Identification of sixteen novel candidate genes for late onset Parkinson’s disease
Authors: Alessandro Gialluisi, Mafalda Giovanna Reccia, Nicola Modugno, Teresa Nutile, Alessia Lombardi, Luca Giovanni Di Giovannantonio, Sara Pietracupa, Daniela Ruggiero, Simona Scala, Stefano Gambardella, Alastair J. Noyce, Rauan Kaiyrzhanov, Ben Middlehurst, Demis A. Kia, Manuela Tan, Henry Houlden, Huw R. Morris, Helene Plun-Favreau, Peter Holmans, John Hardy, Daniah Trabzuni, John Quinn, Vivien Bubb, Kin Y. Mok, Kerri J. Kinghorn, Kimberley Billingsley, Nicholas W. Wood, Patrick Lewis, Sebastian Schreglmann, Ruth Lovering, Lea R’Bibo, Claudia Manzoni, Mie Rizig, Mina Ryten, Sebastian Guelfi, Valentina Escott-Price, Viorica Chelban, Thomas Foltynie, Nigel Williams, Karen E. Morrison, Carl Clarke, Alexis Brice, Fabrice Danjou, Suzanne Lesage, Jean-Christophe Corvol, Maria Martinez, Claudia Schulte, Kathrin Brockmann, Javier Simón-Sánchez, Peter Heutink, Patrizia Rizzu, Manu Sharma, Thomas Gasser, Mark R. Cookson, Sara Bandres-Ciga, Cornelis Blauwendraat, David W. Craig, Derek Narendra, Faraz Faghri, J. Raphael Gibbs, Dena G. Hernandez, Kendall Van Keuren-Jensen, Joshua M. Shulman, Hirotaka Iwaki, Hampton L. Leonard, Mike A. Nalls, Laurie Robak, Jose Bras, Rita Guerreiro, Steven Lubbe, Steven Finkbeiner, Niccolo E. Mencacci, Codrin Lungu, Andrew B. Singleton, Sonja W. Scholz, Xylena Reed, Roy N. Alcalay, Ziv Gan-Or, Guy A. Rouleau, Lynne Krohn, Lynne Krohn, Jacobus J. van Hilten, Johan Marinus, Astrid D. Adarmes-Gómez, Miquel Aguilar, Ignacio Alvarez, Victoria Alvarez, Francisco Javier Barrero, Jesús Alberto Bergareche Yarza, Inmaculada Bernal-Bernal, Marta Blazquez, Marta Bonilla-Toribio, Juan A. Botía, María Teresa Boungiorno, Dolores Buiza-Rueda, Fátima Carrillo, Mario Carrión-Claro, Debora Cerdan, Jordi Clarimón, Yaroslau Compta, Monica Diez-Fairen, Oriol Dols-Icardo, Jacinto Duarte, Raquel Duran, Francisco Escamilla-Sevilla, Mario Ezquerra, Cici Feliz, Manel Fernández, Rubén Fernández-Santiago, Ciara Garcia, Pedro García-Ruiz, Pilar Gómez-Garre, Maria Jose Gomez Heredia, Isabel Gonzalez-Aramburu, Ana Gorostidi Pagola, Janet Hoenicka, Jon Infante, Silvia Jesús, Adriano Jimenez-Escrig, Jaime Kulisevsky, Miguel A. Labrador-Espinosa, Jose Luis Lopez-Sendon, Adolfo López de Munain Arregui, Daniel Macias, Irene Martínez Torres, Juan Marín, Maria Jose Marti, Juan Carlos Martínez-Castrillo, Carlota Méndez-del-Barrio, Manuel Menéndez González, Marina Mata, Adolfo Mínguez, Pablo Mir, Elisabet Mondragon Rezola, Esteban Muñoz, Javier Pagonabarraga, Pau Pastor, Francisco Perez Errazquin, Teresa Periñán-Tocino, Javier Ruiz-Martínez, Clara Ruz, Antonio Sanchez Rodriguez, María Sierra, Esther Suarez-Sanmartin, Cesar Tabernero, Juan Pablo Tartari, Cristina Tejera-Parrado, Eduard Tolosa, Francesc Valldeoriola, Laura Vargas-González, Lydia Vela, Francisco Vives, Alexander Zimprich, Lasse Pihlstrom, Mathias Toft, Sulev Koks, Pille Taba, Sharon Hassin-Baer, Kari Majamaa, Ari Siitonen, Njideka U. Okubadejo, Oluwadamilola O. Ojo, Rauan Kaiyrzhanov, Chingiz Shashkin, Nazira Zharkynbekova, Vadim Akhmetzhanov, Akbota Aitkulova, Elena Zholdybayeva, Zharkyn Zharmukhanov, Gulnaz Kaishybayeva, Altynay Karimova, Dinara Sadykova, Licia Iacoviello, Fernando Gianfrancesco, Dario Acampora, Maurizio D’Esposito, Antonio Simeone, Marina Ciullo, Teresa Esposito
Journal: Molecular Neurodegeneration (2021)

Abstract Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2 , CHMP1A, GIPC1, HMOX2, HSPA8 , IMMT , KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21 . Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases ( p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (&gt; 93%; p = 4.4 × 10 − 5 ). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment.