NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

被引：194

作者：

Kenna, Kevin P. ^{[1
]}

van Doormaal, Perry T. C. ^{[2
]}

Dekker, Annelot M. ^{[2
]}

Ticozzi, Nicola ^{[3
,4
]}

Kenna, Brendan J. ^{[1
]}

Diekstra, Frank P. ^{[2
]}

van Rheenen, Wouter ^{[2
]}

van Eijk, Kristel R. ^{[2
]}

Jones, Ashley R. ^{[5
]}

Keaglel, Pamela ^{[1
]}

Shatunov, Aleksey ^{[5
]}

Sproviero, William ^{[5
]}

Smiths, Bradley N. ^{[5
]}

van Es, Michael A. ^{[2
]}

Topps, Simon D. ^{[5
]}

Kenna, Aoife ^{[1
]}

Miller, Jack W. ^{[5
]}

Fallini, Claudia ^{[1
]}

Tiloca, Cinzia ^{[3
,6
]}

McLaughlin, Russell L. ^{[7
]}

Vance, Caroline ^{[5
]}

Troakes, Claire ^{[5
]}

Colombrita, Claudia ^{[3
,4
]}

Mora, Gabriele ^{[8
]}

Calvo, Andrea ^{[9
]}

Verde, Federico ^{[3
,4
]}

Al-Sarraj, Safa ^{[5
]}

King, Andrew ^{[5
]}

Calini, Daniela ^{[3
]}

de Belleroche, Jacqueline ^{[10
]}

Baas, Frank ^{[11
]}

van der Kooi, Anneke J. ^{[12
]}

de Visser, Marianne ^{[12
]}

ten Asbroek, Anneloor L. M. A. ^{[11
]}

Sapp, Peter C. ^{[1
]}

McKenna-Yasek, Diane ^{[1
]}

Polak, Meraida ^{[13
]}

Asress, Seneshaw ^{[13
]}

Luis Munoz-Blanco, Jose ^{[14
]}

Strom, Tim M. ^{[15
]}

Meitinger, Thomas ^{[16
]}

Morrison, Karen E. ^{[17
]}

Lauria, Giuseppe ^{[18
]}

Williams, Kelly L. ^{[19
]}

Leigh, P. Nigel ^{[20
]}

Nicholson, Garth A. ^{[19
,21
]}

Blair, Ian P. ^{[19
]}

Leblond, Claire S. ^{[22
]}

Dion, Patrick A. ^{[22
]}

Rouleau, Guy A. ^{[22
]}

机构：

[1] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01655 USA

[2] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Brain Ctr, Dept Neurol, Utrecht, Netherlands

[3] IRCCS Ist Auxol Italiano, Dept Neurol, Milan, Italy

[4] Univ Milan, Dino Ferrari Ctr, Dept Pathophysiol & Transplantat, Milan, Italy

[5] Kings Coll London, Maurice Wohl Clin Neurosci Inst, Inst Psychiat Psychol & Neurosci, Dept Basic & Clin Neurosci, London, England

[6] Univ Milan, Doctoral Sch Mol Med, Dept Sci & Biomed Technol, Milan, Italy

[7] Trinity Coll Dublin, Trinity Biomed Sci Inst, Acad Unit Neurol, Dublin, Ireland

[8] Salvatore Maugeri Fdn, IRCCS, Sci Inst Milano, Milan, Italy

[9] Univ Turin, ALS Ctr, Rita Levi Montalcini Dept Neurosci, Turin, Italy

[10] Imperial Coll London, Div Brain Sci, Neurogenet Grp, London, England

[11] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, Amsterdam, Netherlands

[12] Univ Amsterdam, Acad Med Ctr, Dept Neurogenet & Neurol, Amsterdam, Netherlands

[13] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA

[14] Inst Invest Hosp Gregorio Maranon Madrid, Unidad ELA, Madrid, Spain

[15] Helmholtz Zentrurn Munchen, German Res Ctr Fnvironm Hlth, Inst Human Genet, Neuherberg, Germany

[16] Tech Univ Munich, Inst Human Genet, Munich, Germany

[17] Univ Southampton, Fac Med, Southampton, Hants, England

[18] Fdn IRCCS Ist Neurol Carlo Besta, Motor Neuron Dis Ctr, Neurol Unit 3, Milan, Italy

[19] Macquarie Univ, Fac Med & Hlth Sci, Sydney, NSW, Australia

[20] Brighton & Sussex Med Sch, Trafford Ctr Med Res, Falmer, England

[21] Univ Sydney, Concord Hosp, ANZAC Res Inst, Sydney, NSW, Australia

[22] McGill Univ, Montreal Neurol Inst, Dept Neurol & Neurosurg, Montreal, PQ, Canada

[23] Univ Birmingham, Coll Med & Dent Sci, Inst Clin Studies, Birmingham, W Midlands, England

[24] Queen Elizabeth Hosp Birmingham, Dept Neurol, Birmingham, W Midlands, England

[25] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England

[26] Fdn IRCCS Ist Neurol Carlo Besta, Unit Genet Neurodegenerat & Metab Dis, Milan, Italy

[27] Mayo Clin Florida, Dept Neurol, Jacksonville, FL 32224 USA

[28] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

[29] Inst Invest Hosp 12 Octubre Madrid, Unidad ELA, Madrid, Spain

[30] CIBERER, U 723, Madrid, Spain

[31] Katholieke Univ Leuven, Dept Neurosci, Neurobiol Lab, Leuven, Belgium

[32] VIB, Vesalius Res Ctr, Leuven, Belgium

[33] Univ Hosp, Dept Neurol, Leuven, Belgium

[34] Univ Hosp Wurzburg, Inst Clin Neurobiol, Wurzburg, Germany

[35] Univ Hosp Wurzburg, Dept Child & Adolescent Psychiat, Wurzburg, Germany

[36] Hosp San Rafael, ALS Unit Neurol, Madrid, Spain

[37] Bogazici Univ, NDAL, Dept Mol Biol & Genet, Istanbul, Turkey

[38] Univ Ulm, Dept Neurol, Ulm, Germany

[39] Umea Univ, Dept Pharmacol & Clin Neurosci, Umea, Sweden

[40] Univ Piemonte Orientale, Dept Hlth Sci, Novara, Italy

[41] A Avogadro Univ Eastern Piedmont, ALS Ctr, Dept Neurol, Novara, Italy

[42] IRCCS Fdn Ca Granda Osped Maggiore Policlin, Neurol Unit, Milan, Italy

[43] IRCCS, C Mondino Natl Inst Neurol Fdn, Expt Neurobiol Lab, Pavia, Italy

[44] Univ Pavia, Dept Neurol Sci, Pavia, Italy

[45] Univ Padua, Dept Neurosci, Padua, Italy

来源：

NATURE GENETICS | 2016年 / 48卷 / 09期

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会; 美国国家卫生研究院; 欧洲研究理事会; 英国惠康基金;

关键词：

NIMA-FAMILY KINASE; WHOLE-GENOME; PRIMARY CILIA; DNA-DAMAGE; MUTATIONS; IDENTIFICATION; ASSOCIATION; FRAMEWORK; DATABASE; GENES;

D O I：

10.1038/ng.3626

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261 His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261 His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.

引用

页码：1037 / +

页数：8

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