O3–01–05: The role of functional genetic variation in Alzheimer's disease: The CHARGE consortium

For validation, we performed gene-based case-control association testing in 13,748 individuals (7,652 affected) from the Alzheimer’s Disease Genetics Consortium (ADGC) genotyped on the Illumina Exome SNPArray, which included 195,039 variants with MAF<2%. Results: In each pedigree, 4-18 variants passed stringent filtering criteria (e.g., evolutionary conservation, predicted deleteriousness, identity-by-descent >75%). as potential causative LOAD variants. Examining the 60 genes implicated by these variants, five (CAPZA3, LONRF3, LRP1B, MYO3B and TBC1D17) showed nominally significant associations in gene-based tests in the ADGC dataset, with CAPZA3 and TBC1D17 withstanding correction for multiple comparison.CAPZA3 is located in the published chromosome 12 AD linkage region and encodes an actin-capping protein that stabilizes actin filaments and TBC1D17 is a Rab GTPase-activating protein implicated in endocytosis, both AD-relevant processes. Moreover, LRP1B is a low-density lipoprotein receptor that allows endocytosis of a complex of ApoE-containing lipoprotein particles bound to beta-amyloid. Conclusions: Identifying LOAD candidates from whole exome sequencing of extended LOAD families is challenging due to reduced penetrance, potential phenotypic heterogeneity and rarity of candidate alleles. Here we mitigated these challenges by validating candidates using gene-based association testing in a large consortium dataset, identifying several new LOAD candidate genes.