Reduced expression of the Kinesin-Associated Protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis

doi:10.1073/pnas.0812937106

Proc Natl Acad Sci U S A. 2009 June 2; 106(22): 9004–9009.

Published online 2009 May 18. doi: 10.1073/pnas.0812937106.

PMCID: PMC2683883

Genetics

Reduced expression of the Kinesin-Associated Protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis

John E. Landers,^a¹ Judith Melki,^b² Vincent Meininger,^c Jonathan D. Glass,^d Leonard H. van den Berg,^e Michael A. van Es,^e Peter C. Sapp,^a^f Paul W. J. van Vught,^e Diane M. McKenna-Yasek,^a Hylke M. Blauw,^e Ting-Jan Cho,^a Meraida Polak,^d Lijia Shi,^a Anne-Marie Wills,^a Wendy J. Broom,^a Nicola Ticozzi,^a^g Vincenzo Silani,^g Aslihan Ozoguz,^h Ildefonso Rodriguez-Leyva,^aⁱ Jan H. Veldink,^e Adrian J. Ivinson,^j Christiaan G. J. Saris,^e Betsy A. Hosler,^a Alayna Barnes-Nessa,^a Nicole Couture,^a John H. J. Wokke,^e Thomas J. Kwiatkowski, Jr.,^a Roel A. Ophoff,^k^l Simon Cronin,^m Orla Hardiman,^m Frank P. Diekstra,ⁿ P. Nigel Leigh,ⁿ Christopher E. Shaw,ⁿ Claire L. Simpson,ⁿ Valerie K. Hansen,ⁿ John F. Powell,ⁿ Philippe Corcia,^o François Salachas,^c Simon Heath,^p Pilar Galan,^q Franck Georges,^b H. Robert Horvitz,^f Mark Lathrop,^p Shaun Purcell,^r Ammar Al-Chalabi,ⁿ³ and Robert H. Brown, Jr.^a^1,³

^aCecil B. Day Neuromuscular Research Laboratory, Massachusetts General Hospital-East, Building 114, Navy Yard, Charlestown, MA 02129;

^bLaboratoire de Neurogenetique Moleculaire, Institut National de la Santé et de la Recherche Médicale U-798, Universite d'Evry et Paris 11, 2 rue Gaston Crémieux, CP5724, 91057 Evry France;

^cFédération des maladies du système nerveux, Assistance Publique—Hôpitaux de Paris, Hôpital de la Salpêtrière, 75651 Paris, France;

^dDepartment of Neurology, Emory University, Atlanta, GA 30322;

Departments of ^eNeurology and

^kMedical Genetics, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands;

^fHoward Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139;

^gDepartment of Neurology and Laboratory of Neuroscience, ‘Dino Ferrari‘ Center, University of Milan Medical School—Istituto Di Ricovero e Cura a Carattere Scientifico Istituto Auxologico Italiano, 20149 Milan, Italy;

^hDepartment of Molecular Biology and Genetics, Neurodegeneration Research Laboratory, Bogazici University, Istanbul, Turkey;

ⁱFaculty of Medicine, Universidad Autonoma de San Luis Potosi, San Luis Potosi, Mexico S.L.P., CP 78210;

^jHarvard NeuroDiscovery Center, Harvard Medical School, Boston, MA 02115;

^lNeuropsychiatric Institute, University of California, Los Angeles;

^mDepartment of Neurology, Beaumont Hospital, Dublin 9, Ireland;

ⁿMedical Research Council Centre for Neurodegeneration Research, Department of Clinical Neuroscience, PO43, Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom;

^oService de Neurologie, Centre Hospitalier Universitaire Bretonneau, 37044 Tours, France;

^pCentre National de Génotypage, Institut Génomique, Commissariat à l'Énergie Atomique, 91057 Evry, France;

^qUnité de Recherche en Epidémiologie Nutritionnelle, l'UFR Sante Médecine et Biologie Humaine, 74 rue Marcel Cachin, 93017 Bobigny, France; and

^rCenter for Human Genetics Research, Massachusetts General Hospital, Richard B. Simches Research Building, CPZN-6254, 185 Cambridge Street, Boston, MA 02114

