Structural variations (SVs) are important contributors to the genetics of human diseases. However, their role in Alzheimer's disease (AD) remains largely unstudied due to challenges in accurately detecting SVs. We analyzed whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (N = 16,905) and identified 400,234 (168,223 high-quality) SVs. Laboratory validation yielded a sensitivity of 82% (85% for high-quality). We found a significant burden of deletions and duplications in AD cases, particularly for singletons and homozygous events. On AD genes, we observed the ultra-rare SVs associated with the disease, including protein-altering SVs in ABCA7, APP, PLCG2, and SORL1. Twenty-one SVs are in linkage disequilibrium (LD) with known AD-risk variants, exemplified by a 5k deletion in complete LD with rs143080277 in NCK2. We also identified 16 SVs associated with AD and 13 SVs linked to AD-related pathological/cognitive endophenotypes. This study highlights the pivotal role of SVs in shaping our understanding of AD genetics.
Keywords: Alzheimer’s disease; Copy number variation; Structural variation.