Genome sequence analyses identify novel risk loci for multiple system atrophy

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

doi:10.1016/j.neuron.2024.04.002

Genome sequence analyses identify novel risk loci for multiple system atrophy

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 SeppiSusanne 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English
Pages (from-to)	2142-2156.e5
Journal	Neuron
Volume	112
Issue number	13
DOIs	https://doi.org/10.1016/j.neuron.2024.04.002
State	Published - 3 Jul 2024
Externally published	Yes

Keywords

GWAS
MSA
TWAS
colocalization
gene-burden analysis
genome-wide association study
multiple system atrophy
pathway analysis
repeat expansion mapping
transcriptome-wide association study
whole genome sequencing

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10.1016/j.neuron.2024.04.002

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Chia, R., Ray, A., Shah, Z., Ding, J., Ruffo, P., Fujita, M., Menon, V., Saez-Atienzar, S., Reho, P., Kaivola, K., Walton, R. L., Reynolds, R. H., Karra, R., Sait, S., Akcimen, F., Diez-Fairen, M., Alvarez, I., Fanciulli, A., Stefanova, N., ... Scholz, S. W. (2024). Genome sequence analyses identify novel risk loci for multiple system atrophy. Neuron, 112(13), 2142-2156.e5. https://doi.org/10.1016/j.neuron.2024.04.002

@article{335227f704004fa0811b0c7365956ec0,

title = "Genome sequence analyses identify novel risk loci for multiple system atrophy",

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.",

keywords = "GWAS, MSA, TWAS, colocalization, gene-burden analysis, genome-wide association study, multiple system atrophy, pathway analysis, repeat expansion mapping, transcriptome-wide association study, whole genome sequencing",

author = "Ruth Chia and Anindita Ray and Zalak Shah and Jinhui Ding and Paola Ruffo and Masashi Fujita and Vilas Menon and Sara Saez-Atienzar and Paolo Reho and Karri Kaivola and Walton, {Ronald L.} and Reynolds, {Regina H.} and Ramita Karra and Shaimaa Sait and Fulya Akcimen and Monica Diez-Fairen and Ignacio Alvarez and Alessandra Fanciulli and Nadia Stefanova and Klaus Seppi and Susanne Duerr and Fabian Leys and Florian Krismer and Victoria Sidoroff and Alexander Zimprich and Walter Pirker and Olivier Rascol and Alexandra Foubert-Samier and Meissner, {Wassilios G.} and Fran{\c c}ois Tison and {Pavy-Le Traon}, Anne and Pellecchia, {Maria Teresa} and Paolo Barone and Russillo, {Maria Claudia} and Juan Mar{\'i}n-Lahoz and Jaime Kulisevsky and Soraya Torres and Pablo Mir and Peri{\~n}{\'a}n, {Maria Teresa} and Christos Proukakis and Viorica Chelban and Lesley Wu and Goh, {Yee Y.} and Laura Parkkinen and Hu, {Michele T.} and Christopher Kobylecki and Saxon, {Jennifer A.} and Sara Rollinson and Emily Garland and Italo Biaggioni and Irene Litvan and Ileana Rubio and Alcalay, {Roy N.} and Kwei, {Kimberly T.} and Lubbe, {Steven J.} and Qinwen Mao and Flanagan, {Margaret E.} and Castellani, {Rudolph J.} and Vikram Khurana and Alain Ndayisaba and Andrea Calvo and Gabriele Mora and Antonio Canosa and Gianluca Floris and Bohannan, {Ryan C.} and Anni Moore and Lucy Norcliffe-Kaufmann and Palma, {Jose Alberto} and Horacio Kaufmann and Changyoun Kim and Michiyo Iba and Eliezer Masliah and Dawson, {Ted M.} and Rosenthal, {Liana S.} and Alexander Pantelyat and Albert, {Marilyn S.} and Olga Pletnikova and Troncoso, {Juan C.} and Jon Infante and Carmen Lage and Pascual S{\'a}nchez-Juan and Serrano, {Geidy E.} and Beach, {Thomas G.} and Pau Pastor and Morris, {Huw R.} and Diego Albani and Jordi Clarimon and Wenning, {Gregor K.} and Hardy, {John A.} and Mina Ryten and Eric Topol and Ali Torkamani and Adriano Chi{\`o} and Bennett, {David A.} and {De Jager}, {Philip L.} and Low, {Philip A.} and Wolfgang Singer and Cheshire, {William P.} and Wszolek, {Zbigniew K.} and Dickson, {Dennis W.} and Traynor, {Bryan J.} and Gibbs, {J. Raphael} and Dalgard, {Clifton L.} and Ross, {Owen A.} and Henry Houlden and Scholz, {Sonja W.}",

note = "Publisher Copyright: {\textcopyright} 2024",

year = "2024",

month = jul,

day = "3",

doi = "10.1016/j.neuron.2024.04.002",

language = "English",

volume = "112",

pages = "2142--2156.e5",

journal = "Neuron",

issn = "0896-6273",

number = "13",

}

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, JA, 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 2024, 'Genome sequence analyses identify novel risk loci for multiple system atrophy', Neuron, vol. 112, no. 13, pp. 2142-2156.e5. https://doi.org/10.1016/j.neuron.2024.04.002