¹To whom correspondence should be addressed at the present address: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605., E-mail: john.landers/at/umassmed.edu

Edited by David E. Housman, Massachusetts Institute of Technology, Cambridge, MA, and approved April 1, 2009

Author contributions: J.E.L., J.M., V.M., J.D.G., L.H.v.d.B., M.A.v.E., P.C.S., P.W.J.v.V., D.M.M.-Y., H.M.B., T.-J.C., M.P., L.S., A.-M.W., W.J.B., N.T., V.S., A.O., I.R.-L., J.H.V., A.J.I., C.G.J.S., B.A.H., J.H.J.W., R.A.O., S.C., O.H., F.P.D., P.N.L., C.E.S., C.L.S., V.K.H., J.F.P., P.C., F.S., S.H., P.G., F.G., H.R.H., M.L., S.P., A.A.-C., and R.H.B. designed research; J.E.L., M.A.v.E., P.C.S., P.W.J.v.V., D.M.M.-Y., H.M.B., T.-J.C., M.P., L.S., A.-M.W., W.J.B., N.T., V.S., A.O., I.R.-L., J.H.V., C.G.J.S., B.A.H., A.B.-N., N.C., T.J.K., R.A.O., S.C., O.H., F.P.D., C.L.S., V.K.H., J.F.P., P.C., F.S., S.H., P.G., F.G., M.L., S.P., A.A.-C., and R.H.B. performed research; J.M., V.M., J.D.G., L.H.v.d.B., W.J.B., I.R.-L., A.J.I., P.N.L., C.E.S., J.F.P., S.P., A.A.-C., and R.H.B. contributed new reagents/analytic tools; J.E.L., J.M., V.M., L.H.v.d.B., M.A.v.E., P.C.S., P.W.J.v.V., D.M.M.-Y., H.M.B., T.-J.C., M.P., L.S., A.-M.W., W.J.B., N.T., V.S., A.O., I.R.-L., J.H.V., A.J.I., C.G.J.S., B.A.H., A.B.-N., N.C., J.H.J.W., T.J.K., R.A.O., S.C., O.H., F.P.D., P.N.L., C.E.S., C.L.S., V.K.H., J.F.P., P.C., F.S., S.H., P.G., F.G., H.R.H., M.L., S.P., A.A.-C., and R.H.B. analyzed data; and J.E.L., S.P., A.A.-C., and R.H.B. wrote the paper.

²Present address: Department of Human Genetics, Hadassah University Hospital, P.O. Box 12000, 91120 Jerusalem, Israel.

³A.A.-C. and R.H.B. contributed equally to this work.

Received December 22, 2008.

Freely available online through the PNAS open access option.

Abstract

Amyotrophic lateral sclerosis is a degenerative disorder of motor neurons that typically develops in the 6th decade and is uniformly fatal, usually within 5 years. To identify genetic variants associated with susceptibility and phenotypes in sporadic ALS, we performed a genome-wide SNP analysis in sporadic ALS cases and controls. A total of 288,357 SNPs were screened in a set of 1,821 sporadic ALS cases and 2,258 controls from the U.S. and Europe. Survival analysis was performed using 1,014 deceased sporadic cases. Top results for susceptibility were further screened in an independent sample set of 538 ALS cases and 556 controls. SNP rs1541160 within the KIFAP3 gene (encoding a kinesin-associated protein) yielded a genome-wide significant result (P = 1.84 × 10⁻⁸) that withstood Bonferroni correction for association with survival. Homozygosity for the favorable allele (CC) conferred a 14.0 months survival advantage. Sequence, genotypic and functional analyses revealed that there is linkage disequilibrium between rs1541160 and SNP rs522444 within the KIFAP3 promoter and that the favorable alleles of rs1541160 and rs522444 correlate with reduced KIFAP3 expression. No SNPs were associated with risk of sporadic ALS, site of onset, or age of onset. We have identified a variant within the KIFAP3 gene that is associated with decreased KIFAP3 expression and increased survival in sporadic ALS. These findings support the view that genetic factors modify phenotypes in this disease and that cellular motor proteins are determinants of motor neuron viability.

Keywords: genome-wide association study, single nucleotide polymorphism

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