APOE∗E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease

J. I. Vélez, F. Lopera, D. Sepulveda-Falla, H. R. Patel, A. S. Johar, A. Chuah, C. Tobón, D. Rivera, A. Villegas, Y. Cai, K. Peng, R. Arkell, F. X. Castellanos, S. J. Andrews, M. F. Silva Lara, P. K. Creagh, S. Easteal, J. De Leon, M. L. Wong, J. Licinio & 2 others C. A. Mastronardi, M. Arcos-Burgos

Research output: Contribution to journalArticle

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Abstract

Alzheimer's disease (AD) age of onset (ADAOO) varies greatly between individuals, with unique causal mutations suggesting the role of modifying genetic and environmental interactions. We analyzed ∼50 000 common and rare functional genomic variants from 71 individuals of the 'Paisa' pedigree, the world's largest pedigree segregating a severe form of early-onset AD, who were affected carriers of the fully penetrant E280A mutation in the presenilin-1 (PSEN1) gene. Affected carriers with ages at the extremes of the ADAOO distribution (30s-70s age range), and linear mixed-effects models were used to build single-locus regression models outlining the ADAOO. We identified the rs7412 (APOE∗E2 allele) as a whole exome-wide ADAOO modifier that delays ADAOO by ∼12 years (β=11.74, 95% confidence interval (CI): 8.07-15.41, P=6.31 × 10 -8, P FDR =2.48 × 10 -3). Subsequently, to evaluate comprehensively the APOE (apolipoprotein E) haplotype variants (E1/E2/E3/E4), the markers rs7412 and rs429358 were genotyped in 93 AD affected carriers of the E280A mutation. We found that the APOE∗E2 allele, and not APOE∗E4, modifies ADAOO in carriers of the E280A mutation (β=8.24, 95% CI: 4.45-12.01, P=3.84 × 10 -5). Exploratory linear mixed-effects multilocus analysis suggested that other functional variants harbored in genes involved in cell proliferation, protein degradation, apoptotic and immune dysregulation processes (i.e., GPR20, TRIM22, FCRL5, AOAH, PINLYP, IFI16, RC3H1 and DFNA5) might interact with the APOE∗E2 allele. Interestingly, suggestive evidence as an ADAOO modifier was found for one of these variants (GPR20) in a set of patients with sporadic AD from the Paisa genetic isolate. This is the first study demonstrating that the APOE∗E2 allele modifies the natural history of AD typified by the age of onset in E280A mutation carriers. To the best of our knowledge, this is the largest analyzed sample of patients with a unique mutation sharing uniform environment. Formal replication of our results in other populations and in other forms of AD will be crucial for prediction, follow-up and presumably developing new therapeutic strategies for patients either at risk or affected by AD.

