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Considering the APOE locus in polygenic scores for Alzheimer’s disease

Polygenic scores are a strategy to aggregate the small, additive effects of single nucleotide polymorphisms across the genome. With phenotypes like Alzheimer’s disease, which have a strong and well established genomic locus (APOE), the cumulative effect of genetic variants outside of this area has not been well established in a population-representative sample. Here we examine the association between polygenic scores both with and without the APOE region at different P value thresholds. We also investigate the addition of APOE-ε4 carrier status and its effect on the polygenic score – dementia association. We found that including the APOE region through weighted variants in a polygenic score was insufficient to capture the large amount of risk attributed to this region. We recommend removing this region from polygenic score calculation and treating the APOE locus as an independent covariate.