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

Abstract

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.

Keywords: Alzheimer’s disease; Copy number variation; Structural variation.

Fig. 1:. Characteristics of high-quality SVs

A. Number of high-quality SVs per individual by ancestry. B. Principal component analysis of high-quality SV with MAF > 0.01 and Hardy-Weinberg Equilibrium (HWE) > 1e-5. C. The cumulative fractions of variants by allele frequency. D. The size distribution of high-quality SVs.

Fig. 2:. Functional annotation of SVs.

A. AnnotSV ranking scores of common (AF ≥ 0.01) and rare (AF < 0.01) high-quality SVs. The rare SVs are more likely to be deleterious with higher AnnotSV ranking scores. B. VEP annotation of common (AF ≥ 0.01) and rare (AF < 0.01) high-quality SVs. The protein-altering SVs tend to be rare. C. Percent of singletons in a specified functional category by VEP.

Fig. 4:. Ultra-rare deletion and duplication on SORL1.

A. Deletion and duplication on SORL1. B. The 192 Kb duplication covers part of SORL1 and SC5D. C. The 8.45 Kb deletion covers exon 6 of SORL1.

Fig. 5:. Association of SVs with AD and enrichment analysis.

A. Association of SVs with AD. Red line represents an FDR of 0.05. Gray line represents an FDR of 0.2. B. Enrichment analysis for high-quality SVs (nominal P < 0.05) that are not in problematic regions. BP, Biological Process; CC, Cellular Component; MF, Molecular Function; KEGG, Kyoto Encyclopedia of Genes and Genomes.