TY - JOUR
T1 - Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy
AU - P. S. P. genetics study group
AU - Wang, Hui
AU - Chang, Timothy S.
AU - Dombroski, Beth A.
AU - Cheng, Po Liang
AU - Patil, Vishakha
AU - Valiente-Banuet, Leopoldo
AU - Farrell, Kurt
AU - Mclean, Catriona
AU - Molina-Porcel, Laura
AU - Rajput, Alex
AU - De Deyn, Peter Paul
AU - Le Bastard, Nathalie
AU - Gearing, Marla
AU - Kaat, Laura Donker
AU - Van Swieten, John C.
AU - Dopper, Elise
AU - Ghetti, Bernardino F.
AU - Newell, Kathy L.
AU - Troakes, Claire
AU - de Yébenes, Justo G.
AU - Rábano-Gutierrez, Alberto
AU - Meller, Tina
AU - Oertel, Wolfgang H.
AU - Respondek, Gesine
AU - Stamelou, Maria
AU - Arzberger, Thomas
AU - Roeber, Sigrun
AU - Müller, Ulrich
AU - Hopfner, Franziska
AU - Pastor, Pau
AU - Brice, Alexis
AU - Durr, Alexandra
AU - Le Ber, Isabelle
AU - Beach, Thomas G.
AU - Serrano, Geidy E.
AU - Hazrati, Lili Naz
AU - Litvan, Irene
AU - Rademakers, Rosa
AU - Ross, Owen A.
AU - Galasko, Douglas
AU - Boxer, Adam L.
AU - Miller, Bruce L.
AU - Seeley, Willian W.
AU - Van Deerlin, Vivanna M.
AU - Lee, Edward B.
AU - White, Charles L.
AU - Morris, Huw
AU - de Silva, Rohan
AU - Crary, John F.
AU - Goate, Alison M.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
KW - Apolipoprotein E (APOE)
KW - Genome-Wide Association Study (GWAS)
KW - Progressive Supranuclear Palsy (PSP)
KW - Structural Variants (SVs)
KW - Whole-Genome Sequencing (WGS)
UR - http://www.scopus.com/inward/record.url?scp=85201568640&partnerID=8YFLogxK
U2 - 10.1186/s13024-024-00747-3
DO - 10.1186/s13024-024-00747-3
M3 - Article
AN - SCOPUS:85201568640
SN - 1750-1326
VL - 19
JO - Molecular Neurodegeneration
JF - Molecular Neurodegeneration
IS - 1
M1 - 61
ER -