Missense and Loss of Function Variants at GWAS Loci in Familial Alzheimer’s Disease

BACKGROUND Few rare variants have been identified in genetic loci from genome wide association studies of Alzheimer’s disease (AD), limiting understanding of mechanisms and risk assessment, and genetic counseling. METHODS Using genome sequencing data from 197 families in The NIA Alzheimer’s Disease Family Based Study, and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study. RESULTS Eighty-six rare missense or loss of function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) of families APOE-e4 was the only variant segregating. However, in 60.3% of families neither APOE-e4 nor missense or LoF variants were found within the GWAS loci. DISCUSSION Although APOE-ε4 and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants.