@article {11204, title = {Considering the APOE locus in Alzheimer{\textquoteright}s disease polygenic scores in the Health and Retirement Study: a longitudinal panel study.}, journal = {BMC Medical Genomics}, volume = {13}, year = {2020}, pages = {164}, abstract = {

BACKGROUND: Polygenic scores are a strategy to aggregate the small, additive effects of single nucleotide polymorphisms across the genome. With phenotypes like Alzheimer{\textquoteright}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.

METHODS: Here we examine the association between polygenic scores for Alzheimer{\textquoteright}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.

RESULTS: In 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).

CONCLUSION: We 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{\textquoteright}s disease on dementia. These recommendations may help elucidate relationships between polygenic scores and regions of strong significance for phenotypes similar to Alzheimer{\textquoteright}s disease.

}, keywords = {Alzheimer{\textquoteright}s disease, Apolipoprotein E, Dementia, P-value, polygenic score, Thresholding}, issn = {1755-8794}, doi = {10.1186/s12920-020-00815-9}, author = {Erin B Ware and Jessica Faul and Colter Mitchell and Kelly M Bakulski} }