NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

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.; Mclaughlin, R.L.; 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, A.J.; De Visser, M.; Ten Asbroek, A.L.M.A.; Sapp, P.C.; McKenna-Yasek, D.; Polak, M.; Asress, S.; Munoz-Blanco, J.L.; Strom, T.M.; Meitinger, T.; Morrison, K.E.; Lauria, G.; Williams, K.L.; Leigh, P.N.; Nicholson, G.A.; Blair, I.P.; Leblond, C.S.; Dion, P.A.; Rouleau, G.A.; Pall, H.; Shaw, P.J.; Turner, M.R.; Talbot, K.; Taroni, F.; Boylan, K.B.; Van Blitterswijk, M.; Rademakers, R.; Esteban-Perez, J.; Garcia-Redondo, A.; Van Damme, P.; Robberecht, W.; Chio, A.; Gellera, C.; Drepper, C.; Sendtner, M.; Ratti, A.; Glass, J.D.; Mora, J.S.; Basak, N.A.; Hardiman, O.; Ludolph, A.C.; Andersen, P.M.; Weishaupt, J.H.; Brown, R.H.; Al-Chalabi, A.; Silani, V.; Shaw, C.E.; Van Den Berg, L.H.; Veldink, J.H.; Landers, J.E.; D'Alfonso, S.; Mazzini, L.; Comi, G.P.; Del Bo, R.; Ceroni, M.; Gagliardi, S.; Querin, G.; Bertolin, C.; Corti, S.; Cereda, C.; Corrado, L.; Soraru, G.; Pensato, V.; Castellotti, B.

doi:10.1038/ng.3626

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.

NEK1 variants confer susceptibility to amyotrophic lateral sclerosis / K.P. Kenna, P.T.C. Van Doormaal, A.M. Dekker, N. Ticozzi, B.J. Kenna, F.P. Diekstra, W. Van Rheenen, K.R. Van Eijk, A.R. Jones, P. Keagle, A. Shatunov, W. Sproviero, B.N. Smith, M.A. Van Es, S.D. Topp, A. Kenna, J.W. Miller, C. Fallini, C. Tiloca, R.L. Mclaughlin, C. Vance, C. Troakes, C. Colombrita, G. Mora, A. Calvo, F. Verde, S. Al-Sarraj, A. King, D. Calini, J. De Belleroche, F. Baas, A.J. Van Der Kooi, M. De Visser, A.L.M.A. Ten Asbroek, P.C. Sapp, D. McKenna-Yasek, M. Polak, S. Asress, J.L. Munoz-Blanco, T.M. Strom, T. Meitinger, K.E. Morrison, G. Lauria, K.L. Williams, P.N. Leigh, G.A. Nicholson, I.P. Blair, C.S. Leblond, P.A. Dion, G.A. Rouleau, H. Pall, P.J. Shaw, M.R. Turner, K. Talbot, F. Taroni, K.B. Boylan, M. Van Blitterswijk, R. Rademakers, J. Esteban-Perez, A. Garcia-Redondo, P. Van Damme, W. Robberecht, A. Chio, C. Gellera, C. Drepper, M. Sendtner, A. Ratti, J.D. Glass, J.S. Mora, N.A. Basak, O. Hardiman, A.C. Ludolph, P.M. Andersen, J.H. Weishaupt, R.H. Brown, A. Al-Chalabi, V. Silani, C.E. Shaw, L.H. Van Den Berg, J.H. Veldink, J.E. Landers, S. D'Alfonso, L. Mazzini, G.P. Comi, R. Del Bo, M. Ceroni, S. Gagliardi, G. Querin, C. Bertolin, S. Corti, C. Cereda, L. Corrado, G. Soraru, V. Pensato, B. Castellotti. - In: NATURE GENETICS. - ISSN 1061-4036. - 48:9(2016 Sep), pp. 1037-1042. [10.1038/ng.3626]

NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

Kenna K. P.;Van Doormaal P. T. C.;Dekker A. M.;N. Ticozzi;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.;C. Tiloca;McLaughlin R. L.;Vance C.;Troakes C.;C. Colombrita;Mora G.;Calvo A.;F. Verde;Al-Sarraj S.;King A.;Calini D.;De Belleroche J.;Baas F.;Van Der Kooi A. J.;De Visser M.;Ten Asbroek A. L. M. A.;Sapp P. C.;McKenna-Yasek D.;Polak M.;Asress S.;Munoz-Blanco J. L.;Strom T. M.;Meitinger T.;Morrison K. E.;G. Lauria;Williams K. L.;Leigh P. N.;Nicholson G. A.;Blair I. P.;Leblond C. S.;Dion P. A.;Rouleau G. A.;Pall H.;Shaw P. J.;Turner M. R.;Talbot K.;Taroni F.;Boylan K. B.;Van Blitterswijk M.;Rademakers R.;Esteban-Perez J.;Garcia-Redondo A.;Van Damme P.;Robberecht W.;Chio A.;Gellera C.;Drepper C.;Sendtner M.;A. Ratti;Glass J. D.;Mora J. S.;Basak N. A.;Hardiman O.;Ludolph A. C.;Andersen P. M.;Weishaupt J. H.;Brown R. H.;Al-Chalabi A.;V. Silani;Shaw C. E.;Van Den Berg L. H.;Veldink J. H.;Landers J. E.;D'Alfonso S.;Mazzini L.;G.P. Comi;R. Del Bo;Ceroni M.;Gagliardi S.;Querin G.;Bertolin C.;S. Corti;C. Cereda;L. Corrado;Soraru G.;V. Pensato;B. Castellotti

2016

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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Scheda completa (DC)

	Parole chiave
	
				Amyotrophic Lateral Sclerosis; Case-Control Studies; Cohort Studies; Exome; Genetic Association Studies; Humans; Mutation; NIMA-Related Kinase 1; Netherlands; Genetic Predisposition to Disease; Genetics
			
	Settori scientifico-disciplinari dell'articolo (sola visualizzazione)
	
				Settore MED/26 - Neurologia
Settore MED/03 - Genetica Medica
Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica
Settore BIO/18 - Genetica
			
	Settori scientifico-disciplinari dell'articolo (validi dal 09/05/2024)
	
				Settore MEDS-01/A - Genetica medica
Settore MEDS-12/A - Neurologia
Settore BIOS-09/A - Biochimica clinica e biologia molecolare clinica
Settore BIOS-14/A - Genetica
			
	Data di pubblicazione
	
				set-2016
			
	Data ahead of print o data di stampa
	
				25-lug-2016
			
	Rivista in ANCE
	
				NATURE GENETICS
			
	DOI
	
				https://dx.doi.org/10.1038/ng.3626
			
	Tipologia
	
				Article (author)
			
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				01 - Articolo su periodico

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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/425939

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