ORCID: https://orcid.org/0000-0003-4043-5060; Chang, Timothy S. ORCID: https://orcid.org/0000-0002-9225-9874; Dombroski, Beth A. ORCID: https://orcid.org/0000-0002-5334-1306; Cheng, Po‐Liang ORCID: https://orcid.org/0009-0007-0046-0313; Si, Ya‐Qin ORCID: https://orcid.org/0000-0002-9968-9754; Tucci, Albert ORCID: https://orcid.org/0000-0001-5703-7208; Patil, Vishakha; Valiente‐Banuet, Leopoldo; Li, Chong ORCID: https://orcid.org/0000-0003-1949-4074; Farrell, Kurt ORCID: https://orcid.org/0000-0001-6955-7278; Mclean, Catriona ORCID: https://orcid.org/0000-0002-0302-5727; Molina‐Porcel, Laura ORCID: https://orcid.org/0000-0003-4068-8578; Rajput, Alex ORCID: https://orcid.org/0000-0001-9656-318X; De Deyn, Peter Paul ORCID: https://orcid.org/0000-0002-2228-2964; Le Bastard, Nathalie ORCID: https://orcid.org/0000-0002-7981-2866; Gearing, Marla ORCID: https://orcid.org/0000-0002-1959-7412; Donker Kaat, Laura ORCID: https://orcid.org/0009-0007-2436-0931; Swieten, John C. Van ORCID: https://orcid.org/0000-0001-6278-6844; Dopper, Elise; Ghetti, Bernardino F. ORCID: https://orcid.org/0000-0002-1842-8019; Newell, Kathy L.; Troakes, Claire ORCID: https://orcid.org/0000-0002-1790-7376; Yébenes, Justo G. de ORCID: https://orcid.org/0000-0003-0452-3223; Rábano‐Gutierrez, Alberto; Meller, Tina ORCID: https://orcid.org/0000-0002-0239-6585; Oertel, Wolfgang H. ORCID: https://orcid.org/0000-0002-7582-8166; Respondek, Gesine ORCID: https://orcid.org/0000-0002-6851-6164; Stamelou, Maria; Arzberger, Thomas; Roeber, Sigrun; Müller, Ulrich; Hopfner, Franziska ORCID: https://orcid.org/0000-0001-6524-0281; Pastor, Pau ORCID: https://orcid.org/0000-0002-7493-8777; Brice, Alexis ORCID: https://orcid.org/0000-0002-0941-3990; Durr, Alexandra ORCID: https://orcid.org/0000-0002-8921-7104; Le Ber, Isabelle; Beach, Thomas G. ORCID: https://orcid.org/0000-0003-3296-6128; Serrano, Geidy E. ORCID: https://orcid.org/0000-0002-9527-2011; Hazrati, Lili‐Naz ORCID: https://orcid.org/0000-0003-2715-1485; Litvan, Irene ORCID: https://orcid.org/0000-0002-3485-3445; Rademakers, Rosa; Ross, Owen A. ORCID: https://orcid.org/0000-0003-4813-756X; Galasko, Douglas ORCID: https://orcid.org/0000-0001-6195-3241; Boxer, Adam L. ORCID: https://orcid.org/0000-0002-1215-5064; Miller, Bruce L. ORCID: https://orcid.org/0000-0002-2152-4220; Seeley, Willian W.; Deerlin, Vivianna M. Van ORCID: https://orcid.org/0000-0002-7400-9097; Lee, Edward B. ORCID: https://orcid.org/0000-0002-4589-1180; White, Charles L. ORCID: https://orcid.org/0000-0002-3870-2804; Morris, Huw R. ORCID: https://orcid.org/0000-0002-5473-3774; Silva, Rohan de; Crary, John F. ORCID: https://orcid.org/0000-0002-0556-293X; Goate, Alison M. ORCID: https://orcid.org/0000-0002-0576-2472; Friedman, Jeffrey S.; Compta, Yaroslau; Leung, Yuk Yee ORCID: https://orcid.org/0000-0002-3047-5440; Coppola, Giovanni; Naj, Adam C.; Wang, Li‐San ORCID: https://orcid.org/0000-0002-3684-0031; Dalgard, Clifton; Dickson, Dennis W. ORCID: https://orcid.org/0000-0001-7189-7917; Höglinger, Günter U. ORCID: https://orcid.org/0000-0001-7587-6187; Tzeng, Jung‐Ying ORCID: https://orcid.org/0000-0002-5505-1775; Geschwind, Daniel H.; Schellenberg, Gerard D. ORCID: https://orcid.org/0000-0003-1115-2475 und Lee, Wan‐Ping ORCID: https://orcid.org/0000-0002-5305-1181
(2025):
Copy Number Variation and Haplotype Analysis of 17q21.31 Reveals Increased Risk Associated with Progressive Supranuclear Palsy and Gene Expression Changes in Neuronal Cells.
In: Movement Disorders [Forthcoming]
Abstract
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.
| Dokumententyp: | Zeitschriftenartikel |
|---|---|
| Fakultät: | Medizin
Medizin > Munich Cluster for Systems Neurology (SyNergy) Medizin > Klinikum der LMU München > Klinik und Poliklink für Psychiatrie und Psychotherapie |
| Themengebiete: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit |
| ISSN: | 0885-3185 |
| Sprache: | Englisch |
| Dokumenten ID: | 124915 |
| Datum der Veröffentlichung auf Open Access LMU: | 26. Apr. 2025 07:53 |
| Letzte Änderungen: | 26. Apr. 2025 07:53 |
| DFG: | Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198 |
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