NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

Kevin P. Kenna, Perry T C van Doormaal, Annelot M. Dekker, N. Ticozzi, Brendan J. Kenna, Frank P. Diekstra, Wouter Van Rheenen, Kristel R. van Eijk, R. A. Jones, Pamela J. Keagle, Aleksey Shatunov, William Sproviero, Bradley N. Smith, Michael A. van Es, S.D. Topp, Margaret A. Kenna, William J. Miller, Claudia Fallini, C. Tiloca, Russell L. McLaughlinCarl Vance, Claire Troakes, C. Colombrita, G. Mora, Felipe A. Calvo, Federico Verde, S. Al-Sarraj, A. King, Daniela Calini, Jacqueline De Belleroche, Annette F. Baas, Anneke J. Van Der Kooi, M. De Visser, Anneloor L M A ten Asbroek, Peter C. Sapp, Diane McKenna-Yasek, M. Polak, Seneshaw Asress, JoséLuis L. Muñoz-Blanco, T. M. Strom, T. Meitinger, Karen E. Morrison, G. Lauria, Kelly L. Williams, P. Nigel Leigh, A. G. Nicholson, Ian P. Blair, Claire S. Leblond, Patrick A. Dion, Guy A. Rouleau, Hardev Pall, P. J. Shaw, Martin R. Turner, K. Talbot, F. Taroni, Kevin B. Boylan, Marka Van Blitterswijk, Rosa Rademakers, Jesús Esteban-Pérez, A. García-Redondo, Philip van Damme, Wim Robberecht, A. Di Chio, C. Gellera, Carsten Drepper, Michael Sendtner, A. Ratti, Jonathan D. Glass, Jesus S. Mora, Ayse N. Basak, Orla Hardiman, A. C. Ludolph, P. M. Andersen, Jochen H. Weishaupt, R. H. Brown, Ammar Al-Chalabi, V. Silani, E. C. Shaw, Leonard H. Van Den Berg, Jan H. Veldink, J.E. Landers, Giacomo Pietro Comi, Roberto Del Bo, Stefania Paola Corti

Research output: Contribution to journalArticle

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. © 2016 Nature America, Inc. All rights reserved.
Original languageEnglish
Pages (from-to)1037-1042
Number of pages6
JournalNature Genetics
Volume48
Issue number9
DOIs
Publication statusPublished - 2016

Cite this

Kenna, K. P., van Doormaal, P. T. C., Dekker, A. M., Ticozzi, N., Kenna, B. J., Diekstra, F. P., ... Corti, S. P. (2016). NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Nature Genetics, 48(9), 1037-1042. https://doi.org/10.1038/ng.3626

NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. / Kenna, Kevin P.; van Doormaal, Perry T C; Dekker, Annelot M.; Ticozzi, N.; Kenna, Brendan J.; Diekstra, Frank P.; Van Rheenen, Wouter; van Eijk, Kristel R.; Jones, R. A.; Keagle, Pamela J.; Shatunov, Aleksey; Sproviero, William; Smith, Bradley N.; van Es, Michael A.; Topp, S.D.; Kenna, Margaret A.; Miller, William J.; Fallini, Claudia; Tiloca, C.; McLaughlin, Russell L.; Vance, Carl; Troakes, Claire; Colombrita, C.; Mora, G.; Calvo, Felipe A.; Verde, Federico; Al-Sarraj, S.; King, A.; Calini, Daniela; De Belleroche, Jacqueline; Baas, Annette F.; Van Der Kooi, Anneke J.; De Visser, M.; ten Asbroek, Anneloor L M A; Sapp, Peter C.; McKenna-Yasek, Diane; Polak, M.; Asress, Seneshaw; Muñoz-Blanco, JoséLuis L.; Strom, T. M.; Meitinger, T.; Morrison, Karen E.; Lauria, G.; Williams, Kelly L.; Leigh, P. Nigel; Nicholson, A. G.; Blair, Ian P.; Leblond, Claire S.; Dion, Patrick A.; Rouleau, Guy A.; Pall, Hardev; Shaw, P. J.; Turner, Martin R.; Talbot, K.; Taroni, F.; Boylan, Kevin B.; Van Blitterswijk, Marka; Rademakers, Rosa; Esteban-Pérez, Jesús; García-Redondo, A.; van Damme, Philip; Robberecht, Wim; Di Chio, A.; Gellera, C.; Drepper, Carsten; Sendtner, Michael; Ratti, A.; Glass, Jonathan D.; Mora, Jesus S.; Basak, Ayse N.; Hardiman, Orla; Ludolph, A. C.; Andersen, P. M.; Weishaupt, Jochen H.; Brown, R. H.; Al-Chalabi, Ammar; Silani, V.; Shaw, E. C.; Van Den Berg, Leonard H.; Veldink, Jan H.; Landers, J.E.; Comi, Giacomo Pietro; Del Bo, Roberto; Corti, Stefania Paola.

