Biology subjects

Ibanez, L.

Publications and source records attributed to Ibanez, L..

12 recordsLinked to original sources

bioRxiv2026

Parietal Cortex Transcriptomics Refines Parkinson Disease GWAS Nomination and Highlights STAT3 as a Putative Upstream Glial Regulator

Parkinson disease (PD) affects more than 1.1 million individuals in the United States and around 12 million worldwide. Although Genome Wide Association Studies (GWAS) have substantially advanced our understanding of PD genetic architecture, the regulatory mechanisms linking PD risk loci to disease-relevant gene expression remain incompletely characterized, limiting our ability to infer disease mechanisms from genetic associations. Here, we integrated disease-state parietal cortex transcriptomics with the International Parkinsons Disease Genomics Consortium (iPDGC) locus prioritization to refine PD gene nomination and identify biologically plausible candidates missed by GWAS-only approaches. Using bulk RNA-seq from 99 neuropathologically confirmed PD cases and 30 neuropathologically confirmed controls, we prioritized candidate genes across 78 loci and classified them according to concordance between genetic evidence and differential expression in diseased cortices. This integrative approach recovered candidate genes not captured by external GWAS-based prioritization methods and highlighted synaptic, lysosomal, and proteostasis pathways as major components of PD risk biology. Network and transcription factor analyses further suggested coordinated regulation of these genes, with STAT3 emerging as a putative upstream glial regulator. Together, these findings suggest that integrating disease-state transcriptomics with genetic prioritization can refine PD risk-gene nomination and uncover regulatory programs that may be missed by GWAS alone.

neuroscience↗

bioRxiv2026

Biomarker Variability Limits Individualized Amyloid Time Estimation in Alzheimer Disease

ObjectiveDisease progression modeling (DPM) or "amyloid time" is increasingly used to stage Alzheimer disease (AD). DPM performance depends on within-individual heterogeneity in rates of pathological accumulation as well as test-retest reliability of the biomarker. The relative contributions of these variabilities have not been systematically assessed. This would be particularly relevant if extrapolations from DPM were to be used to make individual-level predictions for research, clinical trials, or potentially future clinical practice. MethodsWe conducted simulation studies incorporating empirically-derived noise properties from amyloid biomarkers to assess the contributions of inter- and intra-individual variability. Findings generalized in an autosomal dominant AD cohort with amyloid positron emission tomography (PET), cerebrospinal fluid (CSF), and plasma biomarkers and in a sporadic AD cohort with both amyloid PET and plasma biomarkers. We assessed group level DPM performance via mean average error (MAE) and root mean squared error (RMSE). At the individual level, we evaluated distinctness of distributions of biomarker levels associated with specific disease timings. ResultsInter-individual variability was the dominant source of error in temporal estimates. Intra-individual variability reduced estimate stability. Optimal performance occurred in biomarkers with positive average accumulation rates where a subset of individuals had exceptionally high levels of accumulation. In research study data, amyloid PET outperformed CSF and plasma biomarkers. InterpretationDPM is fundamentally constrained by dynamic range, variability, and test-retest reliability of the biomarker of interest. Current DPM approaches are more robust at the group level, particularly when applied to biomarkers with more than 10-15% variability like fluid biomarkers. FundingNational Institute on Aging, Alzheimers Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Korean Ministry of Health & Welfare and Ministry of Science and ICT, Spanish Institute of Health.

bioinformatics↗

bioRxiv2023

Increasing hub disruption parallels dementia severity in autosomal dominant Alzheimer disease

