Genetic Architecture of Plasma Amyloid and Tau Biomarkers in the Amish
Wang, P.; Jian, D. Z.; Song, Y. E.; Lynn, A.; Miskimen, K.; Whitehead, P. G.; Gulyayev, A. V.; Prough, M. B.; Dorfsman, D. A.; Laux, R. A.; Fuzzell, S. L.; Miller, D.; Hochstetler, S. D.; Miron, P.; Zaman, A. F.; Adams, L. D.; Caywood, L. J.; Clouse, J. E.; Herington, S. D.; Liu, Y.; Moore, N. C.; Ogrocki, P.; Lerner, A. J.; Griswold, A. J.; Cuccaro, M. L.; Vance, J. M.; Scott, W. K.; Pericak-Vance, M. A.; Haines, J. L.
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Background: Plasma biomarkers offer a minimally invasive alternative for detecting Alzheimer disease (AD) pathology, yet the genetic determinants influencing their levels remain largely underexplored. Objective: To identify genetic variants associated with AD-related plasma biomarker levels in a Midwestern Amish cohort. Methods: We analyzed plasma levels of amyloid beta (A{beta}42/A{beta}40), phosphorylated tau 181 (p-tau181), and the p-tau181/A{beta}42 ratio in the Midwestern Amish. Genome-wide association studies (GWAS) were used to examine associations with common genetic variants, while genetic linkage analysis was used to assess the potential impact of rare variants. Results: GWAS found associations between plasma biomarkers and the APOE gene. Additionally, novel candidate genes were implicated, including MME for A{beta}42/A{beta}40 ratio, and VEGFC and LRRTM4 for p-tau181. Linkage analysis identified significant signals for p-tau181 on chromosome 1, potentially involving the CSF1 and AHCYL1genes. Conclusions: The novel genetic variants associated with AD pathology implicate metabolic, synaptic, neuronal, and immune pathways. The use of GWAS and linkage analysis sheds light on the genetic architecture of AD-related plasma biomarkers.
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