Genome sequence analyses identify novel risk loci for multiple system atrophy
Authors: 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 Foubert-Samier, Wassilios G. Meissner, François Tison, Anne Pavy-Le Traon, Maria Teresa Pellecchia, Paolo Barone, Maria Claudia Russillo, Juan Marín-Lahoz, Jaime Kulisevsky, Soraya Torres, Pablo Mir, Maria Teresa Periñán, 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 Sánchez-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 Chiò, 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
Journal: Neuron (2024)

Highlights•Generation of a foundational genomic resource in multiple system atrophy•GWAS identifies novel risk loci at GAB1, lnc-LRRC49-3, TENM2, and RABGEF1•Functional genomics implicates USP38-DT, KCTD7, and lnc-KCTD7-2 within these loci•Gene-burden analysis identifies nominal enrichment of rare missense mutations in KCTD7SummaryMultiple 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.Graphical abstract