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A novel age-informed approach for genetic association analysis in Alzheimer's disease.

TitleA novel age-informed approach for genetic association analysis in Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2021
AuthorsLe Guen, Y, Belloy, ME, Napolioni, V, Eger, SJ, Kennedy, G, Tao, R, He, Z, Greicius, MD
Corporate AuthorsAlzheimer’s Disease Neuroimaging Initiative
JournalAlzheimers Res Ther
Date Published2021 04 01
KeywordsAlzheimer Disease, Exome, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide

BACKGROUND: Many Alzheimer's disease (AD) genetic association studies disregard age or incorrectly account for it, hampering variant discovery.

METHODS: Using simulated data, we compared the statistical power of several models: logistic regression on AD diagnosis adjusted and not adjusted for age; linear regression on a score integrating case-control status and age; and multivariate Cox regression on age-at-onset. We applied these models to real exome-wide data of 11,127 sequenced individuals (54% cases) and replicated suggestive associations in 21,631 genotype-imputed individuals (51% cases).

RESULTS: Modeling variable AD risk across age results in 5-10% statistical power gain compared to logistic regression without age adjustment, while incorrect age adjustment leads to critical power loss. Applying our novel AD-age score and/or Cox regression, we discovered and replicated novel variants associated with AD on KIF21B, USH2A, RAB10, RIN3, and TAOK2 genes.

CONCLUSION: Our AD-age score provides a simple means for statistical power gain and is recommended for future AD studies.

Alternate JournalAlzheimers Res Ther
PubMed ID33794991
PubMed Central IDPMC8017764
Grant ListU01 AG024904 / AG / NIA NIH HHS / United States
P50 AG047366 / AG / NIA NIH HHS / United States
R01 AG066206 / AG / NIA NIH HHS / United States
AG060747 / NH / NIH HHS / United States