Chia, Ruth;
Ray, Anindita;
Shah, Zalak;
Ding, Jinhui;
Ruffo, Paola;
Fujita, Masashi;
Menon, Vilas;
... Scholz, Sonja W; + view all
(2024)
Genome sequence analyses identify novel risk loci for multiple system atrophy.
Neuron
10.1016/j.neuron.2024.04.002.
(In press).
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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.
| Type: | Article |
|---|---|
| Title: | Genome sequence analyses identify novel risk loci for multiple system atrophy |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.neuron.2024.04.002 |
| Publisher version: | http://dx.doi.org/10.1016/j.neuron.2024.04.002 |
| Language: | English |
| Additional information: | This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | Multiple system atrophy; MSA; whole genome sequencing; genome-wide association study; GWAS; transcriptome-wide association study; TWAS; gene-burden analysis; colocalization; pathway analysis; repeat expansion mapping |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10191935 |
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