Structural variation detection and association analysis of whole-genome-sequence data from 16,543 Alzheimer's disease sequencing project subjects.

Introduction: The role of structural variations (SVs) in Alzheimer's disease (AD) remains understudied.

Methods: We analyzed whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (N = 16,543) and identified 400,234 (168,223 high-quality) SVs. Laboratory validation yielded a sensitivity of 82% (85% for high-quality).

Results: We found a burden of singletons (odds ratio [OR] = 1.07, p = 0.0017) and homozygous deletions (OR = 1.14, p < 0.0001) in cases. 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 LD (R = 0.99) with rs143080277 in NCK2. We identified a rare deletion near RNA5SP293 associated with AD (OR = 1.99, p = 1.3 × 10), which was replicated using an independent dataset.

Discussion: This study highlights the pivotal role of SVs in AD genetics.

Highlights: Observed a significant burden of singletons and homozygous deletions in Alzheimer's disease (AD) patients. Identified rare protein-altering structural variations (SVs) in ABCA7, APP, PLCG2, and SORL1. Established linkages between SVs and AD risk-associated single nucleotide variants (SNVs). Discovered a novel deletion near RNA5SP293 linked to AD, replicated independently. Uncovered over-representation of SVs in neuronal function pathways.