Hub regions in the brain, recognized for their roles in ensuring efficient information transfer, are vulnerable to pathological alterations in neurodegenerative conditions, including Alzheimer Disease (AD). Given their essential role in neural communication, disruptions to these hubs have profound implications for overall brain network integrity and functionality. Hub disruption, or targeted impairment of functional connectivity at the hubs, is recognized in AD patients. Computational models paired with evidence from animal experiments hint at a mechanistic explanation, suggesting that these hubs may be preferentially targeted in neurodegeneration, due to their high neuronal activity levels--a phenomenon termed "activity-dependent degeneration". Yet, two critical issues were unresolved. First, past research hasnt definitively shown whether hub regions face a higher likelihood of impairment (targeted attack) compared to other regions or if impairment likelihood is uniformly distributed (random attack). Second, human studies offering support for activity-dependent explanations remain scarce. We applied a refined hub disruption index to determine the presence of targeted attacks in AD. Furthermore, we explored potential evidence for activity-dependent degeneration by evaluating if hub vulnerability is better explained by global connectivity or connectivity variations across functional systems, as well as comparing its timing relative to amyloid beta deposition in the brain. Our unique cohort of participants with autosomal dominant Alzheimer Disease (ADAD) allowed us to probe into the preclinical stages of AD to determine the hub disruption timeline in relation to expected symptom emergence. Our findings reveal a hub disruption pattern in ADAD aligned with targeted attacks, detectable even in pre-clinical stages. Notably, the disruptions severity amplified alongside symptomatic progression. Moreover, since excessive local neuronal activity has been shown to increase amyloid deposition and high connectivity regions show high level of neuronal activity, our observation that hub disruption was primarily tied to regional differences in global connectivity and sequentially followed changes observed in A{beta} PET cortical markers is consistent with the activity-dependent degeneration model. Intriguingly, these disruptions were discernible 8 years before the expected age of symptom onset. Taken together, our findings not only align with the targeted attack on hubs model but also suggest that activity-dependent degeneration might be the cause of hub vulnerability. This deepened understanding could be instrumental in refining diagnostic techniques and developing targeted therapeutic strategies for AD in the future.

neuroscience↗

bioRxiv2022

Specific targeting of inflammatory osteoclastogenesis by the probiotic yeast S. boulardii CNCM I-745 reduces bone loss in osteoporosis

Bone destruction is a hallmark of chronic inflammation, and bone-resorbing osteoclasts arising under such a condition differ from steady-state ones. However, osteoclast diversity remains poorly explored. Here, we combined transcriptomic profiling, differentiation assays and in vivo analysis in mouse to decipher specific traits for inflammatory and steady state osteoclasts. We identified and validated the pattern-recognition receptors (PRR) TLR2, Dectin-1 and Mincle, all involved in yeast recognition as major regulators of inflammatory osteoclasts. We showed that administration of the yeast probiotic Saccharomyces boulardi CNCM I-745 (Sb) in vivo reduced bone loss in OVX but not sham mice by reducing inflammatory osteoclasts. This beneficial impact of Sb is mediated by the regulation of the inflammatory environment required for the generation of inflammatory osteoclasts. We also showed that Sb derivatives as well as agonists of TLR2, Dectin-1 and Mincle specifically inhibited directly the differentiation of inflammatory but not steady state osteoclasts in vitro. These findings demonstrate a preferential use of the PRR-associated costimulatory differentiation pathway by inflammatory osteoclasts, thus enabling their specific inhibition, which opens new therapeutic perspectives for inflammatory bone loss.

physiology↗

bioRxiv2020

Osteoclasts contribute to early development of chronic inflammation by promoting dysregulated hematopoiesis and myeloid skewing

Increased myelopoiesis is a hallmark of many chronic inflammatory diseases. However, the mechanisms involved in the myeloid skewing of hematopoiesis upon inflammation are still incompletely understood. Here, we identify an unexpected role of bone-resorbing osteoclasts in promoting hematopoietic stem cell (HSC) proliferation and differentiation towards myeloipoiesis in the early phases of chronic colitis. RNAseq analysis revealed that osteoclasts in colitis differ from control ones and overexpress genes involved in the remodeling of HSC niches. We showed that colitic osteoclasts modulate the interaction of HSCs with their niche and promote myeloid differentiation. Increased osteoclast activity was correlated with an augmentation of myelopoiesis in patients with chronic colitis. Therapeutic blockade of osteoclasts reduced HSC proliferation and myeloid skewing and resulted in a decreased inflammation and severity of colitis. Together, these data identify osteoclasts as potent regulators of HSCs and promising target in chronic colitis.

immunology↗

bioRxiv2019

Overlapping Genetic Architecture between Parkinson Disease and Melanoma

Epidemiologic studies have reported inconsistent results regarding an association between Parkinson disease (PD) and cutaneous melanoma (melanoma). Identifying shared genetic architecture between these diseases can support epidemiologic findings and identify common risk genes and biological pathways. Here we apply polygenic, linkage disequilibrium-informed methods to the largest available case-control, genome-wide association study summary statistic data for melanoma and PD. We identify positive and significant genetic correlation (correlation: 0.17, 95% CI 0.10 to 0.24; P = 4.09 x 10-06) between melanoma and PD. We further demonstrate melanoma and PD-inferred gene expression to overlap across tissues (correlation: 0.14, 95% CI 0.06 to 0.22; P = 7.87 x 10-04), and highlight seven genes including PIEZO1, TRAPPC2L, and SOX6 as potential mediators of the genetic correlation between melanoma and PD. These findings demonstrate specific, shared genetic architecture between PD and melanoma that manifests at the level of gene expression.

