Although it is well established that familial Alzheimer disease (AD) has a strong genetic basis, additional Mendelian genes remain to be identified. Mutations in the APP, PSEN1 or PSEN2 genes are involved in minority of AD families and are characterized with early disease onset. Large genome-wide association studies have not found strong evidence for the contribution of common variants besides the APOE gene. Although many families with pedigrees suggestive of autosomal dominant inheritance have been described and linkage studies have found evidence for multiple contributing loci, no new genes have been identified in the last 20 years. The goal of this proposal is to apply novel analytic approaches to identify families in which AD is likely to have a single gene etiology and to utilize next generation sequencing technologies to find these genes. The University of Washington (UW) AD collection contains more than twenty families where pedigrees are consistent with Mendelian inheritance. To identify additional families where single genes are likely to be causal, we will use the existing, well characterized National Institute of Aging (NIA) and National Institute of Mental Health (NIMH) AD collections with more than 700 families. In these collections, for which extensive genotype data is available, we will perform segmental Identity-by-Descent (IBD) mapping and Homozygosity-by-Descent (HBD) analysis to detect families that share a common ancestor within the past three to nine generations. Given the ascertainment of probands based on disease status it is expected that the relatedness uncovered by these analyses reflects inheritance of a shared causal mutation from the recent common ancestor. To identify candidate genes in UW families with pedigrees, and NIA and NIMH families that share recent ancestry as defined by IBD and HBD analyses, we will perform exome capture and massively parallel sequencing followed by bioinformatics analysis and evaluation of co-segregation. To establish association of identified candidate genes with AD we will perform gene-based mutational load case-control studies with more than 200 familial AD cases and 2,000 population controls. Finally, to facilitate validation of our findings we will deposit sequence information in a public database. The identification of novel AD genes would be a significant step towards an increased understanding of the genetic architecture of AD. These genes would enable development of diagnostic tests and implicate new or expanded molecular pathways involved in AD pathogenesis. Examination of these pathways will likely reveal additional therapeutic targets. This study will also establish the utility of our innovative analytical approach combined with exome sequencing as a powerful method for the identification of genes for Mendelian forms of common genetically heterogeneous disorders.

Public Health Relevance

The proposed research has major relevance for public health. Alzheimer disease (AD) affects 5% of individuals by age 70 and is a leading cause of morbidity and mortality in the aging US population. It constitutes a significant familial and societal burden. Some medications that slow the progression of disease are available, but there are no known preventions or cures. AD has a substantial genetic contribution and although some single gene subtypes are known, more AD genes remain to be found. The goal of this proposal is to discover novel single gene causes of AD. The identification of new genes and pathways involved in AD will provide a foundation for improved diagnostic and therapeutic strategies. .

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Miller, Marilyn
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University of Washington
Schools of Medicine
United States
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Saad, Mohamad; Nato Jr, Alejandro Q; Grimson, Fiona L et al. (2016) Identity-by-descent estimation with population- and pedigree-based imputation in admixed family data. BMC Proc 10:295-301
Nato Jr, Alejandro Q; Chapman, Nicola H; Sohi, Harkirat K et al. (2015) PBAP: a pipeline for file processing and quality control of pedigree data with dense genetic markers. Bioinformatics 31:3790-8
Korvatska, Olena; Leverenz, James B; Jayadev, Suman et al. (2015) R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family: Clinical, Genetic, and Neuropathological Study. JAMA Neurol 72:920-7
Saad, M; Brkanac, Z; 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 Behav 14:607-17
Cheung, Charles Y K; Marchani Blue, Elizabeth; Wijsman, Ellen M (2014) A statistical framework to guide sequencing choices in pedigrees. Am J Hum Genet 94:257-67
Saad, Mohamad; Wijsman, Ellen M (2014) Combining family- and population-based imputation data for association analysis of rare and common variants in large pedigrees. Genet Epidemiol 38:579-90
Cheung, Charles Y K; Thompson, Elizabeth A; Wijsman, Ellen M (2014) Detection of Mendelian consistent genotyping errors in pedigrees. Genet Epidemiol 38:291-9
Cruchaga, Carlos; Karch, Celeste M; Jin, Sheng Chih et al. (2014) Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease. Nature 505:550-554
Saad, Mohamad; Wijsman, Ellen M (2014) Power of family-based association designs to detect rare variants in large pedigrees using imputed genotypes. Genet Epidemiol 38:1-9
Blue, Elizabeth M; Sun, Lei; Tintle, Nathan L et al. (2014) Value of Mendelian laws of segregation in families: data quality control, imputation, and beyond. Genet Epidemiol 38 Suppl 1:S21-8

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