A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease

Daniela Hartl, Patrick May, Wei Gu, Manuel Mayhaus, Sabrina Pichler, Christian Spaniol, Enrico Glaab, Dheeraj Reddy Bobbili, Paul Antony, Sandra Koegelsberger, Alexander Kurz, Timo Grimmer, Kevin Morgan, Badri N. Vardarajan, Christiane Reitz, John Hardy, Jose Bras, Rita Guerreiro, Rudi Balling, Jochen G. Schneider, Matthias Riemenschneider

Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might be explained by rare but functionally important variants. One of the so far identified genes with rare AD causing variants is ADAM10. Using whole-genome sequencing we now identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 co-segregating with an autosomal-dominant pattern of late-onset AD in one family. Subsequent genotyping and analysis of available whole-exome sequencing data of additional case/control samples from Germany, UK, and USA identified five variant carriers among AD patients only. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to loss-of-function of ADAM17 alpha-secretase. Further, we identified a strong negative correlation between ADAM17 and APP gene expression in human brain and present in vitro evidence that ADAM17 negatively controls the expression of APP. As a consequence, p.R215I mutation of ADAM17 leads to elevated Aß formation in vitro. Together our data supports a causative association of the identified ADAM17 variant in the pathogenesis of AD.