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

Hui Wang; Beth A Dombroski; Po-Liang Cheng; Albert Tucci; Ya-Qin Si; John J Farrell; Jung-Ying Tzeng; Yuk Yee Leung; John S Malamon; Alzheimer’s Disease Sequencing Project; Li-San Wang; Badri N Vardarajan; Lindsay A Farrer; Gerard D Schellenberg; Wan-Ping Lee

doi:10.1101/2023.09.13.23295505

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

medRxiv [Preprint]. 2023 Sep 13:2023.09.13.23295505. doi: 10.1101/2023.09.13.23295505.

Authors

Hui Wang^{1

2}, Beth A Dombroski^{1

2}, Po-Liang Cheng^{1

2}, Albert Tucci³, Ya-Qin Si³, John J Farrell⁴, Jung-Ying Tzeng³, Yuk Yee Leung^{1

2}, John S Malamon⁵; Alzheimer’s Disease Sequencing Project; Li-San Wang^{1

2}, Badri N Vardarajan^{6

7}, Lindsay A Farrer^{4

8

9

10

11}, Gerard D Schellenberg^{1

2}, Wan-Ping Lee^{1

2}

Affiliations

¹ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA.
² Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA.
³ Bioinformatics Research Center, North Carolina State University, NC 27695, USA.
⁴ Department of Medicine (Biomedical Genetics), Boston University School of Medicine, MA 02118, USA.
⁵ Department of Surgery, Scholl of Medicine, University of Colorado, CO 80045, USA.
⁶ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, NY 10032, USA.
⁷ Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, NY 10032, USA.
⁸ Department of Neurology, Boston University School of Medicine, MA 02118, USA.
⁹ Department of Ophthalmology, Boston University School of Medicine, MA 02118, USA.
¹⁰ Department of Biostatistics, Boston University School of Public Health, MA 02118, USA.
¹¹ Department of Epidemiology, Boston University School of Public Health, MA 02118, USA.

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.

Publication types

Preprint

Abstract

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