Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy.
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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, Kaat Laura Donker, Van Swieten John C, Dopper Elise, Ghetti Bernardino F, Newell Kathy L, Troakes Claire, de Yébenes Justo G, Rábano-Gutierrez Alberto, Meller Tina, Oertel Wolfgang H, Respondek Gesine, Stamelou Maria, Arzberger Thomas, Roeber Sigrun, Müller Ulrich, Hopfner Franziska, Pastor Pau, Brice Alexis, Durr Alexandra, Le Ber Isabelle, Beach Thomas G, Serrano Geidy E, Hazrati Lili-Naz, Litvan Irene, Rademakers Rosa, Ross Owen A, Galasko Douglas, Boxer Adam L, Miller Bruce L, Seeley Willian W, Van Deerlin Vivanna M, Lee Edward B, White Charles L, Morris Huw, de Silva Rohan, Crary John F, Goate Alison M, Friedman Jeffrey S, Leung Yuk Yee, Coppola Giovanni, Naj Adam C, Wang Li-San, P. S. P. genetics study group, Dalgard Clifton, Dickson Dennis W, Höglinger Günter U, Schellenberg Gerard D, Geschwind Daniel H, Lee Wan-Ping
Аннотация
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.