Objectives: Genetic studies have identified numerous single-nucleotide polymorphisms (SNPs) associated with Alzheimer’s disease (AD). However, the association between AD and structural variations (SVs) remains largely unknown. We aimed to identify novel AD-risk loci through a genome-wide association study of SVs and investigate the genome-wide contribution of SVs to AD risk.

Methods: We identified 44,122 high-confidence SVs using the long-read sequencing data of 11 Chinese genomes. We then genotyped these SVs using 35X short-read sequencing in Chinese AD cohorts, obtaining high-quality genotypes for 17,294 SVs for association analysis.

Results: We showed that the polygenic effects of common SVs account for additional AD risk beyond that explained by common SNPs. Notably, we identified a common SV in the FAM193B locus that is associated with AD risk with genome-wide significance (P = 5.5 × 10⁻¹³), revealing a new susceptibility locus of AD. Moreover, we showed that this SV acts as a causal variant by upregulating FAM193B expression and mediating the pleiotropic association between brain FAM193B expression and AD risk.

Conclusions: This study reveals a significant contribution of common SVs to AD heritability and identifies a new AD risk SV in the FAM193B locus, highlighting the importance of integrating SVs into genetic studies of AD.