Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy

Author:

Wang HuiORCID,Chang Timothy SORCID,Dombroski Beth A,Cheng Po-LiangORCID,Patil Vishakha,Valiente-Banuet Leopoldo,Farrell Kurt,Mclean Catriona,Molina-Porcel Laura,Rajput Alex,De Deyn Peter PaulORCID,Bastard Nathalie LeORCID,Gearing Marla,Kaat Laura Donker,Van Swieten John C,Dopper Elise,Ghetti Bernardino FORCID,Newell Kathy LORCID,Troakes ClaireORCID,de Yébenes Justo G,Rábano-Gutierrez Alberto,Meller Tina,Oertel Wolfgang HORCID,Respondek GesineORCID,Stamelou Maria,Arzberger Thomas,Roeber Sigrun,Müller Ulrich,Hopfner Franziska,Pastor PauORCID,Brice AlexisORCID,Durr AlexandraORCID,Ber Isabelle Le,Beach Thomas G,Serrano Geidy EORCID,Hazrati Lili-Naz,Litvan IreneORCID,Rademakers RosaORCID,Ross Owen A,Galasko Douglas,Boxer Adam L,Miller Bruce LORCID,Seeley Willian W,Van Deerlin Vivanna MORCID,Lee Edward B,White Charles LORCID,Morris HuwORCID,de Silva RohanORCID,Crary John F,Goate Alison MORCID,Friedman Jeffrey S,Leung Yuk YeeORCID,Coppola GiovanniORCID,Naj Adam CORCID,Wang Li-San,Dickson Dennis WORCID,Höglinger Günter U,Schellenberg Gerard D,Geschwind Daniel H,Lee Wan-PingORCID,

Abstract

AbstractBackgroundProgressive 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).MethodIn 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.ResultsOur analysis of common SNVs and indels confirmed known genetic loci atMAPT,MOBP, STX6,SLCO1A2,DUSP10, andSP1, and further uncovered novel signals inAPOE,FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer’s disease (AD), we observed theAPOEε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association inZNF592and 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, includingIGH,PCMT1,CYP2A13, andSMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P= 6.73×10-3) in PSP.ConclusionsThrough WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Publisher

Cold Spring Harbor Laboratory

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