Brain Advance Access originally published online on April 17, 2007
Brain 2007 130(9):2292-2301; doi:10.1093/brain/awm055
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Large-scale pathways-based association study in amyotrophic lateral sclerosis
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11Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK, 2IGSP Center for Population Genomics and Pharmacogenetics, Duke University, 3IGSP Center for Applied Genomics and Technology, Duke University, Durham, NC, USA, 4MRC Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, Department of Neurology, London, 5Department of Clinical Neurosciences, Division of Neuroscience, The Medical School, University of Birmingham, 6Neuroscience Centre, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, 7Department of Clinical Neurosciences, Royal Free and University College Medical School, University College London, London, UK, 8Department of Neurology, University of Wuerzburg, 9Institute of Clinical Neurobiology, University of Wuerzburg, Wuerzburg, Germany, 10Academic Neurology Unit, Section of Neuroscience, University of Sheffield Medical School, Sheffield, 11Molecular NeuroPathobiology Laboratory, Cancer Research UK London Research Institute, and 12Department of Molecular Neuroscience, Institute of Neurology, London, UK
Correspondence to: Dr D. Kasperaviit, Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK E-mail: d.kasperaviciute{at}prion.ucl.ac.uk
Sporadic amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, most likely results from complex genetic and environmental interactions. Although a number of association studies have been performed in an effort to find genetic components of sporadic ALS, most of them resulted in inconsistent findings due to a small number of genes investigated in relatively small sample sizes, while the replication of results was rarely attempted. Defects in retrograde axonal transport, vesicle trafficking and xenobiotic metabolism have been implicated in neurodegeneration and motor neuron death both in human disease and animal models. To assess the role of common genetic variation in these pathways in susceptibility to sporadic ALS, we performed a pathway-based candidate gene case-control association study with replication. Furthermore, we determined reliability of whole genome amplified DNA in a large-scale association study. In the first stage of the study, 1277 putative functional and tagging SNPs in 134 genes spanning 8.7 Mb were genotyped in 822 British sporadic ALS patients and 872 controls using whole genome amplified DNA. To detect variants with modest effect size and discriminate among false positive findings 19 SNPs showing a trend of association in the initial screen were genotyped in a replication sample of 580 German sporadic ALS patients and 361 controls. We did not detect strong evidence of association with any of the genes investigated in the discovery sample (lowest uncorrected P-value 0.00037, lowest permutation corrected P-value 0.353). None of the suggestive associations was replicated in a second sample, further excluding variants with moderate effect size. We conclude that common variation in the investigated pathways is unlikely to have a major effect on susceptibility to sporadic ALS. The genotyping efficiency was only slightly decreased (
1%) and genotyping quality was not affected using whole genome amplified DNA. It is reliable for large scale genotyping studies of diseases such as ALS, where DNA sample collections are limited because of low disease prevalence and short survival time.
Key Words: amyotrophic lateral sclerosis; genetic association; axonal transport; whole genome amplification
Abbreviations: ALS, Amyotrophic lateral sclerosis; SMN, Survival motor neuron
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Received December 11, 2006. Revised January 25, 2007. Accepted February 26, 2007.
This paper is now available under the Oxford Open initiative
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