Considering the APOE locus in Alzheimer’s disease polygenic scores in the Health and Retirement Study: a longitudinal panel study
Year: 2020
Type: article
Study design: Observational Study
Abstract: BACKGROUND: 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. METHODS: Here 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. 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'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.
Source: BMC Medical Genomics
Institutions: University of Michigan, Institute for Social Research
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,380
Awards: G2639381427, Identifying modifiable aspects of gene-by-environment interplay in later-life cognitive decline, G4428411940, G6902288782, Epigenetic Mediation of Adverse Social Context on Stress Response, Socioemotional Development, and Health in a Population-based Study of Minority and Low SES Children and Adolescents, Characterizing disparities in late-onset Alzheimer's disease risk through polygenic risk and epidemiologic factors in the Health and Retirement Survey, DNA Methylation,Genetics, and Modifiable Risk Factors of Dementia in a Nationally Representative, Multi-Ethnic Cohort, Health and Retirement Study: Yrs 35-40
OpenAlex ID: W3094695348