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 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.

Original languageEnglish
JournalNature Genetics
DOIs
Publication statusPublished - 2016

Fingerprint

Amyotrophic Lateral Sclerosis
Exome
Cilia
Microtubules
Netherlands
Genes
DNA Damage
Amyotrophic lateral sclerosis 1

ASJC Scopus subject areas

  • Medicine(all)
  • Genetics

Cite this

Kenna, K. P., van Doormaal, P. T. C., Dekker, A. M., Ticozzi, N., Kenna, B. J., Diekstra, F. P., ... Landers, J. (2016). NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Nature Genetics. 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, Nicola; Kenna, Brendan J.; Diekstra, Frank P.; Van Rheenen, Wouter; van Eijk, Kristel R.; Jones, Ashley; Keagle, Pamela J.; Shatunov, Aleksey; Sproviero, William; Smith, Bradley N.; van Es, Michael A.; Topp, Simon; Kenna, Aoife; Miller, Jack; Fallini, Claudia; Tiloca, Cinzia; McLaughlin, Russell L.; Vance, Caroline; Troakes, Claire; Colombrita, Claudia; Mora, Gabriele; Calvo, Andrea; Verde, Federico; Al-Sarraj, S.; King, Andrew; Calini, Daniela; De Belleroche, Jacqueline; Baas, Frank; Van Der Kooi, Anneke J.; De Visser, M.; ten Asbroek, Anneloor L M A; Sapp, Peter C.; McKenna-Yasek, Diane; Polak, Meraida; Asress, Seneshaw; Muñoz-Blanco, José Luis; Strom, Tim M.; Meitinger, Thomas; Morrison, Karen E.; Lauria, Giuseppe; Lauria, Giuseppe; Leigh, P. Nigel; Nicholson, Garth A.; Blair, Ian P.; Leblond, Claire S.; Dion, Patrick A.; Rouleau, Guy A.; Pall, Hardev; Shaw, Pamela J.; Turner, Martin R.; Talbot, Kevin; Taroni, Franco; Taroni, Franco; Van Blitterswijk, Marka; Rademakers, Rosa; Esteban-Pérez, Jesús; Garcia Redondo, Alberto; van Damme, Philip; Robberecht, Wim; Chiò, Adriano; Gellera, Cinzia; Gellera, Cinzia; Sendtner, Michael; Ratti, Antonia; Ratti, Antonia; Mora, Jesus S.; Basak, Nazli A.; Hardiman, Orla; Ludolph, Albert C.; Andersen, Peter M.; Weishaupt, Jochen H.; Brown, Robert H.; Al-Chalabi, Ammar; Silani, Vincenzo; Silani, Vincenzo; Van Den Berg, Leonard H.; Veldink, Jan; Landers, John.

In: Nature Genetics, 2016.

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, 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
Kenna, Kevin P. ; van Doormaal, Perry T C ; Dekker, Annelot M. ; Ticozzi, Nicola ; Kenna, Brendan J. ; Diekstra, Frank P. ; Van Rheenen, Wouter ; van Eijk, Kristel R. ; Jones, Ashley ; Keagle, Pamela J. ; Shatunov, Aleksey ; Sproviero, William ; Smith, Bradley N. ; van Es, Michael A. ; Topp, Simon ; Kenna, Aoife ; Miller, Jack ; Fallini, Claudia ; Tiloca, Cinzia ; McLaughlin, Russell L. ; Vance, Caroline ; Troakes, Claire ; Colombrita, Claudia ; Mora, Gabriele ; Calvo, Andrea ; Verde, Federico ; Al-Sarraj, S. ; King, Andrew ; Calini, Daniela ; De Belleroche, Jacqueline ; Baas, Frank ; Van Der Kooi, Anneke J. ; De Visser, M. ; ten Asbroek, Anneloor L M A ; Sapp, Peter C. ; McKenna-Yasek, Diane ; Polak, Meraida ; Asress, Seneshaw ; Muñoz-Blanco, José Luis ; Strom, Tim M. ; Meitinger, Thomas ; Morrison, Karen E. ; Lauria, Giuseppe ; Lauria, Giuseppe ; Leigh, P. Nigel ; Nicholson, Garth A. ; Blair, Ian P. ; Leblond, Claire S. ; Dion, Patrick A. ; Rouleau, Guy A. ; Pall, Hardev ; Shaw, Pamela J. ; Turner, Martin R. ; Talbot, Kevin ; Taroni, Franco ; Taroni, Franco ; Van Blitterswijk, Marka ; Rademakers, Rosa ; Esteban-Pérez, Jesús ; Garcia Redondo, Alberto ; van Damme, Philip ; Robberecht, Wim ; Chiò, Adriano ; Gellera, Cinzia ; Gellera, Cinzia ; Sendtner, Michael ; Ratti, Antonia ; Ratti, Antonia ; Mora, Jesus S. ; Basak, Nazli A. ; Hardiman, Orla ; Ludolph, Albert C. ; Andersen, Peter M. ; Weishaupt, Jochen H. ; Brown, Robert H. ; Al-Chalabi, Ammar ; Silani, Vincenzo ; Silani, Vincenzo ; Van Den Berg, Leonard H. ; Veldink, Jan ; Landers, John. / NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. In: Nature Genetics. 2016.
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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.",
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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 - 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 - 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 - Gellera, Cinzia

AU - Sendtner, Michael

AU - Ratti, Antonia

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 - 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.

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