NG00086 - NACC Polygenic Hazard Score

Based on a combination of APOE and 31 other genetic variants, a ‘polygenic hazard score’ (PHS) has been developed and validated for quantifying AD dementia age of onset.

AD-associated SNPs (at p < 10-5) were first delineated using genotype data from 17,008 AD cases and 37,154 controls from Stage 1 of the International Genomics of Alzheimer’s Project. Next, using genotype data from 6,409 AD patients and 9,386 older controls from Phase 1 of the Alzheimer’s Disease Genetics Consortium (ADGC Phase 1), and corrected for the baseline allele frequencies using European genotypes from 1000 Genomes Project, a total of 31 AD-associated SNPs were identified from a stepwise Cox proportional hazards model to derive a polygenic hazard score (PHS) for each participant. PHS computed for every participant represents the vector product of an individual’s genotype for the 31 SNPs and the corresponding parameter estimates from the ADGC Phase 1 Cox proportional hazard model in addition to the APOE effects. Beyond APOE, PHS has been shown to predict cognitive and clinical decline, postmortem and in vivo measures of amyloid and tau pathology, and MRI measures of medial temporal volume.

This data was first reported in the Desikan et al. publication.

Please refer to the attached documents Polygenic Hazard Score (PHS) Methods.docx and NG00086_README.txt for additional information.