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. Display omitted •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 KCTD7 Chia et al. comprehensively analyzed genome sequence data from patients with multiple system atrophy (MSA) and controls. The study identified four novel risk loci associated with MSA and prioritized significantly associated genes (USP38-DT, KCTD7, and lnc-KCTD7-2) within these loci. This initiative's data constitute a valuable resource for the research community.