--- title: "Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy– Wang et al., 2024" id: "7268" type: "study" slug: "sa000064" published_at: "2024-12-17T20:55:29+00:00" modified_at: "2026-03-26T16:35:50+00:00" url: "https://dss.niagads.org/studies/sa000064/" markdown_url: "https://dss.niagads.org/studies/sa000064.md" excerpt: "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..." --- ## Description 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). 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. Our analysis of common SNVs and indels confirmed known genetic loci at *MAPT*, *MOBP*, S*TX6*, *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. Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions. ## PI Wan-Ping Lee *University of Pennsylvania* ## Associated Datasets - [NG00172 - GWAS Summary Statistics of SNVs/INDELs/SVs for Progressive Supranuclear Palsy (PSP) – Wang et al., 2024](https://dss.niagads.org/datasets/ng00172/) Participants for this analysis were selected with whole-genome sequencing at 30x coverage from the Alzheimer’s Disease Sequencing Project dataset (ADSP, ng00067.v7). Included were 1,834 PSP cases and 128 controls from… [Learn more](https://dss.niagads.org/datasets/ng00172/) ## Grants 5UG3NS104095 ## Acknowledgement ### Acknowledgment statement for any data distributed by NIAGADS: Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689), funded by the National Institute on Aging. ### For investigators using Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy – Wang et al., 2024 data: This work was supported by NIH 5UG3NS104095, the Rainwater Charitable Foundation, and CurePSP. HW and PLC are supported by RF1-AG074328, P30-AG072979, U54-AG052427 and U24-AG041689. TSC is supported by NIH K08AG065519 and the Larry L Hillblom Foundation 2021-A-005-SUP. KF was supported by CurePSP 685–2023-06-Pathway and K01 AG070326. MG is supported by P30 AG066511. BFG and KLN are supported by P30 AG072976 and R01 AG080001. TGB and GES are supported by P30AG072980. IR is supported by 2R01AG038791-06A, U01NS100610, R25NS098999, U19 AG063911-1 and 1R21NS114764-01A1. OR is support by U54 NS100693. DG is supported by P30AG062429. ALB is supported by U19AG063911, R01AG073482, R01AG038791, and R01AG071756. BLM is supported by P01 AG019724, R01 AG057234 and P0 544014. VMV is supported by P01-AG-066597, P01-AG-017586. HRM is supported by CurePSP, PSPA, MRC, and Michael J Fox Foundation. RDS is supported by CurePSP, PSPA, and Reta Lila Weston Trust. JFC is supported by R01 AG054008, R01 NS095252, R01 AG060961, R01 NS086736, R01 AG062348, P30 AG066514, the Rainwater Charitable Foundation / Tau Consortium, Karen Strauss Cook Research, and Scholar Award, Stuart Katz & Dr. Jane Martin. AMG is supported by the Tau Consortium and U54-NS123746. YYL is supported by U54-AG052427; U24-AG041689. LSW is supported by U01AG032984, U54AG052427, and U24AG041689. GUH was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198); Deutsche Forschungsgemeinschaft (DFG, HO2402/18–1 MSAomics); German Federal Ministry of Education and Research (BMBF, 01KU1403A EpiPD; 01EK1605A HitTau; 01DH18025 TauTherapy). DHG is supported by 3UH3NS104095, Tau Consortium. WPL is supported by RF1-AG074328; P30-AG072979; U54-AG052427; U24-AG041689. Cases from Banner Sun Health Research Institute were supported by the NIH (U24 NS072026, P30 AG19610 and P30AG072980), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05–901 and 1001 to the Arizona Parkinson's Disease Consortium) and the Michael J. Fox Foundation for Parkinson’s Research. The Mayo Clinic Brain Bank is supported through funding by NIA grants P50 AG016574, CurePSP Foundation, and support from Mayo Foundation. ## Publications - Wang H. **Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy.***Molecular neurodegeneration. 2024 Aug 16.*[PubMed link](https://pubmed.ncbi.nlm.nih.gov/39152475/)