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

(Movement disorders : official journal of the Movement Disorder Society, pubmed:40055946)

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.

© 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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TitleCopy Number Variation and Haplotype Analysis of 17q21.31 Reveals Increased Risk Associated with Progressive Supranuclear Palsy and Gene Expression Changes in Neuronal Cells.
Date2025-03-08
Issue nameMovement disorders : official journal of the Movement Disorder Society
Issue numberpubmed:40055946
DOI10.1002/mds.30150
PubMed40055946
AuthorsWang H, Chang TS, Dombroski BA, Cheng PL, Si YQ, Tucci A, Patil V, Valiente-Banuet L, Li C, Farrell K, Mclean C, Molina-Porcel L, Rajput A, De Deyn PP, Le Bastard N, Gearing M, Donker Kaat L, Van Swieten JC, Dopper E, Ghetti BF, Newell KL, Troakes C, de Yébenes JG, Rábano-Gutierrez A, Meller T, Oertel WH, Respondek G, Stamelou M, Arzberger T, Roeber S, Müller U, Hopfner F, Pastor P, Brice A, Durr A, Le Ber I, Beach TG, Serrano GE, Hazrati LN, Litvan I, Rademakers R, Ross OA, Galasko D, Boxer AL, Miller BL, Seeley WW, Van Deerlin VM, Lee EB, White CL, Morris HR, de Silva R, Crary JF, Goate AM, Friedman JS, Compta Y, Leung YY, Coppola G, Naj AC, Wang LS, Dalgard C, Dickson DW, Höglinger GU, Tzeng JY, Geschwind DH, Schellenberg GD & Lee WP
InfoPSP Genetics Study Group, Lang AE, Grossman M, Knopman DS, Schneider LS, Doody RS, Lees A, Golbe LI, Williams DR, Corvol JC, Ludolph A, Burn D, Lorenzl S, Roberson ED, Koestler M, Jack CR, Randolph C, Lobach IV, Heuer HW, Gozes I, Parker L, Whitaker S, Hirman J, Stewart AJ, Gold M, Morimoto BH, Herms J, Gelpi E
Keywords17q21.31, H1 and H2 haplotypes, copy number variations, progressive supranuclear palsy, single‐cell gene expression
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