Abstract
BackgroundPolygenic 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.MethodsHere we examine the association between polygenic scores for Alzheimer’s disease both with and without the APOE region (chr19: 45,384,477 to 45,432,606, build 37/hg 19) at different P value thresholds and dementia. We also investigate the addition of APOE-ε4 carrier status and its effect on the polygenic score—dementia association in the Health and Retirement Study using generalized linear models accounting for repeated measures by individual and use a binomial distribution, logit link, and unstructured correlation structure.ResultsIn a large sample of European ancestry participants of the Health and Retirement Study (n = 9872) with an average of 5.2 (standard deviation 1.8) visit spaced two years apart, 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 also found that a polygenic score with a P value threshold of 0.01 had the strongest association with the odds of dementia in this sample (odds ratio = 1.10 95%CI 1.0 to 1.2).ConclusionWe recommend removing the APOE region from polygenic score calculation and treating the APOE locus as an independent covariate when modeling dementia. We also recommend using a moderately conservative P value threshold (e.g. 0.01) when creating polygenic scores for Alzheimer’s disease on dementia. These recommendations may help elucidate relationships between polygenic scores and regions of strong significance for phenotypes similar to Alzheimer’s disease.
Highlights
Polygenic scores are a strategy to aggregate the small, additive effects of single nucleotide polymorphisms across the genome
The effect of apolipoprotein E (APOE)-ε4 is all the more difficult to capture in a single variant genomewide association studies (GWAS) as APOE-ε4 is a haplotype composed of two Single nucleotide polymorphism (SNP): rs7412 and rs429358—which will never be fully be captured in a traditional linear model GWAS framework
A small portion of the sample had a history of stroke at their first visit during the observation period (n = 417, 4.3%), with a higher proportion of males reporting a history of stroke at their first visit (n = 201, 4.9%) than females (n = 216, 3.8%)
Summary
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. Ware et al BMC Med Genomics (2020) 13:164 genetic loci associated with Alzheimer’s disease [4,5,6,7,8,9,10], being a carrier of the Apolipoprotein E (APOE-ε4) allele remains the strongest genetic predictor of late-onset Alzheimer’s disease [11]. GWAS have identified many independent SNPs in and near the APOE gene locus. The APOE gene region contains many variants in high linkage disequilibrium within roughly 100 kilobases, including several additional highrisk sites in the translocase of outer mitochondrial membrane 40 (TOMM40) gene
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