Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis

Abstract

We conducted a genome-wide association study among 2,323 individuals with sporadic amyotrophic lateral sclerosis (ALS) and 9,013 control subjects and evaluated all SNPs with P < 1.0 × 10−4 in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Analysis of the genome-wide data revealed genome-wide significance for one SNP, rs12608932, with P = 1.30 × 10−9. This SNP showed robust replication in the second cohort (P = 1.86 × 10−6), and a combined analysis over the two stages yielded P = 2.53 × 10−14. The rs12608932 SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A, which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses. Follow-up of additional SNPs showed genome-wide significance for two further SNPs (rs2814707, with P = 7.45 × 10−9, and rs3849942, with P = 1.01 × 10−8) in the combined analysis of both stages. These SNPs are located at chromosome 9p21.2, in a linkage region for familial ALS with frontotemporal dementia found previously in several large pedigrees.

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Figure 1: Top, −log10 P values for all SNPs in a 500-kb region on chromosome 19 surrounding rs12308932.
Figure 2: Top, −log10 P values for all SNPs in a 300-kb region on chromosome 9 surrounding rs2814707 and rs3849942.

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Acknowledgements

We thank the individuals and their families who participated in this project; the study staff, general practitioners and pharmacists; P. Arp, M. Jhamai, M. Moorhouse, M. Verkerk and S. Bervoets for their help in creating the GWAS database; D.B. Goldstein for his contribution to the genotyping and analysis of the control sample from the German schizophrenia study; and N. Freimer for critical comments and reading of the manuscript. This project was supported by the Prinses Beatrix Fonds, VSB fonds, H. Kersten and M. Kersten (Kersten Foundation), The Netherlands ALS Foundation, and J.R. van Dijk and the Adessium Foundation (L.H.v.d.B.). J.H.V. was supported by the Brain Foundation of The Netherlands. The generation and management of GWAS genotype data for the Rotterdam Study was supported by The Netherlands Organisation for Scientific Research (NWO) investments (no. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (RIDE; 014-93-015) and the Netherlands Genomics Initiative/NWO (project no. 050-060-810). The controls from the Dutch schizophrenia GWAS were genotyped with the support of the National Institute for Mental Health (R.A.O.). The Rotterdam study was funded by Erasmus Medical Center and Erasmus University, Rotterdam; the Netherlands Organization for Health Research and Development; RIDE; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The Irish studies were funded by the Muscular Dystrophy Association USA (S.C., O.H.), the Health Research Board of Ireland (O.H.) and the Irish Motor Neuron Disease Research Foundation. In Sweden, this project was supported by the Swedish Brain Research Foundation, the Hållstens Research Foundation, the Swedish Medical Society, the Björklund Foundation for ALS Research and the Swedish Association for the Neurologically Disabled (P.M.A.). W.R. was supported through the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders and by the Interuniversity Attraction Poles program P6/43 of the Belgian Federal Science Policy Office. The Polish study was partially funded by the Polish Ministry of Science and Higher Education (nos. N N402 083934 and N402 092 32/3216). In France, this study was funded by the Association pour la Recherche sur la SLA and the Association Réseau SLA Ile de France. We thank the Motor Neurone Disease Association of Great Britain and Ireland, the Medical Research Council (UK), the Wellcome Trust and the Psychiatry Research Trust (Tim Perkins Fund and Charcot Fund). Support was also provided by the ALS Therapy Alliance, Project ALS, the Angel Fund, the Pierre L. de Bourgknecht ALS Research Foundation, the Al-Athel ALS Research Foundation, the ALS Family Charitable Foundation and the National Institute of Neurological Disorders and Stroke (NS050557). R.H.B. is a cofounder of AviTx, which targets development of therapies.

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The following authors diagnosed patients, collected phenotypic data and DNA samples from patients and healthy controls, and participated in sample preparation and quality control: M.A.v.E., J.H.V., C.G.J.S., H.M.B., R.L., H.J.S., M.H.B.H., A.J.v.d.K., M.d.V., A.B., C.D., M.J.Z., P.T.C.v.D., B.T., A.S., C.H., S.W., T.M., A.C.L., J.H.J.W., S. Cronin, R.L.M., O.H., V.M., J.M., P.N.L., C.E.S., J.D.G., J.E.L., A.A.-C., R.H.B., W.R., P.M.A. and L.H.v.d.B. Validation genotyping and data management for genome-wide data used in the replication sample were conducted by P.W.J.v.V., M.A.v.E., E.J.N.G., K.F., R.J.P., S. Cronin, R.L.M., O.H., V.M., J.M., S.P., J.E.L., A.A.-C. and R.H.B. Sample collection, genome-wide genotyping, data management and quality control procedures for the Dutch urinary bladder GWA, Dutch schizophrenia GWA, RS-I cohort of the Rotterdam study, German controls from the schizophrenia GWA, KORA, HNR and PopGen studies were conducted by S.H.H.M.V., L.A.K., E.S., R.A.O., K.E., F.R., A.H., A.G.U., D.R., I.G., P.M., S. Cichon, M.M.N., H.-E.W. and S.S. Data management for the project was handled by H.M.B., P.W.J.v.V., J.H.V. and M.A.v.E. Statistical analysis was done by M.A.v.E. and J.H.V. All authors participated in critical revision of the manuscript for intellectual content. The study was designed and supervised by R.A.O. and L.H.v.d.B. The manuscript was drafted by M.A.v.E.

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Correspondence to Roel A Ophoff or Leonard H van den Berg.

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van Es, M., Veldink, J., Saris, C. et al. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet 41, 1083–1087 (2009). https://doi.org/10.1038/ng.442

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