biostudies-literatureChia RIntramural NIH HHSNIA NIH HHSNHLBI NIH HHSNINDS NIH HHSWellcome Trust2142-2156.e5https://www.ebi.ac.uk/biostudies/studies/S-EPMC11223971biostudies-literatureUnknown112(13)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 variantsNeuronGenome sequence analyses identify novel risk loci for multiple system atrophy.PMC11223971U01 AG061356R01 HL120393R01 HL117626P30 AG072980P30 AG066507U24 NS072026U01 HL120393R01 NS109209P30 AG072977ZIA NS003154P30 AG019610ZIA AG000935P50 NS038377U19 AG063911Krismer FFoubert-Samier ASidoroff VProukakis CChelban VFloris GRay AKwei KTHardy JACanosa AMasliah EShah ZBarone PTopol EDalgard CLSait SMarin-Lahoz JKarra RPavy-Le Traon AReynolds RHSinger WCheshire WPClarimon JRussillo MCPerinan MTMorris HRKim CBohannan RCIba MTorres SKobylecki CSanchez-Juan PRubio IZimprich AHu MTFanciulli ALow PAPellecchia MTAlbert MSKaufmann HGibbs JRFujita MMeissner WGRascol OChia RTraynor BJDiez-Fairen MBennett DAKaivola KBeach TGPantelyat ASeppi KScholz SWDickson DWTison FWu LMir PWszolek ZKParkkinen LLitvan IGoh YYWalton RLWenning GKRollinson SGarland ENorcliffe-Kaufmann LLeys FLage CHoulden HKhurana VNdayisaba AFlanagan MERuffo PAkcimen FStefanova NCalvo APalma JABiaggioni IInfante JMao QRyten MRosenthal LSDing JAlcalay RNMenon VDawson TMPletnikova OTroncoso JCKulisevsky JDuerr SSaxon JAPirker WDe Jager PLAlvarez ICastellani RJSaez-Atienzar SReho PRoss OAPastor PSerrano GEMora GChio AMoore ALubbe SJAlbani DTorkamani AfalseGenome sequence analyses identify novel risk loci for multiple system atrophy.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 variants2024-01-01T00:00:00Z2024 Jul2026-06-02T17:48:43.027Z2026-05-27T03:07:51.616ZS-EPMC112239713870179010.1016/j.neuron.2024.04.002