Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer’s Diseases Sequencing Project Subjects

Structural variations (SVs) are important contributors to the genetics of numerous human diseases. However, their role in Alzheimer’s disease (AD) remains largely unstudied due to challenges in accurately detecting SVs. Here, we analyzed whole-genome sequencing data from the Alzheimer’s Disease Sequencing Project (ADSP, N=16,905 subjects) and identified 400,234 (168,223 high-quality) SVs. We found a significant burden of deletions and duplications in AD cases (OR=1.05, P =0.03), particularly for singletons (OR=1.12, P =0.0002) and homozygous events (OR=1.10, P <0.0004). On AD genes, the ultra-rare SVs, including protein-altering SVs in ABCA7 , APP , PLCG2 , and SORL1 , were associated with AD (SKAT-O P =0.004). Twenty-one SVs are in linkage disequilibrium (LD) with known AD-risk variants, e.g., a deletion (chr2:105731359-105736864) in complete LD (R2=0.99) with rs143080277 (chr2:105749599) in NCK2 . We also identified 16 SVs associated with AD and 13 SVs associated with AD-related pathological/cognitive endophenotypes. Our findings demonstrate the broad impact of SVs on AD genetics. Search Terms Alzheimer’s disease, Structural variation, Copy number variation ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement HW and PLC report grant support from RF1-AG074328 and P30-AG072979. AT, YQS, and JYT report grant support from RF1-AG074328. YYL reports grant support from U54-AG052427 and U24-AG041689. LSW reports grant support from U24-AG041689, U54-AG052427, U01-AG032984, U01-AG058654, and P30AG072979. LAF reports grant support from U54-AG052427, U01-AG058654, U01-AG062602, R01-AG048927, and P30-AG072978. WPL reports grant support from RF1-AG074328, P30-AG072979, U54-AG052427, and U24-AG041689. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes https://www.niagads.org/home