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Journal Articles Neuron Year : 2024

Genome sequence analyses identify novel risk loci for multiple system atrophy

Ruth Chia , Anindita Ray , Zalak Shah , Jinhui Ding , Paola Ruffo , Masashi Fujita , Vilas Menon , Sara Saez-Atienzar , Paolo Reho , Karri Kaivola , Ronald L Walton , Regina H Reynolds , Ramita Karra , Shaimaa Sait , Fulya Akcimen , Monica Diez-Fairen , Ignacio Alvarez , Alessandra Fanciulli , Nadia Stefanova , Klaus Seppi , Susanne Duerr , Fabian Leys , Florian Krismer , Victoria Sidoroff , Alexander Zimprich , Walter Pirker , Olivier Rascol , Alexandra Samier Foubert (1) , Wassilios Meissner (2) , Francois Tison (2) , Anne Pavy-Le Traon , Maria Teresa Pellecchia , Paolo Barone , Maria Claudia Russillo , Juan Marin-Lahoz , Jaime Kulisevsky , Soraya Torres , Pablo Mir , Maria Teresa Perinan , Christos Proukakis , Viorica Chelban , Lesley Wu , Yee Y Goh , Laura Parkkinen , Michele T Hu , Christopher Kobylecki , Jennifer A Saxon , Sara Rollinson , Emily Garland , Italo Biaggioni , Irene Litvan , Ileana Rubio , Roy N Alcalay , Kimberly T Kwei , Steven J Lubbe , Qinwen Mao , Margaret E Flanagan , Rudolph J Castellani , Vikram Khurana , Alain Ndayisaba , Andrea Calvo , Gabriele Mora , Antonio Canosa , Gianluca Floris , Ryan C Bohannan , Anni Moore , Lucy Norcliffe-Kaufmann , Jose-Alberto Palma , Horacio Kaufmann , Changyoun Kim , Michiyo Iba , Eliezer Masliah , Ted M Dawson , Liana S Rosenthal , Alexander Pantelyat , Marilyn S Albert , Olga Pletnikova , Juan C Troncoso , Jon Infante , Carmen Lage , Pascual Sanchez-Juan , Geidy E Serrano , Thomas G Beach , Pau Pastor , Huw R Morris , Diego Albani , Jordi Clarimon , Gregor K Wenning , John A Hardy , Mina Ryten , Eric Topol , Ali Torkamani , Adriano Chio , David A Bennett , Philip L de Jager , Philip A Low , Wolfgang Singer , William P Cheshire , Zbigniew K Wszolek , Dennis W Dickson , Bryan J Traynor , J Raphael Gibbs , Clifton L Dalgard , Owen A Ross , Henry Houlden , Sonja W Scholz
Ruth Chia
  • Function : Author
Anindita Ray
  • Function : Author
Zalak Shah
  • Function : Author
Jinhui Ding
  • Function : Author
Paola Ruffo
  • Function : Author
Masashi Fujita
  • Function : Author
Vilas Menon
  • Function : Author
Sara Saez-Atienzar
  • Function : Author
Paolo Reho
  • Function : Author
Karri Kaivola
  • Function : Author
Ronald L Walton
  • Function : Author
Regina H Reynolds
  • Function : Author
Ramita Karra
  • Function : Author
Shaimaa Sait
  • Function : Author
Fulya Akcimen
  • Function : Author
Monica Diez-Fairen
  • Function : Author
Ignacio Alvarez
  • Function : Author
Alessandra Fanciulli
  • Function : Author
Nadia Stefanova
  • Function : Author
Klaus Seppi
  • Function : Author
Susanne Duerr
  • Function : Author
Fabian Leys
  • Function : Author
Florian Krismer
  • Function : Author
Victoria Sidoroff
  • Function : Author
Alexander Zimprich
  • Function : Author
Walter Pirker
  • Function : Author
Olivier Rascol
  • Function : Author
Anne Pavy-Le Traon
  • Function : Author
Maria Teresa Pellecchia
  • Function : Author
Paolo Barone
  • Function : Author
Maria Claudia Russillo
  • Function : Author
Juan Marin-Lahoz
  • Function : Author
Jaime Kulisevsky
  • Function : Author
Soraya Torres
  • Function : Author
Pablo Mir
  • Function : Author
Maria Teresa Perinan
  • Function : Author
Christos Proukakis
  • Function : Author
Viorica Chelban
  • Function : Author
Lesley Wu
  • Function : Author
Yee Y Goh
  • Function : Author
Laura Parkkinen
  • Function : Author
Michele T Hu
  • Function : Author
Christopher Kobylecki
  • Function : Author
Jennifer A Saxon
  • Function : Author
Sara Rollinson
  • Function : Author
Emily Garland
  • Function : Author
Italo Biaggioni
  • Function : Author
Irene Litvan
  • Function : Author
Ileana Rubio
  • Function : Author
Roy N Alcalay
  • Function : Author
Kimberly T Kwei
  • Function : Author
Steven J Lubbe
  • Function : Author
Qinwen Mao
  • Function : Author
Margaret E Flanagan
  • Function : Author
Rudolph J Castellani
  • Function : Author
Vikram Khurana
  • Function : Author
Alain Ndayisaba
  • Function : Author
Andrea Calvo
  • Function : Author
Gabriele Mora
  • Function : Author
Antonio Canosa
  • Function : Author
Gianluca Floris
  • Function : Author
Ryan C Bohannan
  • Function : Author
Anni Moore
  • Function : Author
Lucy Norcliffe-Kaufmann
  • Function : Author
Jose-Alberto Palma
  • Function : Author
Horacio Kaufmann
  • Function : Author
Changyoun Kim
  • Function : Author
Michiyo Iba
  • Function : Author
Eliezer Masliah
  • Function : Author
Ted M Dawson
  • Function : Author
Liana S Rosenthal
  • Function : Author
Alexander Pantelyat
  • Function : Author
Marilyn S Albert
  • Function : Author
Olga Pletnikova
  • Function : Author
Juan C Troncoso
  • Function : Author
Jon Infante
  • Function : Author
Carmen Lage
  • Function : Author
Pascual Sanchez-Juan
  • Function : Author
Geidy E Serrano
  • Function : Author
Thomas G Beach
  • Function : Author
Pau Pastor
  • Function : Author
Huw R Morris
  • Function : Author
Diego Albani
  • Function : Author
Jordi Clarimon
  • Function : Author
Gregor K Wenning
  • Function : Author
John A Hardy
  • Function : Author
Mina Ryten
  • Function : Author
Eric Topol
  • Function : Author
Ali Torkamani
  • Function : Author
Adriano Chio
  • Function : Author
David A Bennett
  • Function : Author
Philip L de Jager
  • Function : Author
Philip A Low
  • Function : Author
Wolfgang Singer
  • Function : Author
William P Cheshire
  • Function : Author
Zbigniew K Wszolek
  • Function : Author
Dennis W Dickson
  • Function : Author
Bryan J Traynor
  • Function : Author
J Raphael Gibbs
  • Function : Author
Clifton L Dalgard
  • Function : Author
Owen A Ross
  • Function : Author
Henry Houlden
  • Function : Author
Sonja W Scholz
  • Function : Author

Abstract

Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT, KCTD7, and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis-expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study highlights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies.
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hal-04617510 , version 1 (19-06-2024)

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Ruth Chia, Anindita Ray, Zalak Shah, Jinhui Ding, Paola Ruffo, et al.. Genome sequence analyses identify novel risk loci for multiple system atrophy. Neuron, 2024, ⟨10.1016/j.neuron.2024.04.002⟩. ⟨hal-04617510⟩

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