The Dissection of High-Penetrance Variants in Extended Late-Onset Alzheimer Disease Families by Whole-Exome Sequencing (S28.004)

OBJECTIVE: The identification of highly penetrant genetic variants in familial Late-Onset Alzheimer Disease (LOAD). BACKGROUND: Mutations in APP, PSEN1 and 2 cause familial, early-onset AD. Variants in APOE and TREM2 confer high risk to LOAD besides 20 GWAS-identified low risk loci. A considerable proportion of LOAD heritability still remains unexplained. DESIGN/METHODS: We chose 6 multi-generational LOAD families that are consistent with dominant inheritance, have an average of 6 affected subjects, and are free of known AD mutations. We performed whole-exome sequencing (WES) on 4-9 affected subjects per pedigree. For validation, we used the Alzheimer’s Disease Genetics Consortium’s (ADGC) rare variant case-control data set composed of 13,748 individuals (7,652 cases) genotyped on the Illumina Exome Chip. We filtered WES-identified variants by applying the following criteria: (1) segregation with LOAD allowing for one phenocopy per pedigree, (2) MAF<2%,(3) non-synonymous variants at evolutionary conserved sites predicted to be deleterious (4) allelic case-control association odds ratio (OR) >2, if available, in the ADGC data set. RESULTS: Thirty-four variants passed these criteria of which 47% were absent from public data bases and only 7 variants had ADGC data (DYM, EPHA7, LONRF3, MYO3B, PPP1R12A, TBC1D8B, TTC3). Known functions of mentioned genes are regulation of actin-myosin interaction, brain development, Rab GTPase activation and neuronal survival. In a second approach, we did not require an OR>2 and lowered the segregation criterion to two phenocopies per pedigree. We obtained 63 genes of which five (CAPZA3, LONRF3, LRP1B, MYO3B, TBC1D17) showed nominally significant associations in gene-based tests of the ADGC. TBC1D17 is another Rab GTPase-activating protein and LRP1B is a low-density lipoprotein receptor involved in amyloid β clearance. CONCLUSIONS: These variants are extremely rare and may well qualify as high-penetrance AD variants. Most promising are completely segregating variants in genes that also obtained gene-based nominal significance (LONRF3, MYO3B), or have been functionally linked to AD (LRP1B). Study Supported by: Disclosure: Dr. Kohli has nothing to disclose. Dr. Kunkle has nothing to disclose. Dr. Naj has nothing to disclose. Dr. Wang has received license fee payments from Johnson & Johnson. Dr. Hamilton has nothing to disclose. Dr. Perry has nothing to disclose. Dr. Carney has nothing to disclose. Dr. Whitehead has nothing to disclose. Dr. Gilbert has nothing to disclose. Dr. Martin has nothing to disclose. Dr. Beecham has nothing to disclose. Dr. Haines has nothing to disclose. Dr. Schellenberg has nothing to disclose. Dr. Zuchner has received license fee payments from Athena Diagnostics. Dr. Pericak-Vance has received personal compensation for activities with the University of Alaska.