In: Nature Genetics, Vol. 48, No. 9, 2016, p. 1037-1042.

Research output: Contribution to journalArticle

Kenna, KP, van Doormaal, PTC, Dekker, AM, Ticozzi, N, Kenna, BJ, Diekstra, FP, Van Rheenen, W, van Eijk, KR, Jones, RA, Keagle, PJ, Shatunov, A, Sproviero, W, Smith, BN, van Es, MA, Topp, SD, Kenna, MA, Miller, WJ, Fallini, C, Tiloca, C, McLaughlin, RL, Vance, C, Troakes, C, Colombrita, C, Mora, G, Calvo, FA, Verde, F, Al-Sarraj, S, King, A, Calini, D, De Belleroche, J, Baas, AF, 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, AG, 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, Di Chio, A, Gellera, C, Drepper, C, Sendtner, M, Ratti, A, Glass, JD, Mora, JS, Basak, AN, Hardiman, O, Ludolph, AC, Andersen, PM, Weishaupt, JH, Brown, RH, Al-Chalabi, A, Silani, V, Shaw, EC, Van Den Berg, LH, Veldink, JH, Landers, JE, Comi, GP, Del Bo, R & Corti, SP 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
Kenna KP, van Doormaal PTC, Dekker AM, Ticozzi N, Kenna BJ, Diekstra FP et al. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Nature Genetics. 2016;48(9):1037-1042. https://doi.org/10.1038/ng.3626
Kenna, Kevin P. ; van Doormaal, Perry T C ; Dekker, Annelot M. ; Ticozzi, N. ; Kenna, Brendan J. ; Diekstra, Frank P. ; Van Rheenen, Wouter ; van Eijk, Kristel R. ; Jones, R. A. ; Keagle, Pamela J. ; Shatunov, Aleksey ; Sproviero, William ; Smith, Bradley N. ; van Es, Michael A. ; Topp, S.D. ; Kenna, Margaret A. ; Miller, William J. ; Fallini, Claudia ; Tiloca, C. ; McLaughlin, Russell L. ; Vance, Carl ; Troakes, Claire ; Colombrita, C. ; Mora, G. ; Calvo, Felipe A. ; Verde, Federico ; Al-Sarraj, S. ; King, A. ; Calini, Daniela ; De Belleroche, Jacqueline ; Baas, Annette F. ; Van Der Kooi, Anneke J. ; De Visser, M. ; ten Asbroek, Anneloor L M A ; Sapp, Peter C. ; McKenna-Yasek, Diane ; Polak, M. ; Asress, Seneshaw ; Muñoz-Blanco, JoséLuis L. ; Strom, T. M. ; Meitinger, T. ; Morrison, Karen E. ; Lauria, G. ; Williams, Kelly L. ; Leigh, P. Nigel ; Nicholson, A. G. ; Blair, Ian P. ; Leblond, Claire S. ; Dion, Patrick A. ; Rouleau, Guy A. ; Pall, Hardev ; Shaw, P. J. ; Turner, Martin R. ; Talbot, K. ; Taroni, F. ; Boylan, Kevin B. ; Van Blitterswijk, Marka ; Rademakers, Rosa ; Esteban-Pérez, Jesús ; García-Redondo, A. ; van Damme, Philip ; Robberecht, Wim ; Di Chio, A. ; Gellera, C. ; Drepper, Carsten ; Sendtner, Michael ; Ratti, A. ; Glass, Jonathan D. ; Mora, Jesus S. ; Basak, Ayse N. ; Hardiman, Orla ; Ludolph, A. C. ; Andersen, P. M. ; Weishaupt, Jochen H. ; Brown, R. H. ; Al-Chalabi, Ammar ; Silani, V. ; Shaw, E. C. ; Van Den Berg, Leonard H. ; Veldink, Jan H. ; Landers, J.E. ; Comi, Giacomo Pietro ; Del Bo, Roberto ; Corti, Stefania Paola. / NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. In: Nature Genetics. 2016 ; Vol. 48, No. 9. pp. 1037-1042.
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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. {\circledC} 2016 Nature America, Inc. All rights reserved.",
author = "Kenna, {Kevin P.} and {van Doormaal}, {Perry T C} and Dekker, {Annelot M.} and N. Ticozzi and Kenna, {Brendan J.} and Diekstra, {Frank P.} and {Van Rheenen}, Wouter and {van Eijk}, {Kristel R.} and Jones, {R. A.} and Keagle, {Pamela J.} and Aleksey Shatunov and William Sproviero and Smith, {Bradley N.} and {van Es}, {Michael A.} and S.D. Topp and Kenna, {Margaret A.} and Miller, {William J.} and Claudia Fallini and C. Tiloca and McLaughlin, {Russell L.} and Carl Vance and Claire Troakes and C. Colombrita and G. Mora and Calvo, {Felipe A.} and Federico Verde and S. Al-Sarraj and A. King and Daniela Calini and {De Belleroche}, Jacqueline and Baas, {Annette F.} 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 M. Polak and Seneshaw Asress and Mu{\~n}oz-Blanco, {Jos{\'e}Luis L.} and Strom, {T. M.} and T. Meitinger and Morrison, {Karen E.} and G. Lauria and Williams, {Kelly L.} and Leigh, {P. Nigel} and Nicholson, {A. G.} and Blair, {Ian P.} and Leblond, {Claire S.} and Dion, {Patrick A.} and Rouleau, {Guy A.} and Hardev Pall and Shaw, {P. J.} and Turner, {Martin R.} and K. Talbot and F. Taroni and Boylan, {Kevin B.} and {Van Blitterswijk}, Marka and Rosa Rademakers and Jes{\'u}s Esteban-P{\'e}rez and A. Garc{\'i}a-Redondo and {van Damme}, Philip and Wim Robberecht and {Di Chio}, A. and C. Gellera and Carsten Drepper and Michael Sendtner and A. Ratti and Glass, {Jonathan D.} and Mora, {Jesus S.} and Basak, {Ayse N.} and Orla Hardiman and Ludolph, {A. C.} and Andersen, {P. M.} and Weishaupt, {Jochen H.} and Brown, {R. H.} and Ammar Al-Chalabi and V. Silani and Shaw, {E. C.} and {Van Den Berg}, {Leonard H.} and Veldink, {Jan H.} and J.E. Landers and Comi, {Giacomo Pietro} and {Del Bo}, Roberto and Corti, {Stefania Paola}",
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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, N.

