Genome sequence analyses identify novel risk loci for multiple system atrophy

被引：16

作者：

Chia, Ruth ^{[1
]}

Ray, Anindita ^{[2
]}

Shah, Zalak ^{[2
]}

Ding, Jinhui ^{[3
]}

Ruffo, Paola ^{[1
,4
]}

Fujita, Masashi ^{[5
,6
]}

Menon, Vilas ^{[5
,6
]}

Saez-Atienzar, Sara ^{[1
]}

Reho, Paolo ^{[2
]}

Kaivola, Karri ^{[2
]}

Walton, Ronald L. ^{[7
]}

Reynolds, Regina H. ^{[8
,9
,10
]}

Karra, Ramita ^{[1
]}

Sait, Shaimaa ^{[2
]}

Akcimen, Fulya ^{[1
]}

Diez-Fairen, Monica ^{[11
]}

Alvarez, Ignacio ^{[11
]}

Fanciulli, Alessandra ^{[12
]}

Stefanova, Nadia ^{[12
]}

Seppi, Klaus ^{[12
]}

Duerr, Susanne ^{[12
]}

Leys, Fabian ^{[12
]}

Krismer, Florian ^{[12
]}

Sidoroff, Victoria ^{[12
]}

Zimprich, Alexander ^{[13
]}

Pirker, Walter ^{[14
]}

Rascol, Olivier ^{[15
,16
]}

Foubert-Samier, Alexandra ^{[17
]}

Meissner, Wassilios G. ^{[17
,18
,19
,20
]}

Tison, FrancOis ^{[17
,18
]}

Pavy-Le Traon, Anne ^{[21
]}

Pellecchia, Maria Teresa ^{[22
]}

Barone, Paolo ^{[22
]}

Russillo, Maria Claudia ^{[22
]}

Marin-Lahoz, Juan ^{[23
,24
,25
]}

Kulisevsky, Jaime ^{[23
,24
]}

Torres, Soraya ^{[24
]}

Mir, Pablo ^{[26
,27
,28
]}

Perinan, Maria Teresa ^{[26
,29
]}

Proukakis, Christos ^{[30
]}

Chelban, Viorica ^{[31
,32
]}

Wu, Lesley ^{[31
]}

Goh, Yee Y. ^{[31
]}

Parkkinen, Laura ^{[33
]}

Hu, Michele T. ^{[34
]}

Kobylecki, Christopher ^{[35
]}

Saxon, Jennifer A. ^{[36
,37
]}

Rollinson, Sara ^{[37
]}

Garland, Emily ^{[38
]}

Biaggioni, Italo ^{[38
]}

机构：

[1] NIA, Neuromuscular Dis Res Sect, Lab Neurogenet, Bethesda, MD USA

[2] NINDS, Neurodegenerat Dis Res Unit, Bethesda, MD 20892 USA

[3] NIA, Computat Biol Grp, Lab Neurogenet, Bethesda, MD USA

[4] Univ Calabria, Dept Pharm Hlth & Nutr Sci, Med Genet Lab, Arcavacata Di Rende, Italy

[5] Columbia Univ, Ctr Translat & Computat Neuroimmunol, Dept Neurol, Irving Med Ctr, New York, NY USA

[6] Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA

[7] Mayo Clin, Dept Neurosci, Jacksonville, FL USA

[8] UCL, NIHR Great Ormond St Hosp, Biomed Res Ctr, London, England

[9] UCL, Great Ormond St Inst Child Hlth, Genet & Genom Med, London, England

[10] UCL, Dept Neurodegenerat Dis, UCL Queen Sq Inst Neurol, London, England

[11] Univ Hosp Mutua Terrassa, Dept Neurol, Memory & Movement Disorders Units, Barcelona, Spain

[12] Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria

[13] Med Univ Vienna, Dept Neurol, Vienna, Austria

[14] Klin Ottakring Wilhelminenspital, Dept Neurol, Vienna, Austria

[15] Univ Toulouse, MSA French Reference Ctr, Toulouse, France

[16] Univ Toulouse, Dept Clin Pharmacol & Neurosci, CIC 1436, Toulouse, France

[17] CHU Bordeaux, Serv Neurol Malad Neurodegenerat, French Reference Ctr MSA, NS Pk FCRIN Network, Bordeaux, France

[18] Univ Bordeaux, IMN, CNRS, UMR 5293, Bordeaux, France

[19] Univ Otago, Dept Med, Christchurch, New Zealand

[20] New Zealand Brain Res Inst, Christchurch, New Zealand

[21] Univ Hosp Toulouse, Ctr Invest Clin Toulouse CIC1436, Dept Neurosci,French Reference Ctr MSA, UMR 1048,Inst Cardiovasc & Metab Dis I2MC,INSERM, Toulouse, France

[22] Univ Salerno, Dept Med Surg & Dent, Neurosci Sect, Scuola Med Salernitana, Salerno, Italy

[23] Hosp Santa Creu & Sant Pau, Movement Disorders Unit, Neurol Dept, Barcelona, Spain

[24] Univ Autonoma Barcelona, Ctr Invest Red Enfermedades Neurodegenerat CIBERN, Inst Invest Biomed St Pau IIB St Pau, Barcelona, Spain

[25] Hosp Univ Miguel Servet, Serv Neurol, Zaragoza, Spain

[26] Univ Seville, Inst Biomed Sevilla, Unidad Trastornos Movimiento Serv Neurol & Neurof, Hosp Univ Virgen del Rocio, Seville, Spain

[27] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain

[28] Univ Seville, Dept Med, Fac Med, Seville, Spain

[29] Queen Mary Univ, Ctr Prevent Neurol, Wolfson Inst Populat Hlth, London, England

[30] UCL, Dept Clin & Movement Neurosci, Queen Sq Inst Neurol, London, England

[31] UCL, Dept Neuromuscular Dis, Queen Sq Inst Neurol, London, England

[32] Natl Hosp Neurol & Neurosurg, London, England

[33] Univ Oxford, Oxford Parkinsons Dis Ctr, Nuffield Dept Clin Neurosci, Oxford, England

[34] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Oxford, England

[35] Univ Manchester, Northern Care Alliance NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Dept Neurol, Manchester, Lancs, England

[36] Manchester Ctr Clin Neurosci, Cerebral Funct Unit, Salfort, England

[37] Univ Manchester, Fac Biol, Div Neurosci & Expt Psychol, Manchester, Lancs, England

[38] Vanderbilt Univ, Auton Dysfunct Ctr, Med Ctr, Nashville, TN USA

[39] Univ Calif San Diego, Dept Neurosci, San Diego, CA USA

[40] Columbia Univ, Irving Med Ctr, Dept Neurol, New York, NY USA

[41] Tel Aviv Sourasky Med Ctr, Neurol Inst, Tel Aviv, Israel

[42] Northwestern Univ, Feinberg Sch Med, Ken & Ruth Davee Dept Neurol, Chicago, IL USA

[43] Northwestern Univ, Simpson Querrey Ctr Neurogenet, Feinberg Sch Med, Chicago, IL USA

[44] Northwestern Univ, Mesulam Ctr Cognit Neurol & Alzheimers Dis, Feinberg Sch Med, Chicago, IL USA

[45] Univ Utah, Sch Med, Dept Pathol, Salt Lake City, UT USA

[46] Ut Hlth San Antonio, Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX USA

[47] UT Hlth San Antonio, Dept Pathol, San Antonio, TX USA

[48] Brigham & Womens Hosp, Ann Romney Ctr Neurol Dis, Dept Neurol, Boston, MA USA

[49] Harvard Med Sch, Boston, MA USA

[50] Broad Inst MIT & Harvard, Cambridge, MA USA

来源：

NEURON | 2024年 / 112卷 / 13期

基金：

美国国家卫生研究院;

关键词：

SNCA VARIANTS; WIDE ASSOCIATION; DISEASE; SUSCEPTIBILITY; METAANALYSIS; IMPAIRMENT; PATHOLOGY; GENE; COQ2;

D O I：

10.1016/j.neuron.2024.04.002

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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 high-lights 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.

引用

页码：2142 / +

页数：20

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