Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease

Vincent Chouraki, Christiane Reitz, Fleur Maury, Joshua C. Bis, Celine Bellenguez, Lei Yu, Johanna Jakobsdottir, Shubhabrata Mukherjee, Hieab H. Adams, Seung Hoan Choi, Eric B. Larson, Annette Fitzpatrick, Andre G. Uitterlinden, Philip L. De Jager, Albert Hofman, Vilmundur Gudnason, Badri Vardarajan, Carla Ibrahim-Verbaas, Sven J. Van Der Lee, Oscar LopezJean François Dartigues, Claudine Berr, Philippe Amouyel, David A. Bennett, Cornelia Van Duijn, Anita L. Destefano, Lenore J. Launer, M. Arfan Ikram, Paul K. Crane, Jean Charles Lambert, Richard Mayeux, Sudha Seshadri

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Effective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOE ϵ4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17 increase in AD risk (pooled HR=1.17; 95 CI= [1.13-1.21] per standard deviation increase in GRS; p-value= 2.86×10-16). This association was stronger among persons with at least one APOE ϵ4 allele (HRGRS=1.24; 95 CI= [1.15-1.34]) than in others (HRGRS=1.13; 95 CI= [1.08-1.18]; pinteraction=3.45×10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOE ϵ4, and education (Δ-Cindex= 0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOE ϵ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.

Original languageEnglish (US)
Pages (from-to)921-932
Number of pages12
JournalJournal of Alzheimer's Disease
Volume53
Issue number3
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Fingerprint

Alzheimer Disease
Genomics
Alleles
Sex Education
Genome-Wide Association Study
Proportional Hazards Models
Single Nucleotide Polymorphism
Dementia
Education

Keywords

  • Alzheimer's disease
  • clinical utility
  • cohort studies
  • genetic risk score
  • IGAP
  • meta-analysis
  • risk prediction

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Cite this

Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease. / Chouraki, Vincent; Reitz, Christiane; Maury, Fleur; Bis, Joshua C.; Bellenguez, Celine; Yu, Lei; Jakobsdottir, Johanna; Mukherjee, Shubhabrata; Adams, Hieab H.; Choi, Seung Hoan; Larson, Eric B.; Fitzpatrick, Annette; Uitterlinden, Andre G.; De Jager, Philip L.; Hofman, Albert; Gudnason, Vilmundur; Vardarajan, Badri; Ibrahim-Verbaas, Carla; Van Der Lee, Sven J.; Lopez, Oscar; Dartigues, Jean François; Berr, Claudine; Amouyel, Philippe; Bennett, David A.; Van Duijn, Cornelia; Destefano, Anita L.; Launer, Lenore J.; Ikram, M. Arfan; Crane, Paul K.; Lambert, Jean Charles; Mayeux, Richard; Seshadri, Sudha.

In: Journal of Alzheimer's Disease, Vol. 53, No. 3, 01.01.2016, p. 921-932.

