Copy Number Variation and Haplotype Analysis of 17q21.31 Reveals Increased Risk Associated with Progressive Supranuclear Palsy and Gene Expression Changes in Neuronal Cells

• Published in: Movement disorders Vol. 40; no. 5; pp. 950 - 961
• Main Authors: Wang, Hui, Chang, Timothy S., Dombroski, Beth A., Cheng, Po‐Liang, Si, Ya‐Qin, Tucci, Albert, Patil, Vishakha, Valiente‐Banuet, Leopoldo, Li, Chong, 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, 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, Vivianna M., Lee, Edward B., White, Charles L., Morris, Huw R., Silva, Rohan, Crary, John F., Goate, Alison M., Friedman, Jeffrey S., Compta, Yaroslau, Leung, Yuk Yee, Coppola, Giovanni, Naj, Adam C., Wang, Li‐San, Lang, Anthony E., Grossman, Murray, Knopman, David S., Schneider, Lon S., Doody, Rachelle S., Lees, Andrew, Golbe, Lawrence I., Williams, David R., Corvol, Jean‐Cristophe, Ludolph, Albert, Burn, David, Lorenzl, Stefan, Roberson, Erik D., Koestler, Mary, Jack, Clifford R., Randolph, Christopher, Lobach, Iryna V., Heuer, Hilary W., Gozes, Illana, Parker, Lesley, Whitaker, Steve, Hirman, Joe, Stewart, Alistair J., Gold, Michael, Morimoto, Bruce H., Herms, Jochen, Gelpi, Ellen, Dalgard, Clifton, Dickson, Dennis W., Höglinger, Günter U., Tzeng, Jung‐Ying, Geschwind, Daniel H., Schellenberg, Gerard D., Lee, Wan‐Ping
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.05.2025
• Subjects: 17q21.31; Aged; Chromosomes, Human, Pair 17 - genetics; copy number variations; DNA Copy Number Variations - genetics; Female; Gene Expression; Genetic Predisposition to Disease - genetics; H1 and H2 haplotypes; Haplotypes - genetics; Humans; Male; Middle Aged; Neurons - metabolism; progressive supranuclear palsy; single‐cell gene expression; Supranuclear Palsy, Progressive - genetics; 17q21.31; H1 and H2 haplotypes; copy number variations; single‐cell gene expression; progressive supranuclear palsy
• ISSN: 0885-3185; 1531-8257; 1531-8257
• DOI: 10.1002/mds.30150

Background The 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP). Objective To investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP. Methods Utilizing whole genome sequencing data from 1684 PSP cases and 2392 controls, the three large CNVs (α, β, and γ) and structural forms within 17q21.31 were identified and analyzed for their association with PSP. Results We found that the copy number of γ was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1β1γ1 (OR = 1.21) and H1β2γ1 (OR = 1.24) to H1β1γ4 (OR = 1.57), structural forms of H1 with additional copies of γ displayed a higher risk for PSP. The frequency of the risk sub‐haplotype H1c rises from 1% in individuals with two γ copies to 88% in those with eight copies. Additionally, γ duplication up‐regulates expression of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while down‐regulating KANSL1. Single‐nucleus RNA‐seq of the dorsolateral prefrontal cortex analysis reveals γ duplication primarily up‐regulates LRRC37A/LRRC37A2 in neuronal cells. Conclusions The copy number of γ is associated with the risk of PSP after adjusting for H1/H2, indicating that the complex structure at 17q21.31 is an important consideration when evaluating the genetic risk of PSP. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.