genetics↗

bioRxiv2019

Single- nuclei RNA sequencing from human brain to study for Mendelian and sporadic AD

Alzheimer Disease (AD) is the most common form of dementia. This neurodegenerative disorder is associated with neuronal death and gliosis heavily impacting the cerebral cortex. AD has a substantial but heterogeneous genetic component, presenting both Mendelian and complex genetic architectures. Using bulk RNA-seq from parietal lobes and deconvolution methods, we previously reported that brains exhibiting different AD genetic architecture exhibit different cellular proportions. Here, we sought to directly investigate AD brain changes in cell proportion and gene expression using single cell resolution. To do so, we generated unsorted single-nuclei RNA-sequencing data from brain tissue. We leveraged tissue donated from a carrier of a Mendelian genetic mutation and two family members who suffer from AD, but do not have the same mutation. We evaluated alternative alignment approaches to maximize the titer of reads, genes and cells with high quality. In addition, we employed distinct clustering strategies to determine the best approach to identify cell clusters that reveal neuronal and glial cell types and avoid artifacts such as sample and batch effects. We propose an approach to cluster cells that reduces biases and enable further analyses. We identified distinct types of neurons, both excitatory and inhibitory, and glial cells, including astrocytes, oligodendrocytes, and microglia among others. In particular, we identified a reduced proportion of excitatory neurons in the Mendelian mutation carrier, but a similar distribution of inhibitory neurons. Furthermore, we investigated whether single-nuclei RNA-seq from human brains recapitulate the expression profile of Disease Associated Microglia (DAM) discovered in mouse models. We also determined that when analyzing human single-nuclei data it is critical to control for biases introduced by donor specific expression profiles. In conclusion, we propose a collection of best practices to generate a highly-detailed molecular cell atlas of highly informative frozen tissue stored in brain banks. Importantly, we have developed a new web application to make this unique single-nuclei molecular atlas publicly available.

genomics↗

bioRxiv2019

The TMEM106B rs1990621 protective variant is also associated with increased neuronal proportion

BackgroundIn previous studies, we observed decreased neuronal and increased astrocyte proportions in AD cases in parietal brain cortex by using a deconvolution method for bulk RNA-seq. These findings suggested that genetic risk factors associated with AD etiology have a specific effect in the cellular composition of AD brains. The goal of this study is to investigate if there are genetic determinants for brain cell compositions.\n\nMethodsUsing cell type composition inferred from transcriptome as a disease status proxy, we performed cell type association analysis to identify novel loci related to cellular population changes in disease cohort. We imputed and merged genotyping data from seven studies in total of 1,669 samples and derived major CNS cell type proportions from cortical RNAseq data. We also inferred RNA transcript integrity number (TIN) to account for RNA quality variances. The model we performed in the analysis was: normalized neuronal proportion [~] SNP + Age + Gender + PC1 + PC2 + median TIN.\n\nResultsA variant rs1990621 located in the TMEM106B gene region was significantly associated with neuronal proportion (p=6.40x10-07) and replicated in an independent dataset. The association became more significant as we combined both discovery and replication datasets in multi-tissue meta-analysis (p=9.42x10-09) and joint analysis (p=7.66x10-10). This variant is in high LD with rs1990622 (r2 = 0.98) which was previously identified as a protective variant in FTD cohorts. Further analyses indicated that this variant is associated with increased neuronal proportion in participants with neurodegenerative disorders, not only in AD cohort but also in cognitive normal elderly cohort. However, this effect was not observed in a younger schizophrenia cohort with a mean age of death < 65. The second most significant loci for neuron proportion was APOE, which suggested that using neuronal proportion as an informative endophenotype could help identify loci associated with neurodegeneration.\n\nConclusionThis result suggested a common pathway involving TMEM106B shared by aging groups in the present or absence of neurodegenerative pathology may contribute to cognitive preservation and neuronal protection.

neuroscience↗

bioRxiv2018

The MS4A gene cluster is a key regulator of soluble TREM2 and Alzheimer disease risk

