A genome-wide association study of sporadic ALS in a homogenous Irish population
Simon Cronin*,1,2, Stephen Berger3, Jinhui Ding4, Jennifer C. Schymick3,5, Nicole Washecka3, Dena G. Hernandez3, Matthew J. Greenway2, Daniel G. Bradley6, Bryan J. Traynor3,7,8,9 and Orla Hardiman2,10
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, National Institutes of Health, Bethesda, MD, USA 4 Computational Biology Core, Laboratory of Neurogenetics, National Molecular Genetics Unit, National Institutes of Health, Bethesda, MD, USA 5 Department of Physiology, Anatomy and Genetics, University of Oxford, Henry Wellcome Building of Gene Function, Oxford, UK 6 Smurfit Institute of Genetics, Trinity College, Dublin 2, Ireland 7 Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA 8 Molecular Genetics Unit, National Institutes of Health, Bethesda, MD, USA 9 Neurology Department, Johns Hopkins University, Baltimore, MD, USA 10 Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland

* Correspondence to: Dr Simon Cronin, The Irish ALS Research Group, Department of Neurology, Beaumont Hospital, Dublin 9, Ireland. Phone: +353-1-8092174 Fax: +353-1-8092302 Email: scronin@rcsi.ie

Received November 10, 2007; Revised December 4, 2007; Accepted December 4, 2007

Amyotrophic lateral sclerosis 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 populations exhibit extended linkage disequilibrium 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 SNP chips. We demonstrated extended linkage disequilibrium 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 these 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.

http://hmg.oxfordjournals.org/cgi/co...short/ddm361v3