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Your search keyword '"Eduardo Pérez-Palma"' showing total 53 results
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53 results on '"Eduardo Pérez-Palma"'

51. Overrepresentation of Glutamate Signaling in Alzheimer's Disease: Network-Based Pathway Enrichment Using Meta-Analysis of Genome-Wide Association Studies

Author

Camilo F. Villamán, Eduardo Pérez-Palma, Miguel E. Avila, Ariel E. Reyes, Giorgia D. Ugarte, Giancarlo V. De Ferrari, Carlos Opazo, Marcelo A. Alarcón, Bernabé I. Bustos, and Potash, James Bennett

Subjects
Apolipoprotein E, Aging, Gene regulatory network, lcsh:Medicine, Genome-wide association study, Neurodegenerative, Alzheimer's Disease, Biochemistry, Learning and Memory, Glutamates, Molecular Cell Biology, Neurobiology of Disease and Regeneration, Medicine and Health Sciences, 2.1 Biological and endogenous factors, Gene Regulatory Networks, Aetiology, lcsh:Science, Genetics, Multidisciplinary, Brain, Neurochemistry, Neurodegenerative Diseases, Neurotransmitters, Genomics, 3. Good health, Neurology, Research Design, Physical Sciences, Neurological, Glutamate, Neurochemicals, Alzheimer's disease, Statistics (Mathematics), Research Article, Biotechnology, Alzheimer's Disease Neuroimaging Initiative, Signal Transduction, Clinical Research Design, General Science & Technology, Neuropsychiatric Disorders, Locus (genetics), Neuroimaging, Biology, Research and Analysis Methods, Alzheimer Disease, Mental Health and Psychiatry, Genetic variation, Genome-Wide Association Studies, Acquired Cognitive Impairment, medicine, Humans, Statistical Methods, Genetic association, Prevention, lcsh:R, Human Genome, Neurosciences, Biology and Life Sciences, Computational Biology, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Reproducibility of Results, Human Genetics, Cell Biology, Genome Analysis, medicine.disease, Brain Disorders, Gene Ontology, Gene Expression Regulation, Genetics of Disease, Synapses, NIA-LOAD/NCRAD Family Study Group, lcsh:Q, Dementia, Mathematics, Neuroscience, Meta-Analysis, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWAS) have successfully identified several risk loci for Alzheimer's disease (AD). Nonetheless, these loci do not explain the entire susceptibility of the disease, suggesting that other genetic contributions remain to be identified. Here, we performed a meta-analysis combining data of 4,569 individuals (2,540 cases and 2,029 healthy controls) derived from three publicly available GWAS in AD and replicated a broad genomic region (>248,000 bp) associated with the disease near the APOE/TOMM40 locus in chromosome 19. To detect minor effect size contributions that could help to explain the remaining genetic risk, we conducted network-based pathway analyses either by extracting gene-wise p-values (GW), defined as the single strongest association signal within a gene, or calculated a more stringent gene-based association p-value using the extended Simes (GATES) procedure. Comparison of these strategies revealed that ontological sub-networks (SNs) involved in glutamate signaling were significantly overrepresented in AD (p

Published
2014
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52. A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer's disease

Author

Marcelo A. Alarcón, Giorgia D. Ugarte, Paulina Salazar, Matías A. Medina, Randall T. Moon, Alexis Peralta, Bernabé I. Bustos, Giancarlo V. De Ferrari, George M. Martin, Carlos Opazo, Qubai Hu, Ariel E. Reyes, Miguel E. Avila, and Eduardo Pérez-Palma

Subjects
Gene isoform, Male, Aging, Single-nucleotide polymorphism, Biology, Exon, Mice, Alzheimer Disease, Animals, Humans, Protein Isoforms, Gene, Wnt Signaling Pathway, Genetic Association Studies, Aged, Aged, 80 and over, General Neuroscience, Alternative splicing, Wnt signaling pathway, LRP6, Middle Aged, Molecular biology, Alternative Splicing, HEK293 Cells, Low Density Lipoprotein Receptor-Related Protein-6, LDL receptor, Female, Neurology (clinical), Geriatrics and Gerontology, Developmental Biology
Abstract

We previously found that single nucleotide polymorphisms in the low-density lipoprotein receptor-related protein 6 (LRP6) gene are associated with Alzheimer's disease (AD). Here, we studied the posttranscriptional metabolism of the LRP6 message scanning sequentially the 23 LRP6 exons in human tissues and found a novel LRP6 isoform that completely skips exon 3 (LRP6Δ3) in all tissues examined and was also conserved in mice. Expression levels of the LRP6 isoforms were determined in 47 cortical brain messenger (m)RNA samples including 22 AD cases, 11 control subjects, and 14 individuals with other neurological disorders. LRP6Δ3 mRNA levels were significantly augmented in AD brains compared with controls (1.6-fold; p = 0.037) or other pathological samples (2-fold; p = 0.007). Functional analysis in Wnt/β-catenin signaling assays revealed that skipping of exon 3 reduced significantly the signaling activity of the LRP6 coreceptor. We conclude that the LRP6Δ3 isoform is a novel splice variant, which shows diminished Wnt/β-catenin signaling activity and might have a functional role in individuals with AD.

Published
2012

53. Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders

Author

Dennis Lal, Patrick May, Eduardo Perez-Palma, Kaitlin E. Samocha, Jack A. Kosmicki, Elise B. Robinson, Rikke S. Møller, Roland Krause, Peter Nürnberg, Sarah Weckhuysen, Peter De Jonghe, Renzo Guerrini, Lisa M. Niestroj, Juliana Du, Carla Marini, EuroEPINOMICS-RES Consortium, James S. Ware, Mitja Kurki, Padhraig Gormley, Sha Tang, Sitao Wu, Saskia Biskup, Annapurna Poduri, Bernd A. Neubauer, Bobby P. C. Koeleman, Katherine L. Helbig, Yvonne G. Weber, Ingo Helbig, Amit R. Majithia, Aarno Palotie, and Mark J. Daly

Subjects
Paralogs, Gene family, Conservation, Missense variants, Neurodevelopmental disorders, Medicine, Genetics, QH426-470
Abstract

Abstract Background Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene families. The use of gene family information for disease gene discovery and variant interpretation has not yet been investigated on a genome-wide scale. We empirically evaluate whether paralog-conserved or non-conserved sites in human gene families are important in NDDs. Methods Gene family information was collected from Ensembl. Paralog-conserved sites were defined based on paralog sequence alignments; 10,068 NDD patients and 2078 controls were statistically evaluated for de novo variant burden in gene families. Results We demonstrate that disease-associated missense variants are enriched at paralog-conserved sites across all disease groups and inheritance models tested. We developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in NDD patients of which 28 represent novel candidate genes for NDD which are brain expressed and under evolutionary constraint. Conclusion This study represents the first method to incorporate gene family information into a statistical framework to interpret variant data for NDDs and to discover new NDD-associated genes.

Published
2020
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