Recessive missense variants in VWA2 increase risk of developing Alzheimer’s disease

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is the most frequent cause of neurodegenerative dementia and presents at early (age at onset (AAO) ≤65 years, EOAD) or late age (LOAD). Only 5‐10% of EOAD patients are explained by dominant mutations in AD genes, APP, PSEN1 or PSEN2. We aimed at finding recessive mutations in patients that are not genetically explained.MethodsThe Flanders‐Belgian AD cohort (n = 1166) included 170 EOAD (AAO 57.96 ± 6.32 years; range 29‐65) and 996 LOAD (AAO 77.55 ± 6.30 years; range 66‐95) patients. Whole Genome Sequencing (WGS) was provided by Complete Genomics, BGI. The WGS data was searched for recessive variants, altering protein sequences and a minor allele frequencies ≤5%. Gene‐based resequencing was performed using target amplification assays.ResultsWe selected 18 EOAD patients with a well‐documented clinical or pathological diagnosis for WGS analysis. Mean AAO was 56.17 ± 6.90 years (range 37‐65) and 6 patients had pathological confirmed EOAD. One EOAD patient (AAO 64) was homozygous for p.V366M in the gene Von Willebrand Factor A Domain Containing 2 (VWA2). Resequencing of VWA2 in the AD patient cohort identified 1 additional EOAD (AAO 60) and 3 LOAD patients (AAO range 74‐90) with homozygous (p.R69M, p.V366M) or heterozygous (p.V366M/p.L715F) compound variants. Allele sharing analysis of the compound carriers identified common haplotypes flanking p.V366M and p.L715F, suggesting shared ancestors.ConclusionsWe identified 5 AD patients with trans compound variants in VWA2, 2 EOAD patients (2/170; 1.2%) and 3 LOAD patients (3/996; 0.3%). None of the compound carriers had first‐degree relatives with dementia, fitting autosomal recessive inheritance. The observed frequency of compound carriers in the AD patient groups was higher than expected based on the single allele frequencies calculated in our Flemish‐Belgian population. Overall, our genetic results suggest that compound variants in VWA2 might increase risk for AD. VWA2 is likely part of the extracellular exosomes, which are contributing to neuronal interaction and have a role in AD pathology. Genetic replication in independent AD patients cohorts and functional studies will be needed to understand the contribution of the biological function of VWA2 to AD.