AU - Kenna, Brendan J.

AU - Diekstra, Frank P.

AU - Van Rheenen, Wouter

AU - van Eijk, Kristel R.

AU - Jones, R. A.

AU - Keagle, Pamela J.

AU - Shatunov, Aleksey

AU - Sproviero, William

AU - Smith, Bradley N.

AU - van Es, Michael A.

AU - Topp, S.D.

AU - Kenna, Margaret A.

AU - Miller, William J.

AU - Fallini, Claudia

AU - Tiloca, C.

AU - McLaughlin, Russell L.

AU - Vance, Carl

AU - Troakes, Claire

AU - Colombrita, C.

AU - Mora, G.

AU - Calvo, Felipe A.

AU - Verde, Federico

AU - Al-Sarraj, S.

AU - King, A.

AU - Calini, Daniela

AU - De Belleroche, Jacqueline

AU - Baas, Annette F.

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, M.

AU - Asress, Seneshaw

AU - Muñoz-Blanco, JoséLuis L.

AU - Strom, T. M.

AU - Meitinger, T.

AU - Morrison, Karen E.

AU - Lauria, G.

AU - Williams, Kelly L.

AU - Leigh, P. Nigel

AU - Nicholson, A. G.

AU - Blair, Ian P.

AU - Leblond, Claire S.

AU - Dion, Patrick A.

AU - Rouleau, Guy A.

AU - Pall, Hardev

AU - Shaw, P. J.

AU - Turner, Martin R.

AU - Talbot, K.

AU - Taroni, F.

AU - Boylan, Kevin B.

AU - Van Blitterswijk, Marka

AU - Rademakers, Rosa

AU - Esteban-Pérez, Jesús

AU - García-Redondo, A.

AU - van Damme, Philip

AU - Robberecht, Wim

AU - Di Chio, A.

AU - Gellera, C.

AU - Drepper, Carsten

AU - Sendtner, Michael

AU - Ratti, A.

AU - Glass, Jonathan D.

AU - Mora, Jesus S.

AU - Basak, Ayse N.

AU - Hardiman, Orla

AU - Ludolph, A. C.

AU - Andersen, P. M.

AU - Weishaupt, Jochen H.

AU - Brown, R. H.

AU - Al-Chalabi, Ammar

AU - Silani, V.

AU - Shaw, E. C.

AU - Van Den Berg, Leonard H.

AU - Veldink, Jan H.

AU - Landers, J.E.

AU - Comi, Giacomo Pietro

AU - Del Bo, Roberto

AU - Corti, Stefania Paola

N1 - Export Date: 28 March 2017

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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. © 2016 Nature America, Inc. All rights reserved.

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. © 2016 Nature America, Inc. All rights reserved.

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