NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

Kevin P. Kenna; Perry T.C. Van Doormaal; Annelot M. Dekker; Nicola Ticozzi; Brendan J. Kenna; Frank P. Diekstra; Wouter Van Rheenen; Kristel R. Van Eijk; Ashley R. Jones; Pamela Keagle; Aleksey Shatunov; William Sproviero; Bradley N. Smith; Michael A. Van Es; Simon D. Topp; Aoife Kenna; Jack W. Miller; Claudia Fallini; Cinzia Tiloca; Russell L. McLaughlin; Caroline Vance; Claire Troakes; Claudia Colombrita; Gabriele Mora; Andrea Calvo; Federico Verde; Safa Al-Sarraj; Andrew King; Daniela Calini; Jacqueline De Belleroche; Frank Baas; Anneke J. Van Der Kooi; Marianne De Visser; Anneloor L.M.A. Ten Asbroek; Peter C. Sapp; Diane McKenna-Yasek; Meraida Polak; Seneshaw Asress; José Luis Muñoz-Blanco; Tim M. Strom; Thomas Meitinger; Karen E. Morrison; Giuseppe Lauria; Kelly L. Williams; P. Nigel Leigh; Garth A. Nicholson; Ian P. Blair; Claire S. Leblond; Patrick A. Dion; Guy A. Rouleau; Hardev Pall; Pamela J. Shaw; Martin R. Turner; Kevin Talbot; Franco Taroni; Kevin B. Boylan; Marka Van Blitterswijk; Rosa Rademakers; Jesús Esteban-Pérez; Alberto García-Redondo; Phillip Van Damme; Wim Robberecht; Adriano Chio; Cinzia Gellera; Carsten Drepper; Michael Sendtner; Antonia Ratti; Jonathan D. Glass; Jesús S. Mora; Nazli A. Basak; Orla Hardiman; Albert C. Ludolph; Peter M. Andersen; Jochen H. Weishaupt; Robert H. Brown; Ammar Al-Chalabi; Vincenzo Silani; Christopher E. Shaw; Leonard H. Van Den Berg; Jan H. Veldink; John E. Landers; Sandra D’Alfonso; Letizia Mazzini; Giacomo P. Comi; Roberto Del Bo; Mauro Ceroni; Stella Gagliardi; Giorgia Querin; Cinzia Bertolin; Stefania Corti; Cristina Cereda; Lucia Corrado; Gianni Sorarù; Viviana Pensato; Barbara Castellotti

doi:10.1038/ng.3626

NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

Kevin P. Kenna, Perry T.C. Van Doormaal, Annelot M. Dekker, Nicola Ticozzi, Brendan J. Kenna, Frank P. Diekstra, Wouter Van Rheenen, Kristel R. Van Eijk, Ashley R. Jones, Pamela Keagle, Aleksey Shatunov, William Sproviero, Bradley N. Smith, Michael A. Van Es, Simon D. Topp, Aoife Kenna, Jack W. Miller, Claudia Fallini, Cinzia Tiloca, Russell L. McLaughlinCaroline Vance, Claire Troakes, Claudia Colombrita, Gabriele Mora, Andrea Calvo, Federico Verde, Safa Al-Sarraj, Andrew King, Daniela Calini, Jacqueline De Belleroche, Frank Baas, Anneke J. Van Der Kooi, Marianne De Visser, Anneloor L.M.A. Ten Asbroek, Peter C. Sapp, Diane McKenna-Yasek, Meraida Polak, Seneshaw Asress, José Luis Muñoz-Blanco, Tim M. Strom, Thomas Meitinger, Karen E. Morrison, Giuseppe Lauria, Kelly L. Williams, P. Nigel Leigh, Garth A. Nicholson, Ian P. Blair, Claire S. Leblond, Patrick A. Dion, Guy A. Rouleau, Hardev Pall, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Franco Taroni, Kevin B. Boylan, Marka Van Blitterswijk, Rosa Rademakers, Jesús Esteban-Pérez, Alberto García-Redondo, Phillip Van Damme, Wim Robberecht, Adriano Chio, Cinzia Gellera, Carsten Drepper, Michael Sendtner, Antonia Ratti, Jonathan D. Glass, Jesús S. Mora, Nazli A. Basak, Orla Hardiman, Albert C. Ludolph, Peter M. Andersen, Jochen H. Weishaupt, Robert H. Brown, Ammar Al-Chalabi, Vincenzo Silani, Christopher E. Shaw, Leonard H. Van Den Berg, Jan H. Veldink, John E. Landers, Sandra D’Alfonso, Letizia Mazzini, Giacomo P. Comi, Roberto Del Bo, Mauro Ceroni, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Stefania Corti, Cristina Cereda, Lucia Corrado, Gianni Sorarù, Viviana Pensato, Barbara Castellotti

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

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Abstract

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.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (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.

