Identification of sixteen novel candidate genes for late onset Parkinson’s disease
Authors: Gialluisi Alessandro , Reccia Mafalda Giovanna , Modugno Nicola , Nutile Teresa , Lombardi Alessia , Di Giovannantonio Luca Giovanni , Pietracupa Sara , Ruggiero Daniela , Scala Simona , Gambardella Stefano ,   International Parkinson’s Disease Genomics Consortium (IPDGC), 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 , 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 , Muñoz Esteban , Pagonabarraga Javier , Pastor Pau , Errazquin Francisco Perez , Periñán-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. , Kaiyrzhanov Rauan , Shashkin Chingiz , Zharkynbekova Nazira , Akhmetzhanov Vadim , Aitkulova Akbota , Zholdybayeva Elena , Zharmukhanov Zharkyn , Kaishybayeva Gulnaz , Karimova Altynay , Sadykova Dinara , Iacoviello Licia , Gianfrancesco Fernando , Acampora Dario , D’Esposito Maurizio , Simeone Antonio , Ciullo Marina , Esposito Teresa 
Published: June 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 (> 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.