期刊
HUMAN MOLECULAR GENETICS
卷 23, 期 8, 页码 2220-2231出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddt587
关键词
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资金
- Ministero della Salute Italiano (GWA-SLA, Ricerca Finalizzata) [31]
- Fondazione Istituto Auxologico Italiano
- Istituto Superiore di Sanita [526D/34]
- 'Amici del Centro Dino Ferrari'
- Ministero della Salute Italiano (ALS-FTD) [RF-2009-1473856]
- Monte dei Paschi di Siena Foundation [39167]
- Ministero della Salute Italiano [RF-INP-2007-627227]
- Federazione Italiana Giuoco Calcio
- Fondazione Vialli e Mauro per la Sclerosi Laterale Amiotrofica onlus, Ministero della Salute Italiano [RF-PIE-2007-635695]
- Progetto Regione Emilia Romagna-Universita 'RARER'
- TELETHON Italy [GTB07001]
- 'Fondazione Grigioni per il Morbo di Parkinson'
- National Institutes for Health Research Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust
- National Institutes for Health Research Biomedical Research Centre for Mental Health at King's College London
- Medical Research Council [G0701420, G0600974]
- Motor Neurone Disease Association of Great Britain and Northern Ireland
- ALS Association
- ALS Therapy Alliance
- National Institute of Neurological Disorders and Stroke [5RO1-NS050557-05]
- National Institute of Neurological Disorders and Stroke American Recovery and Reinvestment Act Award [RC2-NS070-342]
- Angel Fund
- P2ALS
- Project ALS
- Pierre L. de Bourgknecht ALS Research Foundation
- National Institute of Health/National Institute of Neurological Disorders and Stroke [1R01NS073873]
- Prinses Beatrix Fonds
- VSB fonds
- H. Kersten and M. Kersten (Kersten Foundation)
- Netherlands ALS Foundation
- J.R. van Dijk and the Adessium Foundation
- MRC [MR/K01417X/1, MR/K013041/1, G0701420, G0500289, G0600974, G0902227, G1100695, G0900635, MC_G1000733, G0900688] Funding Source: UKRI
- Alzheimers Research UK [ARUK-PG2014-1] Funding Source: researchfish
- Medical Research Council [MR/K013041/1, MR/L501517/1, MC_G1000733, G0900688, G0902227, MR/L010305/1, G0701420, MR/K01417X/1, G1100695, G0900635, MR/L501529/1, G0500289B, MR/J006742/1, G0600974, G0500289, G9817803B] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10082] Funding Source: researchfish
Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (90) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P 1.11 10(8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P 8.62 10(9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P 7.69 10(9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as 12 using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.
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