Characterizing complex structural variation in Alzheimer's disease

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PROJECT SUMMARY Late-onset Alzheimer’s disease (LOAD) is genetically complex and thought to be associated with variants in a number of different loci, including structural variants (SVs), which could in part explain the additional missing heritability and genetic background. However, the impact of SVs on LOAD has not been systematically explored, while findings regarding CNV associations with AD risk have been overall inconsistent. To address this gap in knowledge, we propose to fully characterize the genetic architecture of SVs in LOAD by leveraging previously generated large-scale whole genome sequencing data. To this end, we will systematically characterize SVs across 39,000 samples from multi-ethnic, well-phenotyped individuals sequenced as a part of Alzheimer’s Disease Sequencing Project (ADSP) discovery, extension replication (ADSP-DEP) and follow-up datasets (ADSP-FUS), as well as in over 1000 multiplex families. Identification of novel SVs associated with LOAD could implicate previously unknown genes and elucidate biological mechanisms that could be leveraged to generate novel therapeutics and diagnostic markers.