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 Jones; Pamela J. Keagle; Aleksey Shatunov; William Sproviero; Bradley N. Smith; Michael A. van Es; Simon Topp; Aoife Kenna; Jack Miller; Claudia Fallini; Cinzia Tiloca; Russell L. McLaughlin; Caroline Vance; Claire Troakes; Claudia Colombrita; Gabriele Mora; Andrea Calvo; Federico Verde; S. Al-Sarraj; Andrew King; Daniela Calini; Jacqueline De Belleroche; Frank Baas; Anneke J. Van Der Kooi; M. 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; Giuseppe Lauria; 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; Franco Taroni; Marka Van Blitterswijk; Rosa Rademakers; Jesús Esteban-Pérez; Alberto Garcia Redondo; Philip van Damme; Wim Robberecht; Adriano Chiò; Cinzia Gellera; Cinzia Gellera; Michael Sendtner; Antonia Ratti; Antonia Ratti; Jesus S. Mora; Nazli A. Basak; Orla Hardiman; Albert C. Ludolph; Peter M. Andersen; Jochen H. Weishaupt; Robert H. Brown; Ammar Al-Chalabi; Vincenzo Silani; Vincenzo Silani; Leonard H. Van Den Berg; Jan Veldink; John Landers

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 Jones, Pamela J. Keagle, Aleksey Shatunov, William Sproviero, Bradley N. Smith, Michael A. van Es, Simon Topp, Aoife Kenna, Jack Miller, Claudia Fallini, Cinzia Tiloca, Russell L. McLaughlinCaroline Vance, Claire Troakes, Claudia Colombrita, Gabriele Mora, Andrea Calvo, Federico Verde, S. Al-Sarraj, Andrew King, Daniela Calini, Jacqueline De Belleroche, Frank Baas, Anneke J. Van Der Kooi, M. 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, Giuseppe Lauria, 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, Franco Taroni, Marka Van Blitterswijk, Rosa Rademakers, Jesús Esteban-Pérez, Alberto Garcia Redondo, Philip van Damme, Wim Robberecht, Adriano Chiò, Cinzia Gellera, Cinzia Gellera, Michael Sendtner, Antonia Ratti, Antonia Ratti, Jesus S. Mora, Nazli A. Basak, Orla Hardiman, Albert C. Ludolph, Peter M. Andersen, Jochen H. Weishaupt, Robert H. Brown, Ammar Al-Chalabi, Vincenzo Silani, Vincenzo Silani, Leonard H. Van Den Berg, Jan Veldink, John Landers

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

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
Journal	Nature Genetics
DOIs	https://doi.org/10.1038/ng.3626
Publication status	Published - 2016

ASJC Scopus subject areas

Medicine(all)
Genetics

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10.1038/ng.3626

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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., Keagle, P. J., Shatunov, A., Sproviero, W., Smith, B. N., van Es, M. A., Topp, S., Kenna, A., Miller, J., Fallini, C., Tiloca, C., ... Landers, J. (2016). NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Nature Genetics. https://doi.org/10.1038/ng.3626

Kenna, KP, van Doormaal, PTC, Dekker, AM, Ticozzi, N, Kenna, BJ, Diekstra, FP, Van Rheenen, W, van Eijk, KR, Jones, A, Keagle, PJ, Shatunov, A, Sproviero, W, Smith, BN, van Es, MA, Topp, S, Kenna, A, Miller, J, 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, Lauria, G, Leigh, PN, Nicholson, GA, Blair, IP, Leblond, CS, Dion, PA, Rouleau, GA, Pall, H, Shaw, PJ, Turner, MR, Talbot, K, Taroni, F, Taroni, F, Van Blitterswijk, M, Rademakers, R, Esteban-Pérez, J, Garcia Redondo, A, van Damme, P, Robberecht, W, Chiò, A, Gellera, C, Gellera, C, Sendtner, M, Ratti, A, Ratti, A, Mora, JS, Basak, NA, Hardiman, O, Ludolph, AC, Andersen, PM, Weishaupt, JH, Brown, RH, Al-Chalabi, A, Silani, V, Silani, V, Van Den Berg, LH, Veldink, J & Landers, J 2016, 'NEK1 variants confer susceptibility to amyotrophic lateral sclerosis', Nature Genetics. https://doi.org/10.1038/ng.3626

@article{39e70b8014ac4e84866e2686ea4795f4,

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 Ashley Jones and Keagle, {Pamela J.} and Aleksey Shatunov and William Sproviero and Smith, {Bradley N.} and {van Es}, {Michael A.} and Simon Topp and Aoife Kenna and Jack Miller 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 S. Al-Sarraj and Andrew King and Daniela Calini and {De Belleroche}, Jacqueline and Frank Baas and {Van Der Kooi}, {Anneke J.} and {De Visser}, M. 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 Giuseppe Lauria 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 Franco Taroni and {Van Blitterswijk}, Marka and Rosa Rademakers and Jes{\'u}s Esteban-P{\'e}rez and {Garcia Redondo}, Alberto and {van Damme}, Philip and Wim Robberecht and Adriano Chi{\`o} and Cinzia Gellera and Cinzia Gellera and Michael Sendtner and Antonia Ratti and Antonia Ratti and Mora, {Jesus 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 Vincenzo Silani and {Van Den Berg}, {Leonard H.} and Jan Veldink and John Landers",

year = "2016",

doi = "10.1038/ng.3626",

language = "English",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

}

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

AU - Keagle, Pamela J.

AU - Shatunov, Aleksey

AU - Sproviero, William

AU - Smith, Bradley N.

AU - van Es, Michael A.

AU - Topp, Simon

AU - Kenna, Aoife

AU - Miller, Jack

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, S.

AU - King, Andrew

AU - Calini, Daniela

AU - De Belleroche, Jacqueline

AU - Baas, Frank

AU - Van Der Kooi, Anneke J.

AU - De Visser, M.

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 - 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 - Van Blitterswijk, Marka

AU - Rademakers, Rosa

AU - Esteban-Pérez, Jesús

AU - Garcia Redondo, Alberto

AU - van Damme, Philip

AU - Robberecht, Wim

AU - Chiò, Adriano

AU - Gellera, Cinzia

AU - Sendtner, Michael

AU - Ratti, Antonia

AU - Mora, Jesus 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 - Van Den Berg, Leonard H.

AU - Veldink, Jan

AU - Landers, John

PY - 2016

Y1 - 2016

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

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

U2 - 10.1038/ng.3626

DO - 10.1038/ng.3626

M3 - Article

SN - 1061-4036

JO - Nature Genetics

JF - Nature Genetics

ER -

NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

Abstract

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