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Familial Alzheimer’s Disease and Recessive Modifiers

Alzheimer’s disease (AD) is progressive brain disorder that affects ~ 50 million people worldwide and has no current effective treatment. AD age of onset (ADAOO) has shown to be critical for the identification of genes that modify the appearance of AD signs and symptoms in a specific population. We...

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Autores principales: Vélez, Jorge I., Lopera, Francisco, Silva, Claudia T., Villegas, Andrés, Espinosa, Lady G., Vidal, Oscar M., Mastronardi, Claudio A., Arcos-Burgos, Mauricio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031188/
https://www.ncbi.nlm.nih.gov/pubmed/31664702
http://dx.doi.org/10.1007/s12035-019-01798-0
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author Vélez, Jorge I.
Lopera, Francisco
Silva, Claudia T.
Villegas, Andrés
Espinosa, Lady G.
Vidal, Oscar M.
Mastronardi, Claudio A.
Arcos-Burgos, Mauricio
author_facet Vélez, Jorge I.
Lopera, Francisco
Silva, Claudia T.
Villegas, Andrés
Espinosa, Lady G.
Vidal, Oscar M.
Mastronardi, Claudio A.
Arcos-Burgos, Mauricio
author_sort Vélez, Jorge I.
collection PubMed
description Alzheimer’s disease (AD) is progressive brain disorder that affects ~ 50 million people worldwide and has no current effective treatment. AD age of onset (ADAOO) has shown to be critical for the identification of genes that modify the appearance of AD signs and symptoms in a specific population. We clinically characterized and whole-exome genotyped 71 individuals with AD from the Paisa genetic isolate, segregating the (PSEN1) E280A dominant fully penetrant mutation, and analyzed the potential recessive effects of ~ 50,000 common functional genomic variants to the ADAOO. Standard quality control and filtering procedures were applied, and recessive single- and multi-locus linear mixed-effects models were used. We identified genetic variants in the SLC9C1, CSN1S1, and LOXL4 acting recessively to delay ADAOO up to ~ 11, ~ 6, and ~ 9 years on average, respectively. In contrast, the CC recessive genotype in marker DHRS4L2-rs2273946 accelerates ADAOO by ~ 8 years. This study, reports new recessive variants modifying ADAOO in PSEN1 E280A mutation carriers. This set of genes are implicated in important biological processes and molecular functions commonly affected by genes associated with the etiology of AD such as APP, APOE, and CLU. Future functional studies using modern techniques such as induced pluripotent stem cells will allow a better understanding of the over expression and down regulation of these recessive modifier variants and hence the pathogenesis of AD. These results are important for prediction of AD and ultimately, substantial to develop new therapeutic strategies for individuals at risk or affected by AD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12035-019-01798-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-70311882020-03-03 Familial Alzheimer’s Disease and Recessive Modifiers Vélez, Jorge I. Lopera, Francisco Silva, Claudia T. Villegas, Andrés Espinosa, Lady G. Vidal, Oscar M. Mastronardi, Claudio A. Arcos-Burgos, Mauricio Mol Neurobiol Article Alzheimer’s disease (AD) is progressive brain disorder that affects ~ 50 million people worldwide and has no current effective treatment. AD age of onset (ADAOO) has shown to be critical for the identification of genes that modify the appearance of AD signs and symptoms in a specific population. We clinically characterized and whole-exome genotyped 71 individuals with AD from the Paisa genetic isolate, segregating the (PSEN1) E280A dominant fully penetrant mutation, and analyzed the potential recessive effects of ~ 50,000 common functional genomic variants to the ADAOO. Standard quality control and filtering procedures were applied, and recessive single- and multi-locus linear mixed-effects models were used. We identified genetic variants in the SLC9C1, CSN1S1, and LOXL4 acting recessively to delay ADAOO up to ~ 11, ~ 6, and ~ 9 years on average, respectively. In contrast, the CC recessive genotype in marker DHRS4L2-rs2273946 accelerates ADAOO by ~ 8 years. This study, reports new recessive variants modifying ADAOO in PSEN1 E280A mutation carriers. This set of genes are implicated in important biological processes and molecular functions commonly affected by genes associated with the etiology of AD such as APP, APOE, and CLU. Future functional studies using modern techniques such as induced pluripotent stem cells will allow a better understanding of the over expression and down regulation of these recessive modifier variants and hence the pathogenesis of AD. These results are important for prediction of AD and ultimately, substantial to develop new therapeutic strategies for individuals at risk or affected by AD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12035-019-01798-0) contains supplementary material, which is available to authorized users. Springer US 2019-10-29 2020 /pmc/articles/PMC7031188/ /pubmed/31664702 http://dx.doi.org/10.1007/s12035-019-01798-0 Text en © The Author(s) 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Article
Vélez, Jorge I.
Lopera, Francisco
Silva, Claudia T.
Villegas, Andrés
Espinosa, Lady G.
Vidal, Oscar M.
Mastronardi, Claudio A.
Arcos-Burgos, Mauricio
Familial Alzheimer’s Disease and Recessive Modifiers
title Familial Alzheimer’s Disease and Recessive Modifiers
title_full Familial Alzheimer’s Disease and Recessive Modifiers
title_fullStr Familial Alzheimer’s Disease and Recessive Modifiers
title_full_unstemmed Familial Alzheimer’s Disease and Recessive Modifiers
title_short Familial Alzheimer’s Disease and Recessive Modifiers
title_sort familial alzheimer’s disease and recessive modifiers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031188/
https://www.ncbi.nlm.nih.gov/pubmed/31664702
http://dx.doi.org/10.1007/s12035-019-01798-0
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