Polygenic risk and hazard scores for Alzheimer's disease prediction

the GERAD consortium

Research output: Contribution to journalArticle

Abstract

Objective: Genome-wide association studies (GWAS) have identified over 30 susceptibility loci associated with Alzheimer's disease (AD). Using AD GWAS data from the International Genomics of Alzheimer's Project (IGAP), Polygenic Risk Score (PRS) was successfully applied to predict life time risk of AD development. A recently introduced Polygenic Hazard Score (PHS) is able to quantify individuals with age-specific genetic risk for AD. The aim of this study was to quantify the age-specific genetic risk for AD with PRS and compare the results generated by PRS with those from PHS. Methods: Quantification of individual differences in age-specific genetic risk for AD identified by the PRS, was performed with Cox Regression on 9903 (2626 cases and 7277 controls) individuals from the Genetic and Environmental Risk in Alzheimer's Disease consortium (GERAD). Polygenic Hazard Scores were generated for the same individuals. The age-specific genetic risk for AD identified by the PRS was compared with that generated by the PHS. This was repeated using varying SNPs P-value thresholds for disease association. Results: Polygenic Risk Score significantly predicted the risk associated with age at AD onset when SNPs were preselected for association to AD at P ≤ 0.001. The strongest effect (B = 0.28, SE = 0.04, P = 2.5 × 10 −12 ) was observed for PRS based upon genome-wide significant SNPs (P ≤ 5 × 10 −8 ). The strength of association was weaker with less stringent SNP selection thresholds. Interpretation: Both PRS and PHS can be used to predict an age-specific risk for developing AD. The PHS approach uses SNP effect sizes derived with the Cox Proportional Hazard Regression model. When SNPs were selected based upon AD GWAS case/control P ≤ 10 −3 , we found no advantage of using SNP effects sizes calculated with the Cox Proportional Hazard Regression model in our study. When SNPs are selected for association with AD risk at P > 10 −3 , the age-specific risk prediction results are not significant for either PRS or PHS. However PHS could be more advantageous than PRS of age specific AD risk predictions when SNPs are prioritized for association with AD age at onset (i.e., powerful Cox Regression GWAS study).

Original languageEnglish
Pages (from-to)456-465
Number of pages10
JournalAnnals of Clinical and Translational Neurology
Volume6
Issue number3
DOIs
Publication statusPublished - Mar 1 2019

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Alzheimer Disease
Single Nucleotide Polymorphism
Genome-Wide Association Study
Proportional Hazards Models
Genomics
Age of Onset
Individuality

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology

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Polygenic risk and hazard scores for Alzheimer's disease prediction. / the GERAD consortium.

In: Annals of Clinical and Translational Neurology, Vol. 6, No. 3, 01.03.2019, p. 456-465.

Research output: Contribution to journalArticle

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abstract = "Objective: Genome-wide association studies (GWAS) have identified over 30 susceptibility loci associated with Alzheimer's disease (AD). Using AD GWAS data from the International Genomics of Alzheimer's Project (IGAP), Polygenic Risk Score (PRS) was successfully applied to predict life time risk of AD development. A recently introduced Polygenic Hazard Score (PHS) is able to quantify individuals with age-specific genetic risk for AD. The aim of this study was to quantify the age-specific genetic risk for AD with PRS and compare the results generated by PRS with those from PHS. Methods: Quantification of individual differences in age-specific genetic risk for AD identified by the PRS, was performed with Cox Regression on 9903 (2626 cases and 7277 controls) individuals from the Genetic and Environmental Risk in Alzheimer's Disease consortium (GERAD). Polygenic Hazard Scores were generated for the same individuals. The age-specific genetic risk for AD identified by the PRS was compared with that generated by the PHS. This was repeated using varying SNPs P-value thresholds for disease association. Results: Polygenic Risk Score significantly predicted the risk associated with age at AD onset when SNPs were preselected for association to AD at P ≤ 0.001. The strongest effect (B = 0.28, SE = 0.04, P = 2.5 × 10 −12 ) was observed for PRS based upon genome-wide significant SNPs (P ≤ 5 × 10 −8 ). The strength of association was weaker with less stringent SNP selection thresholds. Interpretation: Both PRS and PHS can be used to predict an age-specific risk for developing AD. The PHS approach uses SNP effect sizes derived with the Cox Proportional Hazard Regression model. When SNPs were selected based upon AD GWAS case/control P ≤ 10 −3 , we found no advantage of using SNP effects sizes calculated with the Cox Proportional Hazard Regression model in our study. When SNPs are selected for association with AD risk at P > 10 −3 , the age-specific risk prediction results are not significant for either PRS or PHS. However PHS could be more advantageous than PRS of age specific AD risk predictions when SNPs are prioritized for association with AD age at onset (i.e., powerful Cox Regression GWAS study).",
author = "{the GERAD consortium} and Ganna Leonenko and Rebecca Sims and Maryam Shoai and Aura Frizzati and Paola Boss{\`u} and Gianfranco Spalletta and Fox, {Nick C.} and Julie Williams and John Hardy and Valentina Escott-Price",
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AU - the GERAD consortium

AU - Leonenko, Ganna

AU - Sims, Rebecca

AU - Shoai, Maryam

AU - Frizzati, Aura

AU - Bossù, Paola

AU - Spalletta, Gianfranco

AU - Fox, Nick C.

AU - Williams, Julie

AU - Hardy, John

AU - Escott-Price, Valentina

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