A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease.
Daniela HartlPatrick MayWei GuManuel MayhausSabrina PichlerChristian SpaniolEnrico GlaabDheeraj Reddy BobbiliPaul AntonySandra KoegelsbergerAlexander KurzTimo GrimmerKevin MorganBadri N VardarajanChristiane ReitzJohn HardyJose BrasRita GuerreiroRudi BallingJochen G SchneiderMatthias Riemenschneidernull nullPublished in: Molecular psychiatry (2018)
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.
Keyphrases
- late onset
- early onset
- gene expression
- case control
- genome wide
- copy number
- dna methylation
- genome wide association
- ejection fraction
- electronic health record
- end stage renal disease
- prognostic factors
- mild cognitive impairment
- poor prognosis
- high throughput
- small molecule
- artificial intelligence
- genome wide identification
- patient reported outcomes
- binding protein
- bioinformatics analysis
- genome wide analysis