NOVEL CANDIDATE VARIANTS IN LOAD DETECTED BY THE FAMILIAL ALZHEIMER SEQUENCING (FASE) PROJECT

Abstract

Recent studies suggest that the missing heritability in Alzheimer disease (AD) may lie under the cumulative effect of rare variants that cause functional changes. Families enriched in AD cases are a powerful source for detecting novel variants that may confer risk towards disease. In this work we analyze a highly selected cohort of 493 multigenerational families enriched in late onset AD cases for the identification of novel variants and genes implicated on AD. We have performed whole-exome or whole-genome sequencing on 1,077 clinically diagnosed LOAD and 440 non-demented relatives. All samples were recruited by the Knight ADRC or the NIA-LOAD family study group. Variant discovery was performed following GATK's best practice followed by stringent quality control. We focused our analysis on nonsynonymous variants with a minor allele frequency <1% in the general population (ExAC). We perform genome-wide scans to examine the presence of causative and low frequency coding variants in the most common neurodegenerative diseases, as well as in novel candidate genes. Known pathogenic mutations were found in 4.42% of the families as well as an enrichment of non-synonymous variants in AD and frontotemporal lobular dementia (FTLD) genes. We have detected potential risk variants that present perfect segregation in several families of 7 members in addition to few novel candidate genes with genome-wide significance associated to disease risk. Known pathogenic and low frequency coding variants in AD, FTD and PD genes can be found in clinical AD cases; indicating that more stringent selecting criteria and genetic testing must be performed before incorporating new samples into analysis. We have identified some preliminary candidate variants and genes that would confer risk to AD; network analysis and replication are underway.