Contribution of compound variants in VWA2 to Alzheimer’s disease.

Abstract Alzheimer’s disease is the most frequent diagnosis of neurodegenerative dementia with early (≤ 65 years) and late (> 65 years) onset ages in familial and sporadic patients. Causal mutations in three autosomal dominant Alzheimer genes, i.e. amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2), explain only 5-10 % of early-onset patients leaving the majority of patients genetically unresolved. To discover potential missing genetics, we used whole genome sequencing data of 17 early-onset patients with well-documented clinical diagnosis of Alzheimer’s disease. In the discovery group, the mean onset age was 55.71 ± 6.83 years (range 37-65). Six patients had a brain autopsy and neuropathology confirmed Alzheimer’s disease. Analysis of the genetic data identified in one patient a homozygous p.V366M variant in the Von Willebrand factor A domain containing 2 gene (VWA2). Resequencing of the VWA2 coding region in an AD cohort from Flanders-Belgium (n=1148), including 152 early and 996 late onset patients, identified homozygous and compound heterozygous trans variants in one early and three late-onset patients. Allele-sharing analysis identified common haplotypes among the VWA2 variant carriers, suggesting shared ancestors. Overall, we identified five patient carriers of homozygous or compound heterozygous variants (5/1165; 0.43 %), two in early (2/169; 1.18 %) and 3 in late-onset (3/996; 0.30 %) patients. The frequencies of the compound variants in patients are higher than expected from the frequencies calculated based on their combined single alleles. None of the homozygous/compound heterozygous variant carriers had a family history of autosomal dominant Alzheimer’s disease. Our findings suggest that compound variants in VWA2 might contribute to the risk of Alzheimer’s disease in sporadic patients.