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. 

Zoran Brkanac, M.D.

R01 AG039700

P50 AG005136

Acknowledgment statement for any data distributed by NIAGADS:

Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689), funded by the National Institute on Aging.

For investigators using Brkanac_Families data:

This work was partially supported by grant funding from NIH R01 AG039700 and NIH P50 AG005136. Subjects and samples used here were originally collected with grant funding from NIH U24 AG026395, U24 AG021886, P50 AG008702, P01 AG007232, R37 AG015473, P30 AG028377, P50 AG05128, P50 AG16574, P30 AG010133, P50 AG005681, P01 AG003991, U01MH046281, U01 MH046290 and U01 MH046373. The funders had no role in study design, analysis or preparation of the manuscript. The authors declare no competing interests.

Saad, M., Brkanac, Z. and Wijsman, E. M. (2015), Family‐based genome scan for age at onset of late‐onset Alzheimer’s disease in whole exome sequencing data. Genes, Brain and Behavior, 14: 607-617. doi:10.1111/gbb.122506.