifespan. Incorporating early-life factors, including genetics, investigating both will reduce ascribing undue importance causality to proximate adulthood older age. This has implications mechanistic understanding prevention.

Language: Английский

Citations

59
Genetic insights into human cortical organization and development through genome-wide analyses of 2,347 neuroimaging phenotypes DOI
Varun Warrier, Eva-Maria Stauffer, Qin Qin Huang

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(9), P. 1483 - 1493

Published: Aug. 17, 2023

Language: Английский

Citations

45
The genetic architecture of multimodal human brain age DOI Creative Commons
Junhao Wen, Bingxin Zhao, Zhijian Yang

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 23, 2024

Abstract The complex biological mechanisms underlying human brain aging remain incompletely understood. This study investigated the genetic architecture of three age gaps (BAG) derived from gray matter volume (GM-BAG), white microstructure (WM-BAG), and functional connectivity (FC-BAG). We identified sixteen genomic loci that reached genome-wide significance (P-value < 5×10 −8 ). A gene-drug-disease network highlighted genes linked to GM-BAG for treating neurodegenerative neuropsychiatric disorders WM-BAG cancer therapy. displayed most pronounced heritability enrichment in variants within conserved regions. Oligodendrocytes astrocytes, but not neurons, exhibited notable WM FC-BAG, respectively. Mendelian randomization potential causal effects several chronic diseases on aging, such as type 2 diabetes AD WM-BAG. Our results provide insights into genetics with clinical implications lifestyle therapeutic interventions. All are publicly available at https://labs.loni.usc.edu/medicine .

Language: Английский

Citations

21
Genetic architecture of the structural connectome DOI Creative Commons
Michael Wainberg, Natalie J. Forde,

Salim Mansour

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 4, 2024

Abstract Myelinated axons form long-range connections that enable rapid communication between distant brain regions, but how genetics governs the strength and organization of these remains unclear. We perform genome-wide association studies 206 structural connectivity measures derived from diffusion magnetic resonance imaging tractography 26,333 UK Biobank participants, each representing density myelinated within or a pair cortical networks, subcortical structures hemispheres. identify 30 independent significant variants after Bonferroni correction for number studied (126 at nominal significance) implicating genes involved in myelination ( SEMA3A ), neurite elongation guidance NUAK1 , STRN DPYSL2 EPHA3 HGF SHTN1 neural cell proliferation differentiation GMNC CELF4 neuronal migration CCDC88C cytoskeletal CTTNBP2 MAPT DAAM1 MYO16 PLEC metal transport SLC39A8 ). These have four broad patterns spatial with connectivity: some disproportionately strong associations corticothalamic connectivity, interhemispheric both, while others are more spatially diffuse. Structural highly polygenic, median 9.1 percent common estimated to non-zero effects on measure, exhibited signatures negative selection. genetic correlations variety neuropsychiatric cognitive traits, indicating connectivity-altering tend influence health function. Heritability is enriched regions increased chromatin accessibility adult oligodendrocytes (as well as microglia, inhibitory neurons astrocytes) multiple fetal types, suggesting control partially mediated by early development. Our results indicate pervasive, pleiotropic, structured white-matter via diverse neurodevelopmental pathways, support relevance this healthy

Language: Английский

Citations

20
Efficacy of MRI data harmonization in the age of machine learning: a multicenter study across 36 datasets DOI Creative Commons
Chiara Marzi, Marco Giannelli, Andrea Barucci

et al.

Scientific Data, Journal Year: 2024, Volume and Issue: 11(1)

Published: Jan. 23, 2024

Abstract Pooling publicly-available MRI data from multiple sites allows to assemble extensive groups of subjects, increase statistical power, and promote reuse with machine learning techniques. The harmonization multicenter is necessary reduce the confounding effect associated non-biological sources variability in data. However, when applied entire dataset before learning, leads leakage, because information outside training set may affect model building, potentially falsely overestimate performance. We propose a 1) measurement efficacy harmonization; 2) harmonizer transformer, i.e., an implementation ComBat allowing its encapsulation among preprocessing steps pipeline, avoiding leakage by design. tested these tools using brain T 1 -weighted 1740 healthy subjects acquired at 36 sites. After harmonization, site was removed or reduced, we showed predicting individual age data, highlighting that introducing transformer into pipeline for

Language: Английский

Citations

17
Pilot work of the 10K Chinese People Genomic Diversity Project along the Silk Road suggests a complex east-west admixture landscape and biological adaptations DOI
Guanglin He,

Hongbing Yao,

Shuhan Duan

et al.

Science China Life Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Language: Английский

Citations

4
Association and shared biological bases between birth weight and cortical structure DOI Creative Commons
Lu Zhang, Qiaoyue Ge, Zeyuan Sun

et al.

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

Published: March 5, 2025

Associations between birth weight and cortical structural phenotypes have been detected; however, the understanding is incomprehensive, potential biological bases are not well defined. Leveraging data from genome-wide association studies, we investigated associations shared transcriptomic, proteomic cellular of 13 phenotypes. Mendelian randomization analyses were performed to examine structure. Downstream transcriptome-wide study (TWAS), proteome-wide (PWAS) summary-based (SMR) utilized identify cis-regulated gene expressions proteins. Finally, cell-type expression-specific integration for complex traits (CELLECT) conducted explore enriched cell types. The found positive global folding index, intrinsic curvature local gyrification surface area volume. transcriptomic-level TWAS SMR identified three both linked at least one phenotype (CNNM2, RABGAP1 CENPW). Parallel PWAS level four proteins RAB7L1, RAB5B PPA2), which CNNM2 was replicated. CELLECT revealed brain types in weight, including pericytes, inhibitory GABAergic neurons cerebrovascular cells. These findings support importance early life growth structure, suggest underlying bases. results provide intriguing targets further research into mechanisms development.

Language: Английский

Citations

2
Toward Best Practices for Imaging Transcriptomics of the Human Brain DOI Creative Commons
Aurina Arnatkevičiūtė, Ross D. Markello, Ben Fulcher

et al.

Biological Psychiatry, Journal Year: 2022, Volume and Issue: 93(5), P. 391 - 404

Published: Nov. 5, 2022

Language: Английский

Citations

49