Research output: Contribution to journalArticle

Chouraki, V, Reitz, C, Maury, F, Bis, JC, Bellenguez, C, Yu, L, Jakobsdottir, J, Mukherjee, S, Adams, HH, Choi, SH, Larson, EB, Fitzpatrick, A, Uitterlinden, AG, De Jager, PL, Hofman, A, Gudnason, V, Vardarajan, B, Ibrahim-Verbaas, C, Van Der Lee, SJ, Lopez, O, Dartigues, JF, Berr, C, Amouyel, P, Bennett, DA, Van Duijn, C, Destefano, AL, Launer, LJ, Ikram, MA, Crane, PK, Lambert, JC, Mayeux, R & Seshadri, S 2016, 'Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease', Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 921-932. https://doi.org/10.3233/JAD-150749
Chouraki, Vincent ; Reitz, Christiane ; Maury, Fleur ; Bis, Joshua C. ; Bellenguez, Celine ; Yu, Lei ; Jakobsdottir, Johanna ; Mukherjee, Shubhabrata ; Adams, Hieab H. ; Choi, Seung Hoan ; Larson, Eric B. ; Fitzpatrick, Annette ; Uitterlinden, Andre G. ; De Jager, Philip L. ; Hofman, Albert ; Gudnason, Vilmundur ; Vardarajan, Badri ; Ibrahim-Verbaas, Carla ; Van Der Lee, Sven J. ; Lopez, Oscar ; Dartigues, Jean François ; Berr, Claudine ; Amouyel, Philippe ; Bennett, David A. ; Van Duijn, Cornelia ; Destefano, Anita L. ; Launer, Lenore J. ; Ikram, M. Arfan ; Crane, Paul K. ; Lambert, Jean Charles ; Mayeux, Richard ; Seshadri, Sudha. / Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease. In: Journal of Alzheimer's Disease. 2016 ; Vol. 53, No. 3. pp. 921-932.
@article{6fdeb345f2e94c07b49d6e7a9c50dd82,
title = "Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease",
abstract = "Effective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOE ϵ4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17 increase in AD risk (pooled HR=1.17; 95 CI= [1.13-1.21] per standard deviation increase in GRS; p-value= 2.86×10-16). This association was stronger among persons with at least one APOE ϵ4 allele (HRGRS=1.24; 95 CI= [1.15-1.34]) than in others (HRGRS=1.13; 95 CI= [1.08-1.18]; pinteraction=3.45×10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOE ϵ4, and education (Δ-Cindex= 0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOE ϵ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.",
keywords = "Alzheimer's disease, clinical utility, cohort studies, genetic risk score, IGAP, meta-analysis, risk prediction",
author = "Vincent Chouraki and Christiane Reitz and Fleur Maury and Bis, {Joshua C.} and Celine Bellenguez and Lei Yu and Johanna Jakobsdottir and Shubhabrata Mukherjee and Adams, {Hieab H.} and Choi, {Seung Hoan} and Larson, {Eric B.} and Annette Fitzpatrick and Uitterlinden, {Andre G.} and {De Jager}, {Philip L.} and Albert Hofman and Vilmundur Gudnason and Badri Vardarajan and Carla Ibrahim-Verbaas and {Van Der Lee}, {Sven J.} and Oscar Lopez and Dartigues, {Jean Fran{\cc}ois} and Claudine Berr and Philippe Amouyel and Bennett, {David A.} and {Van Duijn}, Cornelia and Destefano, {Anita L.} and Launer, {Lenore J.} and Ikram, {M. Arfan} and Crane, {Paul K.} and Lambert, {Jean Charles} and Richard Mayeux and Sudha Seshadri",
year = "2016",
month = "1",
day = "1",
doi = "10.3233/JAD-150749",
language = "English (US)",
volume = "53",
pages = "921--932",
journal = "Journal of Alzheimer's Disease",
issn = "1387-2877",
publisher = "IOS Press",
number = "3",

}

TY - JOUR

T1 - Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease

AU - Chouraki, Vincent

AU - Reitz, Christiane

AU - Maury, Fleur

AU - Bis, Joshua C.

AU - Bellenguez, Celine

AU - Yu, Lei

AU - Jakobsdottir, Johanna

AU - Mukherjee, Shubhabrata

AU - Adams, Hieab H.

AU - Choi, Seung Hoan

AU - Larson, Eric B.

AU - Fitzpatrick, Annette

AU - Uitterlinden, Andre G.

AU - De Jager, Philip L.

AU - Hofman, Albert

AU - Gudnason, Vilmundur

AU - Vardarajan, Badri

AU - Ibrahim-Verbaas, Carla

AU - Van Der Lee, Sven J.

AU - Lopez, Oscar

AU - Dartigues, Jean François

AU - Berr, Claudine

AU - Amouyel, Philippe

AU - Bennett, David A.

AU - Van Duijn, Cornelia

AU - Destefano, Anita L.

AU - Launer, Lenore J.

AU - Ikram, M. Arfan

AU - Crane, Paul K.

AU - Lambert, Jean Charles

AU - Mayeux, Richard

AU - Seshadri, Sudha

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Effective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOE ϵ4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17 increase in AD risk (pooled HR=1.17; 95 CI= [1.13-1.21] per standard deviation increase in GRS; p-value= 2.86×10-16). This association was stronger among persons with at least one APOE ϵ4 allele (HRGRS=1.24; 95 CI= [1.15-1.34]) than in others (HRGRS=1.13; 95 CI= [1.08-1.18]; pinteraction=3.45×10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOE ϵ4, and education (Δ-Cindex= 0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOE ϵ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.

AB - Effective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOE ϵ4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17 increase in AD risk (pooled HR=1.17; 95 CI= [1.13-1.21] per standard deviation increase in GRS; p-value= 2.86×10-16). This association was stronger among persons with at least one APOE ϵ4 allele (HRGRS=1.24; 95 CI= [1.15-1.34]) than in others (HRGRS=1.13; 95 CI= [1.08-1.18]; pinteraction=3.45×10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOE ϵ4, and education (Δ-Cindex= 0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOE ϵ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.

KW - Alzheimer's disease

KW - clinical utility

KW - cohort studies

KW - genetic risk score

KW - IGAP

KW - meta-analysis

KW - risk prediction

UR - http://www.scopus.com/inward/record.url?scp=84981351563&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84981351563&partnerID=8YFLogxK

U2 - 10.3233/JAD-150749

DO - 10.3233/JAD-150749

M3 - Article

C2 - 27340842

AN - SCOPUS:84981351563

VL - 53

SP - 921

EP - 932

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

SN - 1387-2877

IS - 3

ER -