Copy Number Variation and Haplotype Analysis of 17q21.31 Reveals Increased Risk Associated with Progressive Supranuclear Palsy and Gene Expression Changes in Neuronal Cells.
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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, 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 Vivianna M, Lee Edward B, White Charles L, Morris Huw R, de Silva Rohan, Crary John F, Goate Alison M, Friedman Jeffrey S, Compta Yaroslau, Leung Yuk Yee, Coppola Giovanni, Naj Adam C, Wang Li-San, PSP Genetics Study Group, Dalgard Clifton, Dickson Dennis W, Höglinger Günter U, Tzeng Jung-Ying, Geschwind Daniel H, Schellenberg Gerard D, Lee Wan-Ping
Аннотация
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.