Description
In this study, a family-based genome-wide association study was performed for AAO of late-onset AD in whole exome sequence data generated in multigenerational families with multiple AD cases (n=77). Single marker and gene-based burden tests were conducted for common and rare variants, respectively. Association analyses were combined with variance component linkage analysis, and with reference to prior studies, in order to enhance evidence of the identified genes. For variants and genes implicated by the association study, a gene-set enrichment analysis was performed to identify potential novel pathways associated with AAO of AD. Subjects were selected from pedigrees with multiple cases of late onset AD (>60 years onset age) in multigenerational families. AD affection status was defined as meeting NINCDS-ADRDA criteria for definite, probable or possible AD. Subjects were required to be of European ancestry. Study findings included statistically significant association with AAO for three genes (WRN, NTN4 and LAMC3) with common associated variants, and for four genes (SLC8A3, SLC19A3, MADD and LRRK2) with multiple rare-associated variants that have a plausible biological function related to AD. The genes identified in this study are in pathways that are strong candidates for involvement in the development of AD pathology and may lead to a better understanding of AD pathogenesis.