TY - JOUR

T1 - Genome sequence analyses identify novel risk loci for multiple system atrophy

AU - Chia, Ruth

AU - Ray, Anindita

AU - Shah, Zalak

AU - Ding, Jinhui

AU - Ruffo, Paola

AU - Fujita, Masashi

AU - Menon, Vilas

AU - Saez-Atienzar, Sara

AU - Reho, Paolo

AU - Kaivola, Karri

AU - Walton, Ronald L.

AU - Reynolds, Regina H.

AU - Karra, Ramita

AU - Sait, Shaimaa

AU - Akcimen, Fulya

AU - Diez-Fairen, Monica

AU - Alvarez, Ignacio

AU - Fanciulli, Alessandra

AU - Stefanova, Nadia

AU - Seppi, Klaus

AU - Duerr, Susanne

AU - Leys, Fabian

AU - Krismer, Florian

AU - Sidoroff, Victoria

AU - Zimprich, Alexander

AU - Pirker, Walter

AU - Rascol, Olivier

AU - Foubert-Samier, Alexandra

AU - Meissner, Wassilios G.

AU - Tison, François

AU - Pavy-Le Traon, Anne

AU - Pellecchia, Maria Teresa

AU - Barone, Paolo

AU - Russillo, Maria Claudia

AU - Marín-Lahoz, Juan

AU - Kulisevsky, Jaime

AU - Torres, Soraya

AU - Mir, Pablo

AU - Periñán, Maria Teresa

AU - Proukakis, Christos

AU - Chelban, Viorica

AU - Wu, Lesley

AU - Goh, Yee Y.

AU - Parkkinen, Laura

AU - Hu, Michele T.

AU - Kobylecki, Christopher

AU - Saxon, Jennifer A.

AU - Rollinson, Sara

AU - Garland, Emily

AU - Biaggioni, Italo

AU - Litvan, Irene

AU - Rubio, Ileana

AU - Alcalay, Roy N.

AU - Kwei, Kimberly T.

AU - Lubbe, Steven J.

AU - Mao, Qinwen

AU - Flanagan, Margaret E.

AU - Castellani, Rudolph J.

AU - Khurana, Vikram

AU - Ndayisaba, Alain

AU - Calvo, Andrea

AU - Mora, Gabriele

AU - Canosa, Antonio

AU - Floris, Gianluca

AU - Bohannan, Ryan C.

AU - Moore, Anni

AU - Norcliffe-Kaufmann, Lucy

AU - Palma, Jose Alberto

AU - Kaufmann, Horacio

AU - Kim, Changyoun

AU - Iba, Michiyo

AU - Masliah, Eliezer

AU - Dawson, Ted M.

AU - Rosenthal, Liana S.

AU - Pantelyat, Alexander

AU - Albert, Marilyn S.

AU - Pletnikova, Olga

AU - Troncoso, Juan C.

AU - Infante, Jon

AU - Lage, Carmen

AU - Sánchez-Juan, Pascual

AU - Serrano, Geidy E.

AU - Beach, Thomas G.

AU - Pastor, Pau

AU - Morris, Huw R.

AU - Albani, Diego

AU - Clarimon, Jordi

AU - Wenning, Gregor K.

AU - Hardy, John A.

AU - Ryten, Mina

AU - Topol, Eric

AU - Torkamani, Ali

AU - Chiò, Adriano

AU - Bennett, David A.

AU - De Jager, Philip L.

AU - Low, Philip A.

AU - Singer, Wolfgang

AU - Cheshire, William P.

AU - Wszolek, Zbigniew K.

AU - Dickson, Dennis W.

AU - Traynor, Bryan J.

AU - Gibbs, J. Raphael

AU - Dalgard, Clifton L.

AU - Ross, Owen A.

AU - Houlden, Henry

AU - Scholz, Sonja W.

PY - 2024/7/3

Y1 - 2024/7/3

N2 - 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.

AB - 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.

KW - GWAS

KW - MSA

KW - TWAS

KW - colocalization

KW - gene-burden analysis

KW - genome-wide association study

KW - multiple system atrophy

KW - pathway analysis

KW - repeat expansion mapping

KW - transcriptome-wide association study

KW - whole genome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85193449341&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2024.04.002

DO - 10.1016/j.neuron.2024.04.002

M3 - Article

C2 - 38701790

AN - SCOPUS:85193449341

SN - 0896-6273

VL - 112

SP - 2142-2156.e5

JO - Neuron

JF - Neuron

IS - 13

ER -

Genome sequence analyses identify novel risk loci for multiple system atrophy

Abstract

Keywords

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