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Polygenic risk scores in familial Alzheimer disease.

ABSTRACT: OBJECTIVE:To investigate the association between a genetic risk score (GRS) and familial late-onset Alzheimer disease (LOAD) and its predictive value in families multiply affected by the disease. METHODS:Using data from the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease (National Institute on Aging-Late-Onset Alzheimer's Disease Family Study), mixed regression models tested the association of familial LOAD with a GRS based on single nucleotide polymorphisms (SNPs) previously associated with LOAD. We modeled associations using unweighted and weighted scores with estimates derived from the literature. In secondary models, we adjusted subsequent models for presence of the APOE ?4 allele and further tested the interaction between APOE ?4 and the GRS. We constructed a similar GRS in a cohort of Caribbean Hispanic families multiply affected by LOAD by selecting the SNP with the strongest p value within the same regions. RESULTS:In the NIA-LOAD families, the GRS was significantly associated with LOAD (odds ratio [OR] 1.29; 95% confidence interval 1.21-1.37). The results did not change after adjusting for APOE ?4. In Caribbean Hispanic families, the GRS also significantly predicted LOAD (OR 1.73; 1.57-1.93). Higher scores were associated with lower age at onset in both cohorts. CONCLUSIONS:High GRS increases the risk of familial LOAD and lowers the age at onset, regardless of ethnic group.

SUBMITTER: Tosto G

PROVIDER: S-EPMC5373783 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Polygenic risk scores in familial Alzheimer disease.

Tosto Giuseppe G Bird Thomas D TD Tsuang Debby D Bennett David A DA Boeve Bradley F BF Cruchaga Carlos C Faber Kelley K Foroud Tatiana M TM Farlow Martin M Goate Alison M AM Bertlesen Sarah S Graff-Radford Neill R NR Medrano Martin M Lantigua Rafael R Manly Jennifer J Ottman Ruth R Rosenberg Roger R Schaid Daniel J DJ Schupf Nicole N Stern Yaakov Y Sweet Robert A RA Mayeux Richard R

Neurology 20170217 12

<h4>Objective</h4>To investigate the association between a genetic risk score (GRS) and familial late-onset Alzheimer disease (LOAD) and its predictive value in families multiply affected by the disease.<h4>Methods</h4>Using data from the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease (National Institute on Aging-Late-Onset Alzheimer's Disease Family Study), mixed regression models tested the association of familial LOAD with a GRS based on single nucleotide pol ...[more]

PMID: 28213371

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Project description: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).

Dataset Information

Polygenic risk scores in familial Alzheimer disease.

Publications

Polygenic risk scores in familial Alzheimer disease.

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