Polygenic risk and hazard scores for Alzheimer's disease prediction.

Maryam Shoai,Nick C Fox,Ganna Leonenko,Gianfranco Spalletta,Julie Williams,Valentina Escott‐Price,Aura Frizzati,Paola Bossù,Rebecca Sims,John Hardy

doi:10.1002/acn3.716

Maryam Shoai, Nick C Fox + Show 8 more

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https://doi.org/10.1002/acn3.716

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Abstract

ObjectiveGenome‐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.MethodsQuantification 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.ResultsPolygenic 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.InterpretationBoth 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).

Highlights

IntroductionAlzheimer’s disease (AD) is the most common form of neurodegenerative disorder[1] with over 47 million people affected worldwide and a global economic impact estimated at about US $818 billion.[2]
Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder[1] with over 47 million people affected worldwide and a global economic impact estimated at about US $818 billion.[2]AD is highly heritable with an estimated 80% of the liability explained by genetic factors.[3]
Our study shows that Polygenic Hazard Score (PHS), as constructed in Desikan et al.[10] gives very similar results to Polygenic Risk Score (PRS) when tested in the Genetic and Environmental Risk for Alzheimer’s disease (GERAD) dataset

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder[1] with over 47 million people affected worldwide and a global economic impact estimated at about US $818 billion.[2]. AD is highly heritable with an estimated 80% of the liability explained by genetic factors.[3] Risk for developing a 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

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