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) levels in the cerebrospinal fluid (CSF) have been associated with Alzheimer disease (AD) status. TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may help reveal biological mechanisms underlying AD and identify novel therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 levels. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with higher CSF sTREM2 levels (rs1582763; P = 1.15x10-15) and replicated in independent datasets. The variants associated with increased levels of sTREM2 are also associated with reduced AD risk and delayed age-at-onset. Rs1582763 influences expression of MS4A4A and MS4A6A in multiple tissues, suggesting that one or both of these genes are important for regulating sTREM2. MS4A genes encode transmembrane proteins that may play a role in intracellular protein trafficking in microglia. We used human macrophages to begin to test the relationship between MS4A4A and TREM2 and found that they co-localize intracellularly and that antibody-mediated targeting of MS4A4A reduces sTREM2. Thus, genetic, molecular, and cellular findings suggest that MS4A4A regulates sTREM2. These findings also provide a mechanistic explanation of the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 is involved in sporadic AD risk in general, not only in TREM2 risk-variant carriers.

genomics↗

bioRxiv2018

Evaluation of gene-based family-based methods to detect novel genes associated with familial late onset Alzheimer disease

Gene-based tests to study the combined effect of rare variants towards a particular phenotype have been widely developed for case-control studies, but their evolution and adaptation for family-based studies, especially for complex incomplete families, has been slower. In this study, we have performed a practical examination of all the latest gene-based methods available for family-based study designs using both simulated and real datasets. We have examined the performance of several collapsing, variance-component and transmission disequilibrium tests across eight different software and twenty-two models utilizing a cohort of 285 families (N=1,235) with late-onset Alzheimer disease (LOAD). After a thorough examination of each of these tests, we propose a methodological approach to identify, with high confidence, genes associated with the studied phenotype with high confidence and we provide recommendations to select the best software and model for family-based gene-based analyses. Additionally, in our dataset, we identified PTK2B, a GWAS candidate gene for sporadic AD, along with six novel genes (CHRD, CLCN2, HDLBP, CPAMD8, NLRP9, MAS1L) as candidates genes for familial LOAD.

genetics↗

bioRxiv2017

Polygenic Risk Score of Sporadic Late Onset Alzheimer Disease Reveals a Shared Architecture with the Familial and Early Onset Forms

ObjectiveTo determine whether the genetic architecture of sporadic late-onset Alzheimers Disease (sLOAD) has an effect on familial late-onset AD (fLOAD), sporadic early-onset (sEOAD) and autosomal dominant early-onset (eADAD).\n\nMethodsPolygenic risk scores (PRS) were constructed using previously identified 21 genome-wide significant loci for LOAD risk.\n\nResultsWe found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. sEOAD showed the highest odds for the PRS (OR=2.27; p=1.29x10-7), followed by fLOAD (OR=1.75; p=1.12x10-7) and sLOAD (OR=1.40; p=1.21x10-3). PRS is associated with cerebrospinal fluid ptau181-A{beta}42 on eADAD.\n\nConclusionOur analysis confirms that the genetic factors identified for sLOAD also modulate risk in fLOAD and sEOAD cohorts. Furthermore, our results suggest that the burden of these risk variants is associated with familial clustering and earlier-onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset.

genetics↗

bioRxiv2017

A common haplotype lowers SPI1 (PU.1) expression in myeloid cells and delays age at onset for Alzheimer’s disease

In this study we used age at onset of Alzheimers disease (AD), cerebrospinal fluid (CSF) biomarkers, and cis-expression quantitative trait loci (cis-eQTL) datasets to identify candidate causal genes and mechanisms underlying AD GWAS loci. In a genome-wide survival analysis of 40,255 samples, eight of the previously reported AD risk loci are significantly (P < 5x10-8) or suggestively (P < 1x10-5) associated with age at onset-defined survival (AAOS) and a further fourteen novel loci reached suggestive significance. Using stratified LD score regression we demonstrated a significant enrichment of AD heritability in hematopoietic cells of the myeloid and B-lymphoid lineage. We then investigated the impact of these 22 AAOS-associated variants on CSF biomarkers and gene expression in cells of the myeloid lineage. In particular, the minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, shows association with higher age at onset of AD (P=8.40x10-6), higher CSF levels of A{beta}42 (P=1.2x10-4), and lower expression of SPI1 in monocytes (P=1.50x10-105) and macrophages (P=6.41x10-87). SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability is enriched within the SPI1 cistromes of monocytes and macrophages, implicating a myeloid PU.1 target gene network in the etiology of AD. Finally, experimentally altered PU.1 levels are correlated with phagocytic activity of BV2 mouse microglial cells and specific changes in the expression of multiple myeloid-expressed genes, including the mouse orthologs of AD-associated genes, APOE, CLU/APOJ, CD33, MS4A4A/MS4A6A, and TYROBP. Our results collectively suggest that lower SPI1 expression reduces AD risk by modulating myeloid cell gene expression and function.

neuroscience↗