LanguageEnglish
Pages916-924
Number of pages9
JournalMolecular Psychiatry
Volume21
Issue number7
DOIs
Publication statusPublished - 1 Jul 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Vélez, J. I., Lopera, F., Sepulveda-Falla, D., Patel, H. R., Johar, A. S., Chuah, A., ... Arcos-Burgos, M. (2016). APOE∗E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease. Molecular Psychiatry, 21(7), 916-924. https://doi.org/10.1038/mp.2015.177
Vélez, J. I. ; Lopera, F. ; Sepulveda-Falla, D. ; Patel, H. R. ; Johar, A. S. ; Chuah, A. ; Tobón, C. ; Rivera, D. ; Villegas, A. ; Cai, Y. ; Peng, K. ; Arkell, R. ; Castellanos, F. X. ; Andrews, S. J. ; Silva Lara, M. F. ; Creagh, P. K. ; Easteal, S. ; De Leon, J. ; Wong, M. L. ; Licinio, J. ; Mastronardi, C. A. ; Arcos-Burgos, M. / APOE∗E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease. In: Molecular Psychiatry. 2016 ; Vol. 21, No. 7. pp. 916-924.
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abstract = "Alzheimer's disease (AD) age of onset (ADAOO) varies greatly between individuals, with unique causal mutations suggesting the role of modifying genetic and environmental interactions. We analyzed ∼50 000 common and rare functional genomic variants from 71 individuals of the 'Paisa' pedigree, the world's largest pedigree segregating a severe form of early-onset AD, who were affected carriers of the fully penetrant E280A mutation in the presenilin-1 (PSEN1) gene. Affected carriers with ages at the extremes of the ADAOO distribution (30s-70s age range), and linear mixed-effects models were used to build single-locus regression models outlining the ADAOO. We identified the rs7412 (APOE∗E2 allele) as a whole exome-wide ADAOO modifier that delays ADAOO by ∼12 years (β=11.74, 95{\%} confidence interval (CI): 8.07-15.41, P=6.31 × 10 -8, P FDR =2.48 × 10 -3). Subsequently, to evaluate comprehensively the APOE (apolipoprotein E) haplotype variants (E1/E2/E3/E4), the markers rs7412 and rs429358 were genotyped in 93 AD affected carriers of the E280A mutation. We found that the APOE∗E2 allele, and not APOE∗E4, modifies ADAOO in carriers of the E280A mutation (β=8.24, 95{\%} CI: 4.45-12.01, P=3.84 × 10 -5). Exploratory linear mixed-effects multilocus analysis suggested that other functional variants harbored in genes involved in cell proliferation, protein degradation, apoptotic and immune dysregulation processes (i.e., GPR20, TRIM22, FCRL5, AOAH, PINLYP, IFI16, RC3H1 and DFNA5) might interact with the APOE∗E2 allele. Interestingly, suggestive evidence as an ADAOO modifier was found for one of these variants (GPR20) in a set of patients with sporadic AD from the Paisa genetic isolate. This is the first study demonstrating that the APOE∗E2 allele modifies the natural history of AD typified by the age of onset in E280A mutation carriers. To the best of our knowledge, this is the largest analyzed sample of patients with a unique mutation sharing uniform environment. Formal replication of our results in other populations and in other forms of AD will be crucial for prediction, follow-up and presumably developing new therapeutic strategies for patients either at risk or affected by AD.",
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Vélez, JI, Lopera, F, Sepulveda-Falla, D, Patel, HR, Johar, AS, Chuah, A, Tobón, C, Rivera, D, Villegas, A, Cai, Y, Peng, K, Arkell, R, Castellanos, FX, Andrews, SJ, Silva Lara, MF, Creagh, PK, Easteal, S, De Leon, J, Wong, ML, Licinio, J, Mastronardi, CA & Arcos-Burgos, M 2016, 'APOE∗E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease', Molecular Psychiatry, vol. 21, no. 7, pp. 916-924. https://doi.org/10.1038/mp.2015.177

APOE∗E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease. / Vélez, J. I.; Lopera, F.; Sepulveda-Falla, D.; Patel, H. R.; Johar, A. S.; Chuah, A.; Tobón, C.; Rivera, D.; Villegas, A.; Cai, Y.; Peng, K.; Arkell, R.; Castellanos, F. X.; Andrews, S. J.; Silva Lara, M. F.; Creagh, P. K.; Easteal, S.; De Leon, J.; Wong, M. L.; Licinio, J.; Mastronardi, C. A.; Arcos-Burgos, M.

In: Molecular Psychiatry, Vol. 21, No. 7, 01.07.2016, p. 916-924.

Research output: Contribution to journalArticle

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T1 - APOE∗E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease

AU - Vélez, J. I.

AU - Lopera, F.

AU - Sepulveda-Falla, D.

AU - Patel, H. R.

AU - Johar, A. S.

AU - Chuah, A.

AU - Tobón, C.

AU - Rivera, D.

AU - Villegas, A.

AU - Cai, Y.

AU - Peng, K.

AU - Arkell, R.

AU - Castellanos, F. X.

AU - Andrews, S. J.

AU - Silva Lara, M. F.

AU - Creagh, P. K.

AU - Easteal, S.

AU - De Leon, J.

AU - Wong, M. L.

AU - Licinio, J.

AU - Mastronardi, C. A.

AU - Arcos-Burgos, M.

