Rare highly penetrant variants of late onset Alzheimers disease. J. Rehker1, R. Levy1, R. Nesbitt1, Q. Yi2, B. Martin2, D. Nickerson2, W. Raskind2, J. Shendure2, Z. Brkanac1 1) Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA; 2) Department of Genome Sciences, University of Washington, Seattle, WA.

   Alzheimer's disease (AD) is the most common cause of dementia in US, affecting approximately 5% of individuals older than age 70. Highly penetrant mutations in three genes (APP, PSEN1 and PSEN2) are responsible for majority of cases of early-onset disease (<60-65 years). Late onset disease (age >60-65 years) represents more then 95% of cases and it is familial in 15% to 25%. The main risk factor for late-onset disease is the ApoE gene that contributes to some of family clustering. The whole genome association studies have identified approximately dozen low-risk genes associated with the disease. Recently rare variants in TREM2 gene were identified as significant AD risk factor with odds ratio comparable to ApoE. This indicates that additional rare highly penetrant variants remain to be found. To detect additional highly penetrant AD genes we have identified 19 families with four or more affected cases in NIA and NIMH AD collections. In our sample average age of onset of the disease was 68.97 10.55 years. Under assumption that functional private variants are causal, exome sequencing allows for gene identification in small families. For each person the exome on average has less then 200 private functional variants. We define private functional variants as not seen in 1000 genomes, ESP6500 and dbSNP135 data and having potential for function altering like missense, frameshift, gain of stop codons or changes in splicing sites. Exomes were sequenced at University of Washington Northwest Genomic Center. Sequencing, read alignment and variant calling were performed using stringent parameters for discovery of private variants. We have sequenced 37 exomes. Our variant call and filtering criteria identified 1-23 functional private variants shared between exome sequenced cases in each family. Identified variants were confirmed with capillary sequencing and present in remaining affected cases in each family. This analysis has resulted in the identification of 1-2 private functional variants that are present in all, or most affected cases in each family. To identify genes associated with AD for 23 candidate genes identified in our families we are performing a large case control study involving ~ 1000 cases of familial AD and 500 non-demented elderly controls. For case-control study we are employing gene-based approach and sequencing of candidate genes using molecular inversion probes and next generation sequencing.

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