Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer's Disease

Jorge I. Velez, Francisco Lopera, Penelope K. Creagh, Claudia Tamar Silva Aldana, Gustavo A. Quintero, Laura Piñeros, C. Mastronardi, Mauricio Arcos-Burgos, Debjani Das, Martha L. Cervantes-Henríquez, Johan E. Acosta-López, Mario A. Isaza-Ruget, Lady G. Espinosa, Simon Easteal

Resultado de la investigación: Contribución a RevistaArtículo

Resumen

The identification of novel genetic variants contributing to the widespread in the age of onset (AOO) of Alzheimer's disease (AD) could aid in the prognosis and/or development of new therapeutic strategies focused on early interventions. We recruited 78 individuals with AD from the Paisa genetic isolate in Antioquia, Colombia. These individuals belong to the world largest multigenerational and extended pedigree segregating AD as a consequence of a dominant fully penetrant mutation in the PSEN1 gene and exhibit an AOO ranging from the early 1930s to the late 1970s. To shed light on the genetic underpinning that could explain the large spread of the age of onset (AOO) of AD, 64 single nucleotide polymorphisms (SNP) associated with neuroanatomical, cardiovascular, and cognitive measures in AD were genotyped. Standard quality control and filtering procedures were applied, and single- and multi-locus linear mixed-effects models were used to identify AOO-associated SNPs. A full two-locus interaction model was fitted to define how identified SNPs interact to modulate AOO. We identified two key epistatic interactions between the APOE*E2 allele and SNPs ASTN2-rs7852878 and SNTG1-rs16914781 that delay AOO by up to ~ 8 years (95% CI 3.2-12.7, P = 1.83 × 10-3) and ~ 7.6 years (95% CI 3.3-11.8, P = 8.69 × 10-4), respectively, and validated our previous finding indicating that APOE*E2 delays AOO of AD in PSEN1 E280 mutation carriers. This new evidence involving APOE*E2 as an AOO delayer could be used for developing precision medicine approaches and predictive genomics models to potentially determine AOO in individuals genetically predisposed to AD.
Idioma originalEnglish (US)
Páginas (desde-hasta)3235-3243
Número de páginas9
PublicaciónMolecular Neurobiology
Volumen56
N.º5
EstadoPublished - ago 15 2018

Citar esto

Velez, J. I., Lopera, F., Creagh, P. K., Silva Aldana, C. T., Quintero, G. A., Piñeros, L., ... Easteal, S. (2018). Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer's Disease. Molecular Neurobiology, 56(5), 3235-3243.
Velez, Jorge I. ; Lopera, Francisco ; Creagh, Penelope K. ; Silva Aldana, Claudia Tamar ; Quintero, Gustavo A. ; Piñeros, Laura ; Mastronardi, C. ; Arcos-Burgos, Mauricio ; Das, Debjani ; Cervantes-Henríquez, Martha L. ; Acosta-López, Johan E. ; Isaza-Ruget, Mario A. ; Espinosa, Lady G. ; Easteal, Simon. / Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer's Disease. En: Molecular Neurobiology. 2018 ; Vol. 56, N.º 5. pp. 3235-3243.
@article{1f6afae041464ca59fdc3b5eae73a9b1,
title = "Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer's Disease",
abstract = "The identification of novel genetic variants contributing to the widespread in the age of onset (AOO) of Alzheimer's disease (AD) could aid in the prognosis and/or development of new therapeutic strategies focused on early interventions. We recruited 78 individuals with AD from the Paisa genetic isolate in Antioquia, Colombia. These individuals belong to the world largest multigenerational and extended pedigree segregating AD as a consequence of a dominant fully penetrant mutation in the PSEN1 gene and exhibit an AOO ranging from the early 1930s to the late 1970s. To shed light on the genetic underpinning that could explain the large spread of the age of onset (AOO) of AD, 64 single nucleotide polymorphisms (SNP) associated with neuroanatomical, cardiovascular, and cognitive measures in AD were genotyped. Standard quality control and filtering procedures were applied, and single- and multi-locus linear mixed-effects models were used to identify AOO-associated SNPs. A full two-locus interaction model was fitted to define how identified SNPs interact to modulate AOO. We identified two key epistatic interactions between the APOE*E2 allele and SNPs ASTN2-rs7852878 and SNTG1-rs16914781 that delay AOO by up to ~ 8 years (95{\%} CI 3.2-12.7, P = 1.83 × 10-3) and ~ 7.6 years (95{\%} CI 3.3-11.8, P = 8.69 × 10-4), respectively, and validated our previous finding indicating that APOE*E2 delays AOO of AD in PSEN1 E280 mutation carriers. This new evidence involving APOE*E2 as an AOO delayer could be used for developing precision medicine approaches and predictive genomics models to potentially determine AOO in individuals genetically predisposed to AD.",
author = "Velez, {Jorge I.} and Francisco Lopera and Creagh, {Penelope K.} and {Silva Aldana}, {Claudia Tamar} and Quintero, {Gustavo A.} and Laura Pi{\~n}eros and C. Mastronardi and Mauricio Arcos-Burgos and Debjani Das and Cervantes-Henr{\'i}quez, {Martha L.} and Acosta-L{\'o}pez, {Johan E.} and Isaza-Ruget, {Mario A.} and Espinosa, {Lady G.} and Simon Easteal",
year = "2018",
month = "8",
day = "15",
language = "English (US)",
volume = "56",
pages = "3235--3243",
journal = "Molecular Neurobiology",
issn = "0893-7648",
publisher = "Humana Press Inc.",
number = "5",

}

Velez, JI, Lopera, F, Creagh, PK, Silva Aldana, CT, Quintero, GA, Piñeros, L, Mastronardi, C, Arcos-Burgos, M, Das, D, Cervantes-Henríquez, ML, Acosta-López, JE, Isaza-Ruget, MA, Espinosa, LG & Easteal, S 2018, 'Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer's Disease', Molecular Neurobiology, vol. 56, n.º 5, pp. 3235-3243.

Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer's Disease. / Velez, Jorge I.; Lopera, Francisco; Creagh, Penelope K.; Silva Aldana, Claudia Tamar; Quintero, Gustavo A.; Piñeros, Laura ; Mastronardi, C.; Arcos-Burgos, Mauricio; Das, Debjani; Cervantes-Henríquez, Martha L.; Acosta-López, Johan E.; Isaza-Ruget, Mario A.; Espinosa, Lady G.; Easteal, Simon.

En: Molecular Neurobiology, Vol. 56, N.º 5, 15.08.2018, p. 3235-3243.

Resultado de la investigación: Contribución a RevistaArtículo

TY - JOUR

T1 - Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer's Disease

AU - Velez, Jorge I.

AU - Lopera, Francisco

AU - Creagh, Penelope K.

AU - Silva Aldana, Claudia Tamar

AU - Quintero, Gustavo A.

AU - Piñeros, Laura

AU - Mastronardi, C.

AU - Arcos-Burgos, Mauricio

AU - Das, Debjani

AU - Cervantes-Henríquez, Martha L.

AU - Acosta-López, Johan E.

AU - Isaza-Ruget, Mario A.

AU - Espinosa, Lady G.

AU - Easteal, Simon

PY - 2018/8/15

Y1 - 2018/8/15

N2 - The identification of novel genetic variants contributing to the widespread in the age of onset (AOO) of Alzheimer's disease (AD) could aid in the prognosis and/or development of new therapeutic strategies focused on early interventions. We recruited 78 individuals with AD from the Paisa genetic isolate in Antioquia, Colombia. These individuals belong to the world largest multigenerational and extended pedigree segregating AD as a consequence of a dominant fully penetrant mutation in the PSEN1 gene and exhibit an AOO ranging from the early 1930s to the late 1970s. To shed light on the genetic underpinning that could explain the large spread of the age of onset (AOO) of AD, 64 single nucleotide polymorphisms (SNP) associated with neuroanatomical, cardiovascular, and cognitive measures in AD were genotyped. Standard quality control and filtering procedures were applied, and single- and multi-locus linear mixed-effects models were used to identify AOO-associated SNPs. A full two-locus interaction model was fitted to define how identified SNPs interact to modulate AOO. We identified two key epistatic interactions between the APOE*E2 allele and SNPs ASTN2-rs7852878 and SNTG1-rs16914781 that delay AOO by up to ~ 8 years (95% CI 3.2-12.7, P = 1.83 × 10-3) and ~ 7.6 years (95% CI 3.3-11.8, P = 8.69 × 10-4), respectively, and validated our previous finding indicating that APOE*E2 delays AOO of AD in PSEN1 E280 mutation carriers. This new evidence involving APOE*E2 as an AOO delayer could be used for developing precision medicine approaches and predictive genomics models to potentially determine AOO in individuals genetically predisposed to AD.

AB - The identification of novel genetic variants contributing to the widespread in the age of onset (AOO) of Alzheimer's disease (AD) could aid in the prognosis and/or development of new therapeutic strategies focused on early interventions. We recruited 78 individuals with AD from the Paisa genetic isolate in Antioquia, Colombia. These individuals belong to the world largest multigenerational and extended pedigree segregating AD as a consequence of a dominant fully penetrant mutation in the PSEN1 gene and exhibit an AOO ranging from the early 1930s to the late 1970s. To shed light on the genetic underpinning that could explain the large spread of the age of onset (AOO) of AD, 64 single nucleotide polymorphisms (SNP) associated with neuroanatomical, cardiovascular, and cognitive measures in AD were genotyped. Standard quality control and filtering procedures were applied, and single- and multi-locus linear mixed-effects models were used to identify AOO-associated SNPs. A full two-locus interaction model was fitted to define how identified SNPs interact to modulate AOO. We identified two key epistatic interactions between the APOE*E2 allele and SNPs ASTN2-rs7852878 and SNTG1-rs16914781 that delay AOO by up to ~ 8 years (95% CI 3.2-12.7, P = 1.83 × 10-3) and ~ 7.6 years (95% CI 3.3-11.8, P = 8.69 × 10-4), respectively, and validated our previous finding indicating that APOE*E2 delays AOO of AD in PSEN1 E280 mutation carriers. This new evidence involving APOE*E2 as an AOO delayer could be used for developing precision medicine approaches and predictive genomics models to potentially determine AOO in individuals genetically predisposed to AD.

M3 - Article

VL - 56

SP - 3235

EP - 3243

JO - Molecular Neurobiology

JF - Molecular Neurobiology

SN - 0893-7648

IS - 5

ER -