TY - JOUR
T1 - Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer’s Disease
AU - Vélez, Jorge I.
AU - Lopera, Francisco
AU - Creagh, Penelope K.
AU - Piñeros, Laura B.
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
AU - Quintero, Gustavo A.
AU - Silva, Claudia Tamar
AU - Mastronardi, Claudio A.
AU - Arcos-Burgos, Mauricio
N1 - Funding Information:
Acknowledgements The authors express their highest appreciation to the patients and relatives enrolled in this study for more than 25 years. This study was financed by a research grant from Australian National University (ANU) to MAB to launch his laboratory, and COLCIENCIAS and the University of Antioquia, grant 1115-408-20543. JIV and CAM were supported by grant R42100-2 from the John Curtin School of Medical Research, Canberra, ACT, Australia. MAB and CAM are currently supported by internal funds provided by the Universidad del Rosario. JIV is partially supported by research grant FOFICO 32101 PE0031 from Universidad del Norte. MLC-H is a doctoral student at Universidad del Norte, Barranquilla, Colombia. Some of this work is to be presented in partial fulfillment of the requirements for her PhD degree.
Publisher Copyright:
© 2018, The Author(s).
PY - 2019/5/1
Y1 - 2019/5/1
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.
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U2 - https://doi.org/10.1007/s12035-018-1298-z
DO - https://doi.org/10.1007/s12035-018-1298-z
M3 - Article
C2 - 30112632
AN - SCOPUS:85051856801
SN - 0893-7648
VL - 56
SP - 3235
EP - 3243
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 5
ER -