Human Molecular Genetics Advance Access originally published online on December 5, 2007
Human Molecular Genetics 2008 17(5):768-774; doi:10.1093/hmg/ddm361
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A genome-wide association study of sporadic ALS in a homogenous Irish population
1 Department of Clinical Neurological Sciences, Royal College of Surgeons in Ireland, Dublin 2, Ireland 2 Department of Neurology, Beaumont Hospital, Dublin 9, Ireland 3 Laboratory of Neurogenetics, National Institute on Aging 4 Computational Biology Core, Laboratory of Neurogenetics, National Molecular Genetics Unit 5 Neurogenetics Branch, National Institute of Neurological Disorders and Stroke and and 6 Molecular Genetics Unit, National Institutes of Health, Bethesda, MD, USA 7 Department of Physiology, Anatomy and Genetics, University of Oxford, Henry Wellcome Building of Gene Function, Oxford, UK 8 Neurology Department, Johns Hopkins University, Baltimore, MD, USA 9 Smurfit Institute of Genetics and 10 Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland
* To whom correspondence should be addressed at: The Irish ALS Research Group, Department of Neurology, Beaumont Hospital, Dublin 9, Ireland. Tel: +353 18092174; Fax: +353 18092302; Email: scronin{at}rcsi.ie
Received November 10, 2007; Accepted December 4, 2007
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive limb or bulbar weakness. Efforts to elucidate the disease-associated loci have to date produced conflicting results. One strategy to improve power in genome-wide studies is to genotype a genetically homogenous population. Such a population exhibits extended linkage disequilibrium (LD) and lower allelic heterogeneity to facilitate disease gene mapping. We sought to identify associated variants for ALS in the Irish, a stable population of relatively homogenous genetic background, and to replicate these findings in larger genetically out-bred populations. We conducted a genome-wide association study in 432 Irish individuals using Illumina HumanHap 550K single nucleotide polymorphism chips. We demonstrated extended LD and increased homogeneity in the Irish sample when compared to an out-bred population of mixed European ancestry. The Irish scan identified 35 loci associated with P-values below 0.0001. For replication, we identified seven chromosomal regions commonly associated in a joint analysis of genome-wide data on 958 ALS cases and 932 controls from Ireland and the previously published datasets from the US and The Netherlands. When pooled, the strongest association was a variant in the gene encoding DPP6, a component of type A neuronal transmembrane potassium channels. Further confirmation of the candidate loci is warranted in additional genome-wide datasets. We have made our individual genotyping data publicly available, contributing to a powerful world-wide resource to refine our understanding of the genetics of sporadic ALS.
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