Polygenic Risk Score of Sporadic Late Onset Alzheimer Disease Reveals a Shared Architecture with the Familial and Early Onset Forms

Del Aguila, J. L.; Saef, B.; Black, K.; Fernandez, M.-V.; John Budde, J.; Ibanez, L.; Kapoor, M.; Tosto, G.; Mayeux, R. P.; Holtzman, D. M.; Fagan, A. M.; Morris, J. C.; Bateman, R. J.; Goate, A. M.; Cruchaga, C.; Harari, O.

doi:10.1101/165209

bioRxiv · 10.1101/165209

Polygenic Risk Score of Sporadic Late Onset Alzheimer Disease Reveals a Shared Architecture with the Familial and Early Onset Forms

Del Aguila, J. L.·Saef, B.·Black, K.·Fernandez, M.-V.·John Budde, J.·Ibanez, L.·Kapoor, M.·Tosto, G.·Mayeux, R. P.·Holtzman, D. M.·Fagan, A. M.·Morris, J. C.·Bateman, R. J.·Goate, A. M.·Cruchaga, C.·Harari, O.

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Abstract

ObjectiveTo determine whether the genetic architecture of sporadic late-onset Alzheimers Disease (sLOAD) has an effect on familial late-onset AD (fLOAD), sporadic early-onset (sEOAD) and autosomal dominant early-onset (eADAD).\n\nMethodsPolygenic risk scores (PRS) were constructed using previously identified 21 genome-wide significant loci for LOAD risk.\n\nResultsWe found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. sEOAD showed the highest odds for the PRS (OR=2.27; p=1.29x10-7), followed by fLOAD (OR=1.75; p=1.12x10-7) and sLOAD (OR=1.40; p=1.21x10-3). PRS is associated with cerebrospinal fluid ptau181-A{beta}42 on eADAD.\n\nConclusionOur analysis confirms that the genetic factors identified for sLOAD also modulate risk in fLOAD and sEOAD cohorts. Furthermore, our results suggest that the burden of these risk variants is associated with familial clustering and earlier-onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset.

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Del Aguila, J. L., Saef, B., Black, K., Fernandez, M.-V., John Budde, J., Ibanez, L., Kapoor, M., Tosto, G., Mayeux, R. P., Holtzman, D. M., Fagan, A. M., Morris, J. C., Bateman, R. J., Goate, A. M., Cruchaga, C., Harari, O.. 2017-07-19. Polygenic Risk Score of Sporadic Late Onset Alzheimer Disease Reveals a Shared Architecture with the Familial and Early Onset Forms. https://doi.org/10.1101/165209

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