Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy

Wang, Hui

Chang, Timothy S.

Dombroski, Beth A.

Cheng, Po-Liang

Patil, Vishakha

Valiente-Banuet, Leopoldo

Farrell, Kurt

Mclean, Catriona

Molina-Porcel, Laura

Rajput, Alex

De Deyn, Peter Paul

Le Bastard, Nathalie

Gearing, Marla

Donker Kaat, Laura

Van Swieten, John C.

Dopper, Elise

Ghetti, Bernardino F.

Newell, Kathy L.

Troakes, Claire

de Yébenes, Justo G.

PSP Genetics Study Group

Background Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer’s disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73×10-3) in PSP. Conclusions Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

English

medRxiv , 2024

10.1101/2023.12.28.23300612

(2024) , p. 1-47

38234807

https://doi.org/10.1101/2023.12.28.23300612

Licensed under a CC-BY-NC-ND Attribution-NonCommercial-NoDerivs license

Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences 

Preprint 

Human medicine 

Publications with a UAntwerp address

https://www.medrxiv.org/content/10.1101/2023.12.28.23300612v2

https://hdl.handle.net/10067/2037210151162165141