학술논문
Identification of sixteen novel candidate genes for late onset Parkinson's disease
Document Type
Academic Journal
Author
Gialluisi, Alessandro; Reccia, Mafalda Giovanna; Modugno, Nicola; Nutile, Teresa; Lombardi, Alessia; Di Giovannantonio, Luca Giovanni; Pietracupa, Sara; Ruggiero, Daniela; Scala, Simona; Gambardella, Stefano; Noyce, Alastair J.; Kaiyrzhanov, Rauan; Middlehurst, Ben; Kia, Demis A.; Tan, Manuela; Houlden, Henry; Morris, Huw R.; Plun-Favreau, Helene; Holmans, Peter; Hardy, John; Trabzuni, Daniah; Quinn, John; Bubb, Vivien; Mok, Kin Y.; Kinghorn, Kerri J.; Billingsley, Kimberley; Wood, Nicholas W.; Lewis, Patrick; Schreglmann, Sebastian; Lovering, Ruth; R'Bibo, Lea; Manzoni, Claudia; Rizig, Mie; Ryten, Mina; Guelfi, Sebastian; Escott-Price, Valentina; Chelban, Viorica; Foltynie, Thomas; Williams, Nigel; Morrison, Karen E.; Clarke, Carl; Brice, Alexis; Danjou, Fabrice; Lesage, Suzanne; Corvol, Jean-Christophe; Martinez, Maria; Schulte, Claudia; Brockmann, Kathrin; Simón-Sánchez, Javier; Heutink, Peter; Rizzu, Patrizia; Sharma, Manu; Gasser, Thomas; Cookson, Mark R.; Bandres-Ciga, Sara; Blauwendraat, Cornelis; Craig, David W.; Narendra, Derek; Faghri, Faraz; Gibbs, J. Raphael; Hernandez, Dena G.; Van Keuren-Jensen, Kendall; Shulman, Joshua M.; Iwaki, Hirotaka; Leonard, Hampton L.; Nalls, Mike A.; Robak, Laurie; Bras, Jose; Guerreiro, Rita; Lubbe, Steven; Finkbeiner, Steven; Mencacci, Niccolo E.; Lungu, Codrin; Singleton, Andrew B.; Scholz, Sonja W.; Reed, Xylena; Alcalay, Roy N.; Gan-Or, Ziv; Rouleau, Guy A.; Krohn, Lynne; van Hilten, Jacobus J.; Marinus, Johan; Adarmes-Gómez, Astrid D.; Aguilar, Miquel; Alvarez, Ignacio; Alvarez, Victoria; Barrero, Francisco Javier; Yarza, Jesús Alberto Bergareche; Bernal-Bernal, Inmaculada; Blazquez, Marta; Bonilla-Toribio, Marta; Botía, Juan A.; Boungiorno, María Teresa; Buiza-Rueda, Dolores; Carrillo, Fátima; Carrión-Claro, Mario; Cerdan, Debora; Clarimón, Jordi; Compta, Yaroslau; Diez-Fairen, Monica; Dols-Icardo, Oriol; Duarte, Jacinto; Duran, Raquel; Escamilla-Sevilla, Francisco; Ezquerra, Mario; Feliz, Cici; Fernández, Manel; Fernández-Santiago, Rubén; Garcia, Ciara; García-Ruiz, Pedro; Gómez-Garre, Pilar; Heredia, Maria Jose Gomez; Gonzalez-Aramburu, Isabel; Pagola, Ana Gorostidi; Hoenicka, Janet; Infante, Jon; Jesús, Silvia; Jimenez-Escrig, Adriano; Kulisevsky, Jaime; Labrador-Espinosa, Miguel A.; Lopez-Sendon, Jose Luis; de Munain Arregui, Adolfo López; Macias, Daniel; Torres, Irene Martínez; Marín, Juan; Marti, Maria Jose; Martínez-Castrillo, Juan Carlos; Méndez-del-Barrio, Carlota; González, Manuel Menéndez; Mata, Marina; Mínguez, Adolfo; Mir, Pablo; Rezola, Elisabet Mondragon; Muéoz, Esteban; Pagonabarraga, Javier; Pastor, Pau; Errazquin, Francisco Perez; Periéán-Tocino, Teresa; Ruiz-Martínez, Javier; Ruz, Clara; Rodriguez, Antonio Sanchez; Sierra, María; Suarez-Sanmartin, Esther; Tabernero, Cesar; Tartari, Juan Pablo; Tejera-Parrado, Cristina; Tolosa, Eduard; Valldeoriola, Francesc; Vargas-González, Laura; Vela, Lydia; Vives, Francisco; Zimprich, Alexander; Pihlstrom, Lasse; Toft, Mathias; Koks, Sulev; Taba, Pille; Hassin-Baer, Sharon; Majamaa, Kari; Siitonen, Ari; Okubadejo, Njideka U.; Ojo, Oluwadamilola O.; Shashkin, Chingiz; Zharkynbekova, Nazira; Akhmetzhanov, Vadim; Aitkulova, Akbota; Zholdybayeva, Elena; Zharmukhanov, Zharkyn; Kaishybayeva, Gulnaz; Karimova, Altynay; Sadykova, Dinara
Source
Molecular Neurodegeneration. June 21, 2021, Vol. 16 Issue 1
Subject
Language
English
ISSN
1750-1326
Abstract
Author(s): Alessandro Gialluisi[sup.1], Mafalda Giovanna Reccia[sup.1], Nicola Modugno[sup.1], Teresa Nutile[sup.2], Alessia Lombardi[sup.1], Luca Giovanni Di Giovannantonio[sup.2], Sara Pietracupa[sup.1], Daniela Ruggiero[sup.1,2], Simona Scala[sup.1], Stefano Gambardella[sup.1,3], Alastair J. Noyce, Rauan Kaiyrzhanov, Ben [...]
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 ([greater than or equai to] 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 x 10.sup.- 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. Keywords: Late onset Parkinson's disease, Whole exome sequencing, Novel candidate genes for Parkinson's disease, Rare variant burden analysis
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 ([greater than or equai to] 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 x 10.sup.- 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. Keywords: Late onset Parkinson's disease, Whole exome sequencing, Novel candidate genes for Parkinson's disease, Rare variant burden analysis