A Mutation in DAOA Modifies the Age of Onset in PSEN1 E280A Alzheimer's Disease

J. I. Velez, D. Rivera, C. A. Mastronardi, H. R. Patel, C. Tobon, A. Villegas, Y. P. Cai, S. Easteal, F. Lopera, M. Arcos-Burgos

Resultado de la investigación: Contribución a RevistaArtículo

10 Citas (Scopus)

Resumen

We previously reported age of onset (AOO) modifier genes in the world’s largest pedigree segregating early-onset Alzheimer’s disease (AD), caused by the p.Glu280Ala (E280A) mutation in the PSEN1 gene. Here we report the results of a targeted analysis of functional exonic variants in those AOO modifier genes in sixty individuals with PSEN1 E280A AD who were whole-exome genotyped for ~250,000 variants. Standard quality control, filtering, and annotation for functional variants were applied, and common functional variants located in those previously reported as AOO modifier loci were selected. Multiloci linear mixed-effects models were used to test the association between these variants and AOO. An exonic missense mutation in the G72 (DAOA) gene (rs2391191, P = 1.94 × 10−4, PFDR = 9.34 × 10−3) was found to modify AOO in PSEN1 E280A AD. Nominal associations of missense mutations in the CLUAP1 (rs9790, P = 7.63 × 10−3, PFDR = 0.1832) and EXOC2 (rs17136239, P = 0.0325, PFDR = 0.391) genes were also found. Previous studies have linked polymorphisms in the DAOA gene with the occurrence of neuropsychiatric symptoms such as depression, apathy, aggression, delusions, hallucinations, and psychosis in AD. Our findings strongly suggest that this new conspicuous functional AOO modifier within the G72 (DAOA) gene could be pivotal for understanding the genetic basis of AD.
Idioma originalEnglish
PublicaciónNeural Plasticity
EstadoPublished - 2016

Huella dactilar

Age of Onset
Alzheimer Disease
Mutation
Modifier Genes
Genes
Missense Mutation
Exome
Apathy
Delusions
Hallucinations
Pedigree
Aggression
Quality Control
Psychotic Disorders
Depression

Citar esto

Velez, J. I., Rivera, D., Mastronardi, C. A., Patel, H. R., Tobon, C., Villegas, A., ... Arcos-Burgos, M. (2016). A Mutation in DAOA Modifies the Age of Onset in PSEN1 E280A Alzheimer's Disease. Neural Plasticity.
Velez, J. I. ; Rivera, D. ; Mastronardi, C. A. ; Patel, H. R. ; Tobon, C. ; Villegas, A. ; Cai, Y. P. ; Easteal, S. ; Lopera, F. ; Arcos-Burgos, M. / A Mutation in DAOA Modifies the Age of Onset in PSEN1 E280A Alzheimer's Disease. En: Neural Plasticity. 2016.
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title = "A Mutation in DAOA Modifies the Age of Onset in PSEN1 E280A Alzheimer's Disease",
abstract = "We previously reported age of onset (AOO) modifier genes in the world’s largest pedigree segregating early-onset Alzheimer’s disease (AD), caused by the p.Glu280Ala (E280A) mutation in the PSEN1 gene. Here we report the results of a targeted analysis of functional exonic variants in those AOO modifier genes in sixty individuals with PSEN1 E280A AD who were whole-exome genotyped for ~250,000 variants. Standard quality control, filtering, and annotation for functional variants were applied, and common functional variants located in those previously reported as AOO modifier loci were selected. Multiloci linear mixed-effects models were used to test the association between these variants and AOO. An exonic missense mutation in the G72 (DAOA) gene (rs2391191, P = 1.94 × 10−4, PFDR = 9.34 × 10−3) was found to modify AOO in PSEN1 E280A AD. Nominal associations of missense mutations in the CLUAP1 (rs9790, P = 7.63 × 10−3, PFDR = 0.1832) and EXOC2 (rs17136239, P = 0.0325, PFDR = 0.391) genes were also found. Previous studies have linked polymorphisms in the DAOA gene with the occurrence of neuropsychiatric symptoms such as depression, apathy, aggression, delusions, hallucinations, and psychosis in AD. Our findings strongly suggest that this new conspicuous functional AOO modifier within the G72 (DAOA) gene could be pivotal for understanding the genetic basis of AD.",
author = "Velez, {J. I.} and D. Rivera and Mastronardi, {C. A.} and Patel, {H. R.} and C. Tobon and A. Villegas and Cai, {Y. P.} and S. Easteal and F. Lopera and M. Arcos-Burgos",
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language = "Ingl{\'e}s",
journal = "Neural Plasticity",
issn = "2090-5904",
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Velez, JI, Rivera, D, Mastronardi, CA, Patel, HR, Tobon, C, Villegas, A, Cai, YP, Easteal, S, Lopera, F & Arcos-Burgos, M 2016, 'A Mutation in DAOA Modifies the Age of Onset in PSEN1 E280A Alzheimer's Disease', Neural Plasticity.

