Oertel, Wolfgang H
Mayo Clinic
Department of Neurology, Philipps University Marburg, Marburg 35032, Germany.
Citations 2
Lack of epistatic interaction of SNCA with APOE in synucleinopathies
Saini, Prabhjyot, Estiar, Mehrdad A. , Krohn, Lynne , Mufti, Kheireddin , Ruskey, Jennifer A. , Asayesh, Farnaz , Laurent, Sandra B., Montplaisir, Jacques , Gagnon, Jean‐François , Désautels, Alex , Janes, Francesco , Bernardini, Andrea , Oertel, Wolfgang H. , Janzen, Annette , Figorilli, Michela , Puligheddu, Monica , Mollenhauer, Brit , Trenkwalder, Claudia , Sixel‐Döring, Friederike , Monaca, Christelle, Dijkstra, Femke , Viaene, Mineke , Abril, Beatriz, Anselmi, Victoria, Scholz, Sonja W. , Krohn, Lynne , Mufti, Kheireddin , Arnulf, Isabelle , Dauvilliers, Yves , Kemlink, David , Oertel, Wolfgang H , Kaivola, Karri , Janzen, Annette , Boeve, Brad , Rouleau, Guy Armand , Ibrahim, Abubaker , Stefani, Ambra , Hu, Michele T M , Scholz, Sonja W , Gan-Or, Ziv , Bernardini, Andrea , Janes, Francesco , Figorilli, Michela , Puligheddu, Monica , Yu, Eric , Rudakou, Uladzislau , Spiegelman, Dan , Arnulf, Isabelle , Dauvilliers, Yves , Gigli, Gian Luigi , Valente, Mariarosaria , Šonka, Karel , Plazzi, Giuseppe , Antelmi, Elena , Biscarini, Francesco , Cochen De Cock, Valérie , Heidbreder, Anna , Ferini-Strambi, Luigi , Boeve, Bradley F. , Postuma, Ronald B. , Ibrahim, Abubaker , Stefani, Ambra , Högl, Birgit , Gan‐Or, Ziv
Brain Communications | November 17, 2025 | Volume: 7 | Issue: 6 | Pages: No page available
Abstract Two recent studies suggested that the APOE ε4 haplotype was associated with increased α-synuclein pathology in cell and mouse models. Genetic variants in the SNCA region have strong association with Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and idiopathic REM sleep behaviour disorder (iRBD), while APOE is a genetic risk determinant for only DLB. To determine if genetic-level interactions between SNCA and APOE exists that can explain the protein-level association, we investigated the genotypic interaction of APOE and SNCA in cohorts of PD, DLB and iRBD. We analysed genome-wide association study (GWAS) data from 5229 PD patients and 5480 controls, 2610 DLB patients and 1920 controls, and 1055 iRBD patients and 3667 controls. We used logistic regression interaction models across all three cohorts independently between the (i) top GWAS signals of SNCA single nucleotide polymorphisms (SNPs) and APOE haplotypes and (ii) SNP×SNP and three-way SNP interaction across the entire coding region plus 200 kb flanking each gene. No significant interactions were found to be associated with any of the synucleinopathies after correction for multiple testing. Our results do not support a role for genetic interactions between APOE and SNCA across PD, DLB and iRBD. Since the tested genetic variants affect the expression and function of these proteins, it is likely that any interactions between them do not affect the risk of PD, DLB and iRBD.
Copy Number Variation and Haplotype Analysis of 17q21.31 Reveals Increased Risk Associated with Progressive Supranuclear Palsy and Gene Expression Changes in Neuronal Cells
Wang, Hui , Chang, Timothy S. , Dombroski, Beth A. , Cheng, Po‐Liang , Si, Yaqin , Tucci, Albert , Patil, Vishakha, Valiente‐Banuet, Leopoldo , Li, Chong , Farrell, Kurt , Molina‐Porcel, Laura , Rajput, Alex , Gearing, Marla , Newell, Kathy L. , Rábano‐Gutierrez, Alberto, Oertel, Wolfgang H. , Respondek, Gesine , Stamelou, María , Arzberger, Thomas , Roeber, Sigrun, Müller, Ulrich , Pástor, Pau , Ber, Isabelle Le, Beach, Thomas G. , Litvan, Irene , Rademakers, Rosa , Ross, Owen A. , Boxer, Adam L. , Seeley, Willian W., Lee, Edward B. , Silva, Rohan de , Crary, John F. , Goate, Alison , Friedman, Jeffrey S., Compta, Yaroslau , Coppola, Giovanni , Wang, Li‐San , Group, PSP Genetics Study, Tzeng, Jung‐Ying , Geschwind, Daniel H. , Schellenberg, Gerard D. , Si, Ya-Qin , Mclean, Catriona , Molina-Porcel, Laura , Rajput, Alex , Deyn, Peter Paul De , Le Bastard, Nathalie , Gearing, Marla , Donker Kaat, Laura , Van Swieten, John C , Ghetti, Bernardino F , Troakes, Claire , de Yébenes, Justo G , Meller, Tina , Oertel, Wolfgang H , Respondek, Gesine , Hopfner, Franziska , Pastor, Pau , Brice, Alexis , Dürr, Alexandra , Beach, Thomas G , Serrano, Geidy E , Hazrati, Lili‐Naz , Litvan, Irene , Ross, Owen A , Galasko, Douglas , Boxer, Adam , Miller, Bruce L , Deerlin, Vivianna M. Van , Lee, Edward B , White, Charles L , Morris, Huw R , Crary, John F , Goate, Alison M , Leung, Yuk Yee , Wang, Li-San , Dickson, Dennis W , Höglinger, Günter U , Tzeng, Jung-Ying , Schellenberg, Gerard D , Lee, Wan-Ping , Dombroski, Beth , Farrell, Kurt , McLean, Catriona , Kaat, Laura Donker , Swieten, John C. van , Dopper, Elise G.P. , Ghetti, Bernardino , Troakes, Claire , Müller, Ulrich, Hopfner, Franziska , Brice, Alexis , Ber, Isabelle Le , Serrano, Geidy E. , Galasko, Douglas , Miller, Bruce L. , White, Charles L. , Morris, Huw R. , Naj, Adam Christian , Group, PSP Genetics Study, Dalgard, Clifton L. , Dickson, Dennis W. , Höglinger, Günter U.
Movement Disorders | March 12, 2025 | Volume: 40 | Issue: 5 | Pages: 950-961
AbstractBackgroundThe 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).ObjectiveTo investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP.MethodsUtilizing 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.ResultsWe 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.ConclusionsThe 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.