Original language	English
Pages (from-to)	1037-1042
Number of pages	6
Journal	Nature Genetics
Volume	48
Issue number	9
DOIs	https://doi.org/10.1038/ng.3626
State	Published - 1 Sep 2016
Externally published	Yes

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Kenna, K. P., Van Doormaal, P. T. C., Dekker, A. M., Ticozzi, N., Kenna, B. J., Diekstra, F. P., Van Rheenen, W., Van Eijk, K. R., Jones, A. R., Keagle, P., Shatunov, A., Sproviero, W., Smith, B. N., Van Es, M. A., Topp, S. D., Kenna, A., Miller, J. W., Fallini, C., Tiloca, C., ... Castellotti, B. (2016). NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Nature Genetics, 48(9), 1037-1042. https://doi.org/10.1038/ng.3626

@article{e7854595268b4dbe89dfdb472d3a59e4,

title = "NEK1 variants confer susceptibility to amyotrophic lateral sclerosis",

abstract = "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.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (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.",

author = "Kenna, {Kevin P.} and {Van Doormaal}, {Perry T.C.} and Dekker, {Annelot M.} and Nicola Ticozzi and Kenna, {Brendan J.} and Diekstra, {Frank P.} and {Van Rheenen}, Wouter and {Van Eijk}, {Kristel R.} and Jones, {Ashley R.} and Pamela Keagle and Aleksey Shatunov and William Sproviero and Smith, {Bradley N.} and {Van Es}, {Michael A.} and Topp, {Simon D.} and Aoife Kenna and Miller, {Jack W.} and Claudia Fallini and Cinzia Tiloca and McLaughlin, {Russell L.} and Caroline Vance and Claire Troakes and Claudia Colombrita and Gabriele Mora and Andrea Calvo and Federico Verde and Safa Al-Sarraj and Andrew King and Daniela Calini and {De Belleroche}, Jacqueline and Frank Baas and {Van Der Kooi}, {Anneke J.} and {De Visser}, Marianne and {Ten Asbroek}, {Anneloor L.M.A.} and Sapp, {Peter C.} and Diane McKenna-Yasek and Meraida Polak and Seneshaw Asress and Mu{\~n}oz-Blanco, {Jos{\'e} Luis} and Strom, {Tim M.} and Thomas Meitinger and Morrison, {Karen E.} and Giuseppe Lauria and Williams, {Kelly L.} and Leigh, {P. Nigel} and Nicholson, {Garth A.} and Blair, {Ian P.} and Leblond, {Claire S.} and Dion, {Patrick A.} and Rouleau, {Guy A.} and Hardev Pall and Shaw, {Pamela J.} and Turner, {Martin R.} and Kevin Talbot and Franco Taroni and Boylan, {Kevin B.} and {Van Blitterswijk}, Marka and Rosa Rademakers and Jes{\'u}s Esteban-P{\'e}rez and Alberto Garc{\'i}a-Redondo and {Van Damme}, Phillip and Wim Robberecht and Adriano Chio and Cinzia Gellera and Carsten Drepper and Michael Sendtner and Antonia Ratti and Glass, {Jonathan D.} and Mora, {Jes{\'u}s S.} and Basak, {Nazli A.} and Orla Hardiman and Ludolph, {Albert C.} and Andersen, {Peter M.} and Weishaupt, {Jochen H.} and Brown, {Robert H.} and Ammar Al-Chalabi and Vincenzo Silani and Shaw, {Christopher E.} and {Van Den Berg}, {Leonard H.} and Veldink, {Jan H.} and Landers, {John E.} and Sandra D{\textquoteright}Alfonso and Letizia Mazzini and Comi, {Giacomo P.} and {Del Bo}, Roberto and Mauro Ceroni and Stella Gagliardi and Giorgia Querin and Cinzia Bertolin and Stefania Corti and Cristina Cereda and Lucia Corrado and Gianni Sorar{\`u} and Viviana Pensato and Barbara Castellotti",