A Mutation in DAOA Modifies the Age of Onset in PSEN1 E280A Alzheimer's Disease. / Velez, J. I.; Rivera, D.; Mastronardi, C. A.; Patel, H. R.; Tobon, C.; Villegas, A.; Cai, Y. P.; Easteal, S.; Lopera, F.; Arcos-Burgos, M.

En: Neural Plasticity, 2016.

Resultado de la investigación: Contribución a RevistaArtículo

TY - JOUR

T1 - A Mutation in DAOA Modifies the Age of Onset in PSEN1 E280A Alzheimer's Disease

AU - Velez, J. I.

AU - Rivera, D.

AU - Mastronardi, C. A.

AU - Patel, H. R.

AU - Tobon, C.

AU - Villegas, A.

AU - Cai, Y. P.

AU - Easteal, S.

AU - Lopera, F.

AU - Arcos-Burgos, M.

PY - 2016

Y1 - 2016

N2 - We previously reported age of onset (AOO) modifier genes in the world’s largest pedigree segregating early-onset Alzheimer’s disease (AD), caused by the p.Glu280Ala (E280A) mutation in the PSEN1 gene. Here we report the results of a targeted analysis of functional exonic variants in those AOO modifier genes in sixty individuals with PSEN1 E280A AD who were whole-exome genotyped for ~250,000 variants. Standard quality control, filtering, and annotation for functional variants were applied, and common functional variants located in those previously reported as AOO modifier loci were selected. Multiloci linear mixed-effects models were used to test the association between these variants and AOO. An exonic missense mutation in the G72 (DAOA) gene (rs2391191, P = 1.94 × 10−4, PFDR = 9.34 × 10−3) was found to modify AOO in PSEN1 E280A AD. Nominal associations of missense mutations in the CLUAP1 (rs9790, P = 7.63 × 10−3, PFDR = 0.1832) and EXOC2 (rs17136239, P = 0.0325, PFDR = 0.391) genes were also found. Previous studies have linked polymorphisms in the DAOA gene with the occurrence of neuropsychiatric symptoms such as depression, apathy, aggression, delusions, hallucinations, and psychosis in AD. Our findings strongly suggest that this new conspicuous functional AOO modifier within the G72 (DAOA) gene could be pivotal for understanding the genetic basis of AD.

AB - We previously reported age of onset (AOO) modifier genes in the world’s largest pedigree segregating early-onset Alzheimer’s disease (AD), caused by the p.Glu280Ala (E280A) mutation in the PSEN1 gene. Here we report the results of a targeted analysis of functional exonic variants in those AOO modifier genes in sixty individuals with PSEN1 E280A AD who were whole-exome genotyped for ~250,000 variants. Standard quality control, filtering, and annotation for functional variants were applied, and common functional variants located in those previously reported as AOO modifier loci were selected. Multiloci linear mixed-effects models were used to test the association between these variants and AOO. An exonic missense mutation in the G72 (DAOA) gene (rs2391191, P = 1.94 × 10−4, PFDR = 9.34 × 10−3) was found to modify AOO in PSEN1 E280A AD. Nominal associations of missense mutations in the CLUAP1 (rs9790, P = 7.63 × 10−3, PFDR = 0.1832) and EXOC2 (rs17136239, P = 0.0325, PFDR = 0.391) genes were also found. Previous studies have linked polymorphisms in the DAOA gene with the occurrence of neuropsychiatric symptoms such as depression, apathy, aggression, delusions, hallucinations, and psychosis in AD. Our findings strongly suggest that this new conspicuous functional AOO modifier within the G72 (DAOA) gene could be pivotal for understanding the genetic basis of AD.

M3 - Artículo

JO - Neural Plasticity

JF - Neural Plasticity

SN - 2090-5904

ER -

Velez JI, Rivera D, Mastronardi CA, Patel HR, Tobon C, Villegas A y otros. A Mutation in DAOA Modifies the Age of Onset in PSEN1 E280A Alzheimer's Disease. Neural Plasticity. 2016.