Citations 2
Shared Pathogenic Pathways Between REM Sleep Behavior Disorder and Neurodegenerative and Psychiatric Disorders
Zhang, Zhao, Somerville, Emma N. , Fang, Zih‐Hua , Liu, Lang, Asayesh, Farnaz , Ahmad, Jamil, Amiri, Saeid , Teferra, Meron, Dodet, P., Arnulf, Isabelle, Hu, Michele T.M., Desautels, A., Dauvilliers, Yves, Aktan-Süzgün, Merve , Stefani, A., Högl, Birgit, Gaig, Carles, Mayà, G., Iranzo, Alex, Serradell, Mònica , Valente, Mariarosaria, Dusek, P., Sommerauer, Michael , Röttgen, Sinah, Figorilli, M., Puligheddu, Monica, Mollenhauer, Brit, Trenkwalder, Claudia, Sixel-Doring, Friederike, Plazzi, G., Antelmi, E., Terzaghi, Michele, Fiamingo, Giuseppe , Ferini-Strambi, Luigi, Kulcsarova, Kristina, Bušková, J., Abril, Beatriz, Orso, B., Arnaldi, D., Boeve, Bradley F., Ju, Yo‐El S. , Ross, Owen A., Wu, Shih-Ying, Lee, Jonghun , Prilutsky, Daria, Blauwendraat, Cornelis, Leonard, Hampton, Postuma, Ronald B., Rouleau, Guy A., Gan-Or, Ziv, Arnulf, Isabelle , Hu, Michele T M , Desautels, Alex , Dauvilliers, Yves , Ibrahim, Abubaker , Stefani, Ambra , Högl, Birgit , Montini, Angelica , Maya, Gerard , Serradell, Monica , Gigli, Gian Luigi , Valente, Mariarosaria , Janes, Francesco , Sonka, Karel , Kemlink, David , Dušek, Petr , Figorilli, Michela , Puligheddu, Monica , Mollenhauer, Brit , Trenkwalder, Claudia , Sixel-Doring, Friederike , Plazzi, Giuseppe , Biscarini, Francesco , Antelmi, Elena , Cochen De Cock, Valérie , Terzaghi, Michele , Fiamingo, Giuseppe , Heidbreder, Anna , Ferini-Strambi, Luigi , Ostrozovicova, Miriam , Skorvanek, Matej , Kulcsarova, Kristina , Buskova, Jitka , Orso, Beatrice , Mattioli, Pietro , Arnaldi, Dario , Boeve, Brad , Ross, Owen A , Blauwendraat, Cornelis , Postuma, Ronald B , Rouleau, Guy Armand , Gan-Or, Ziv , Zhang, Zhao , Liu, Lang , Ahmad, Jamil, Teferra, Meron , Dodet, Pauline , Arnulf, Isabelle , Désautels, Alex , Dauvilliers, Yves , Ibrahim, Abubaker , Stefani, Ambra , Högl, Birgit , Gaig, Carles , Mayà, Gerard , Iranzo, Álex , Serradell, Mónica , Janes, Francesco , Bernardini, Andrea , Šonka, Karel , Dušek, Petr , Röttgen, Sinah , Figorilli, Michela , Puligheddu, Monica , Mollenhauer, Brit , Trenkwalder, Claudia , Sixel‐Döring, Friederike , Biscarini, Francesco , Antelmi, Elena, Heidbreder, Anna , Kulcsárová, Kristína , Mattioli, Pietro , Arnaldi, Dario , Boeve, Bradley F. , Blauwendraat, Cornelis , Postuma, Ronald B. , Gan‐Or, Ziv
No container title available | February 6, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Isolated/idiopathic rapid-eye-movement (REM)-Sleep Behavior Disorder (iRBD) is characterized by dream enactment behaviors associated with loss of REM atonia. iRBD is in most cases a prodromal synucleinopathy, and emerging evidence suggests associations between RBD and other neurological and psychiatric conditions. In this study, we performed pathway-based polygenic risk score (PRS) and rare variant burden analyses to examine these potential associations. Pathway-specific PRS were constructed from genome-wide association study summary statistics of five neurodegenerative and seven psychiatric traits across 10 biologically relevant pathway categories, including a total of 279 pathways, in 1,573 iRBD cases and 16,022 controls from the International RBD Study Group and UK Biobank. Rare variant burden tests were performed in 1,264 iRBD cases and 2,581 controls. We identified multiple potential pathways indicating shared polygenic risk between RBD and both neurodegenerative and psychiatric disorders. Lewy body diseases and post-traumatic stress disorder had the most shared polygenic risk pathways in neurological and psychiatric disorders, respectively. Two pathways, the serotonin transport pathway and the chaperone-mediated autophagy pathway, showed the strongest association with iRBD, and gene-based rare variants analyses revealed five genes associated with iRBD: GBA1 , PLEKHM1 , LRP2 , P2RX1 , and HAP1. Subsequent analysis of these genes in Parkinson’s disease and dementia with Lewy bodies replicated several associations. Together, these findings provide novel insights into the shared genetic architecture underlying iRBD, neurodegenerative disorders, and psychiatric traits, with implications for early identification and mechanistic understanding.
Fine‐Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies
Krohn, Lynne , Wu, Richard Y. J. , Heilbron, Karl , Ruskey, Jennifer A. , Laurent, Sandra B., Blauwendraat, Cornelis , Alam, Armaghan , Arnulf, Isabelle , Hu, Michele T.M., Dauvilliers, Yves , Högl, Birgit , Toft, Mathias , Bjørnarå, Kari Anne , Stefani, Ambra , Holzknecht, Evi , Monaca, Christelle, Abril, Beatriz, Young, Peter , Heidbreder, Anna , Mollenhauer, Brit , Sixel‐Döring, Friederike , Trenkwalder, Claudia , Šonka, Karel , Figorilli, Michela , Puligheddu, Monica , Dijkstra, Femke , Viaene, Mineke , Oertel, Wolfang, Toffoli, Marco , Gagnon, Jean‐François , Nalls, Mike A., Singleton, Andrew B., Désautels, Alex , Montplaisir, Jacques , Ross, Owen A. , Dupré, Nicolas , Postuma, Ronald B., Antelmi, Elena , Cochen De Cock, Valérie , Rouleau, Guy Armand , Gan-Or, Ziv , Ross, Owen A , Dauvilliers, Yves , Stefani, Ambra , Toft, Mathias , Arnulf, Isabelle , Högl, Birgit , Sonka, Karel , Figorilli, Michela , Puligheddu, Monica , Heidbreder, Anna , Plazzi, Giuseppe , Antelmi, Elena , Ferini-Strambi, Luigi , Kemlink, David , Gigli, Gian Luigi , Valente, Mariarosaria , Singleton, Andrew , Cannon, Paul, Boeve, Bradley F. , Fon, Edward A , Postuma, Ronald B. , Pihlstrøm, Lasse , Gan‐Or, Ziv
Annals of Neurology | January 24, 2020 | Volume: 87 | Issue: 4 | Pages: 584-598
Objective Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in‐depth analysis of the SNCA locus to identify RBD‐specific risk variants. Methods Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta‐analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan–Meier survival analysis. Results A 5′‐region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E‐08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5′ risk variants across the different synucleinopathies. An independent iRBD‐specific suggestive association (rs11732740) was detected at the 3′ of SNCA (OR = 1.32, p = 4.7E‐04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD‐specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E‐06). The known top PD‐associated variant (3′ variant rs356182) had an opposite direction of effect in iRBD compared to PD. Interpretation There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3′ of SNCA . Several 5′ SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584–598