Effect of prioritized SORL1 missense variants supports clinical consideration for familial Alzheimer's Disease
Holstege, H.; de Waal, M. W. J.; Tesi, N.; van der Lee, S. J.; ADES consortium, ; ADSP consortium, ; StEP-AD consortium, ; Knight-ADRC, ; UCSF/NYGC/UAB, ; Vogel, M.; van Spaendonk, R.; Hulsman, M.; Andersen, O. M.
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BackgroundProtein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimers Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. MethodsTo identify high-priority missense variants (HPVs), we applied domain mapping of disease mutations on the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls. ResultsIn this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is [~]8-10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects. ConclusionOur results justify a debate on whether HPV carriers should be considered for clinical counseling.
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