Journal
NATURE GENETICS
Volume 41, Issue 10, Pages 1083-U53Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.442
Keywords
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Categories
Funding
- Prinses Beatrix Fonds
- VSB fonds
- Kersten Foundation
- Netherlands ALS Foundation
- Adessium Foundation
- Brain Foundation of The Netherlands
- Netherlands Organisation for Scientific Research (NWO) investments [175.010.2005.011, 911-03-012]
- Research Institute for Diseases in the Elderly [014-93015]
- Netherlands Genomics Initiative/NWO [050-060-810]
- National Institute for Mental Health (R.A.O.)
- Erasmus Medical Center
- Erasmus University, Rotterdam
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- European Commission
- Municipality of Rotterdam
- Muscular Dystrophy Association USA
- Health Research Board of Ireland
- Irish Motor Neuron Disease Research Foundation
- Swedish Brain Research Foundation
- Hallstens Research Foundation
- Swedish Medical Society
- Bjorklund Foundation for ALS Research
- Swedish Association for the Neurologically
- Belgian Federal Science Policy Office
- Polish Ministry of Science and Higher Education [N N402 083934, N402 092 32/3216]
- Association pour la Recherche sur la SLA
- Association Reseau SLA Ile de France
- Motor Neurone Disease Association of Great Britain and Ireland
- Medical Research Council (UK)
- Wellcome Trust
- Psychiatry Research Trust
- ALS Therapy Alliance
- Angel Fund
- ALS Research Foundation
- Al-Athel ALS Research Foundation
- ALS Family Charitable Foundation
- National Institute of Neurological Disorders and Stroke [NS050557]
- MRC [G0900688, G0500289, G0600974] Funding Source: UKRI
- Medical Research Council [G0900688, G0500289B, G0600974, G0500289] Funding Source: researchfish
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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 x 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 x 10(-9). This SNP showed robust replication in the second cohort (P = 1.86 x 10(-6)), and a combined analysis over the two stages yielded P = 2.53 x 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 x 10(-9), and rs3849942, with P = 1.01 x 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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