Genome sequence analyses identify novel risk loci for multiple system atrophy.
Chia R., Ray A., Shah Z., Ding J., Ruffo P., Fujita M., Menon V., Saez-Atienzar S., Reho P., Kaivola K., Walton RL., Reynolds RH., Karra R., Sait S., Akcimen F., Diez-Fairen M., Alvarez I., Fanciulli A., Stefanova N., Seppi K., Duerr S., Leys F., Krismer F., Sidoroff V., Zimprich A., Pirker W., Rascol O., Foubert-Samier A., Meissner WG., Tison F., Pavy-Le Traon A., Pellecchia MT., Barone P., Russillo MC., Marín-Lahoz J., Kulisevsky J., Torres S., Mir P., Periñán MT., Proukakis C., Chelban V., Wu L., Goh YY., Parkkinen L., Hu MT., Kobylecki C., Saxon JA., Rollinson S., Garland E., Biaggioni I., Litvan I., Rubio I., Alcalay RN., Kwei KT., Lubbe SJ., Mao Q., Flanagan ME., Castellani RJ., Khurana V., Ndayisaba A., Calvo A., Mora G., Canosa A., Floris G., Bohannan RC., Moore A., Norcliffe-Kaufmann L., Palma J-A., Kaufmann H., Kim C., Iba M., Masliah E., Dawson TM., Rosenthal LS., Pantelyat A., Albert MS., Pletnikova O., Troncoso JC., Infante J., Lage C., Sánchez-Juan P., Serrano GE., Beach TG., Pastor P., Morris HR., Albani D., Clarimon J., Wenning GK., Hardy JA., Ryten M., Topol E., Torkamani A., Chiò A., Bennett DA., De Jager PL., Low PA., Singer W., Cheshire WP., Wszolek ZK., Dickson DW., Traynor BJ., Gibbs JR., Dalgard CL., Ross OA., Houlden H., Scholz SW.
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.