PY - 2016/7/1

Y1 - 2016/7/1

N2 - Alzheimer's disease (AD) age of onset (ADAOO) varies greatly between individuals, with unique causal mutations suggesting the role of modifying genetic and environmental interactions. We analyzed ∼50 000 common and rare functional genomic variants from 71 individuals of the 'Paisa' pedigree, the world's largest pedigree segregating a severe form of early-onset AD, who were affected carriers of the fully penetrant E280A mutation in the presenilin-1 (PSEN1) gene. Affected carriers with ages at the extremes of the ADAOO distribution (30s-70s age range), and linear mixed-effects models were used to build single-locus regression models outlining the ADAOO. We identified the rs7412 (APOE∗E2 allele) as a whole exome-wide ADAOO modifier that delays ADAOO by ∼12 years (β=11.74, 95% confidence interval (CI): 8.07-15.41, P=6.31 × 10 -8, P FDR =2.48 × 10 -3). Subsequently, to evaluate comprehensively the APOE (apolipoprotein E) haplotype variants (E1/E2/E3/E4), the markers rs7412 and rs429358 were genotyped in 93 AD affected carriers of the E280A mutation. We found that the APOE∗E2 allele, and not APOE∗E4, modifies ADAOO in carriers of the E280A mutation (β=8.24, 95% CI: 4.45-12.01, P=3.84 × 10 -5). Exploratory linear mixed-effects multilocus analysis suggested that other functional variants harbored in genes involved in cell proliferation, protein degradation, apoptotic and immune dysregulation processes (i.e., GPR20, TRIM22, FCRL5, AOAH, PINLYP, IFI16, RC3H1 and DFNA5) might interact with the APOE∗E2 allele. Interestingly, suggestive evidence as an ADAOO modifier was found for one of these variants (GPR20) in a set of patients with sporadic AD from the Paisa genetic isolate. This is the first study demonstrating that the APOE∗E2 allele modifies the natural history of AD typified by the age of onset in E280A mutation carriers. To the best of our knowledge, this is the largest analyzed sample of patients with a unique mutation sharing uniform environment. Formal replication of our results in other populations and in other forms of AD will be crucial for prediction, follow-up and presumably developing new therapeutic strategies for patients either at risk or affected by AD.

AB - Alzheimer's disease (AD) age of onset (ADAOO) varies greatly between individuals, with unique causal mutations suggesting the role of modifying genetic and environmental interactions. We analyzed ∼50 000 common and rare functional genomic variants from 71 individuals of the 'Paisa' pedigree, the world's largest pedigree segregating a severe form of early-onset AD, who were affected carriers of the fully penetrant E280A mutation in the presenilin-1 (PSEN1) gene. Affected carriers with ages at the extremes of the ADAOO distribution (30s-70s age range), and linear mixed-effects models were used to build single-locus regression models outlining the ADAOO. We identified the rs7412 (APOE∗E2 allele) as a whole exome-wide ADAOO modifier that delays ADAOO by ∼12 years (β=11.74, 95% confidence interval (CI): 8.07-15.41, P=6.31 × 10 -8, P FDR =2.48 × 10 -3). Subsequently, to evaluate comprehensively the APOE (apolipoprotein E) haplotype variants (E1/E2/E3/E4), the markers rs7412 and rs429358 were genotyped in 93 AD affected carriers of the E280A mutation. We found that the APOE∗E2 allele, and not APOE∗E4, modifies ADAOO in carriers of the E280A mutation (β=8.24, 95% CI: 4.45-12.01, P=3.84 × 10 -5). Exploratory linear mixed-effects multilocus analysis suggested that other functional variants harbored in genes involved in cell proliferation, protein degradation, apoptotic and immune dysregulation processes (i.e., GPR20, TRIM22, FCRL5, AOAH, PINLYP, IFI16, RC3H1 and DFNA5) might interact with the APOE∗E2 allele. Interestingly, suggestive evidence as an ADAOO modifier was found for one of these variants (GPR20) in a set of patients with sporadic AD from the Paisa genetic isolate. This is the first study demonstrating that the APOE∗E2 allele modifies the natural history of AD typified by the age of onset in E280A mutation carriers. To the best of our knowledge, this is the largest analyzed sample of patients with a unique mutation sharing uniform environment. Formal replication of our results in other populations and in other forms of AD will be crucial for prediction, follow-up and presumably developing new therapeutic strategies for patients either at risk or affected by AD.

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Vélez JI, Lopera F, Sepulveda-Falla D, Patel HR, Johar AS, Chuah A et al. APOE∗E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease. Molecular Psychiatry. 2016 Jul 1;21(7):916-924. https://doi.org/10.1038/mp.2015.177