year = "2016",

month = sep,

day = "1",

doi = "10.1038/ng.3626",

language = "English",

volume = "48",

pages = "1037--1042",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "9",

}

Kenna, KP, Van Doormaal, PTC, Dekker, AM, Ticozzi, N, Kenna, BJ, Diekstra, FP, Van Rheenen, W, Van Eijk, KR, Jones, AR, Keagle, P, Shatunov, A, Sproviero, W, Smith, BN, Van Es, MA, Topp, SD, Kenna, A, Miller, JW, Fallini, C, Tiloca, C, McLaughlin, RL, Vance, C, Troakes, C, Colombrita, C, Mora, G, Calvo, A, Verde, F, Al-Sarraj, S, King, A, Calini, D, De Belleroche, J, Baas, F, Van Der Kooi, AJ, De Visser, M, Ten Asbroek, ALMA, Sapp, PC, McKenna-Yasek, D, Polak, M, Asress, S, Muñoz-Blanco, JL, Strom, TM, Meitinger, T, Morrison, KE, Lauria, G, Williams, KL, Leigh, PN, Nicholson, GA, Blair, IP, Leblond, CS, Dion, PA, Rouleau, GA, Pall, H, Shaw, PJ, Turner, MR, Talbot, K, Taroni, F, Boylan, KB, Van Blitterswijk, M, Rademakers, R, Esteban-Pérez, J, García-Redondo, A, Van Damme, P, Robberecht, W, Chio, A, Gellera, C, Drepper, C, Sendtner, M, Ratti, A, Glass, JD, Mora, JS, Basak, NA, Hardiman, O, Ludolph, AC, Andersen, PM, Weishaupt, JH, Brown, RH, Al-Chalabi, A, Silani, V, Shaw, CE, Van Den Berg, LH, Veldink, JH, Landers, JE, D’Alfonso, S, Mazzini, L, Comi, GP, Del Bo, R, Ceroni, M, Gagliardi, S, Querin, G, Bertolin, C, Corti, S, Cereda, C, Corrado, L, Sorarù, G, Pensato, V & Castellotti, B 2016, 'NEK1 variants confer susceptibility to amyotrophic lateral sclerosis', Nature Genetics, vol. 48, no. 9, pp. 1037-1042. https://doi.org/10.1038/ng.3626

TY - JOUR

T1 - NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

AU - Kenna, Kevin P.

AU - Van Doormaal, Perry T.C.

AU - Dekker, Annelot M.

AU - Ticozzi, Nicola

AU - Kenna, Brendan J.

AU - Diekstra, Frank P.

AU - Van Rheenen, Wouter

AU - Van Eijk, Kristel R.

AU - Jones, Ashley R.

AU - Keagle, Pamela

AU - Shatunov, Aleksey

AU - Sproviero, William

AU - Smith, Bradley N.

AU - Van Es, Michael A.

AU - Topp, Simon D.

AU - Kenna, Aoife

AU - Miller, Jack W.

AU - Fallini, Claudia

AU - Tiloca, Cinzia

AU - McLaughlin, Russell L.

AU - Vance, Caroline

AU - Troakes, Claire

AU - Colombrita, Claudia

AU - Mora, Gabriele

AU - Calvo, Andrea

AU - Verde, Federico

AU - Al-Sarraj, Safa

AU - King, Andrew

AU - Calini, Daniela

AU - De Belleroche, Jacqueline

AU - Baas, Frank

AU - Van Der Kooi, Anneke J.

AU - De Visser, Marianne

AU - Ten Asbroek, Anneloor L.M.A.

AU - Sapp, Peter C.

AU - McKenna-Yasek, Diane

AU - Polak, Meraida

AU - Asress, Seneshaw

AU - Muñoz-Blanco, José Luis

AU - Strom, Tim M.

AU - Meitinger, Thomas

AU - Morrison, Karen E.

AU - Lauria, Giuseppe

AU - Williams, Kelly L.

AU - Leigh, P. Nigel

AU - Nicholson, Garth A.

AU - Blair, Ian P.

AU - Leblond, Claire S.

AU - Dion, Patrick A.

AU - Rouleau, Guy A.

AU - Pall, Hardev

AU - Shaw, Pamela J.

AU - Turner, Martin R.

AU - Talbot, Kevin

AU - Taroni, Franco

AU - Boylan, Kevin B.

AU - Van Blitterswijk, Marka

AU - Rademakers, Rosa

AU - Esteban-Pérez, Jesús

AU - García-Redondo, Alberto

AU - Van Damme, Phillip

AU - Robberecht, Wim

AU - Chio, Adriano

AU - Gellera, Cinzia

AU - Drepper, Carsten

AU - Sendtner, Michael

AU - Ratti, Antonia

AU - Glass, Jonathan D.

AU - Mora, Jesús S.

AU - Basak, Nazli A.

AU - Hardiman, Orla

AU - Ludolph, Albert C.

AU - Andersen, Peter M.

AU - Weishaupt, Jochen H.

AU - Brown, Robert H.

AU - Al-Chalabi, Ammar

AU - Silani, Vincenzo

AU - Shaw, Christopher E.

AU - Van Den Berg, Leonard H.

AU - Veldink, Jan H.

AU - Landers, John E.

AU - D’Alfonso, Sandra

AU - Mazzini, Letizia

AU - Comi, Giacomo P.

AU - Del Bo, Roberto

AU - Ceroni, Mauro

AU - Gagliardi, Stella

AU - Querin, Giorgia

AU - Bertolin, Cinzia

AU - Corti, Stefania

AU - Cereda, Cristina

AU - Corrado, Lucia

AU - Sorarù, Gianni

AU - Pensato, Viviana

AU - Castellotti, Barbara

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (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.

AB - 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.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (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.

UR - http://www.scopus.com/inward/record.url?scp=84979585471&partnerID=8YFLogxK

U2 - 10.1038/ng.3626

DO - 10.1038/ng.3626

M3 - Article

C2 - 27455347

AN - SCOPUS:84979585471

SN - 1061-4036

VL - 48

SP - 1037

EP - 1042

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

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