Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/7387
Title: The Role of Copy Number Variation in Susceptibility to Amyotrophic Lateral Sclerosis: Genome-Wide Association Study and Comparison with Published Loci
Authors: Wain, Louise V.
Pedroso, Inti
Landers, John E.
Breen, Gerome
Shaw, Christopher E.
Leigh, P. Nigel
Brown, Robert H.
Tobin, Martin D.
Al-Chalabi, Ammar
First Published: Dec-2009
Publisher: Public Library of Science (PLoS)
Citation: PLoS ONE, 2009, 4 (12), e8175.
Abstract: Background : The genetic contribution to sporadic amyotrophic lateral sclerosis (ALS) has not been fully elucidated. There are increasing efforts to characterise the role of copy number variants (CNVs) in human diseases; two previous studies concluded that CNVs may influence risk of sporadic ALS, with multiple rare CNVs more important than common CNVs. A little-explored issue surrounding genome-wide CNV association studies is that of post-calling filtering and merging of raw CNV calls. We undertook simulations to define filter thresholds and considered optimal ways of merging overlapping CNV calls for association testing, taking into consideration possibly overlapping or nested, but distinct, CNVs and boundary estimation uncertainty. Methodology and Principal Findings : In this study we screened Illumina 300K SNP genotyping data from 730 ALS cases and 789 controls for copy number variation. Following quality control filters using thresholds defined by simulation, a total of 11321 CNV calls were made across 575 cases and 621 controls. Using region-based and gene-based association analyses, we identified several loci showing nominally significant association. However, the choice of criteria for combining calls for association testing has an impact on the ranking of the results by their significance. Several loci which were previously reported as being associated with ALS were identified here. However, of another 15 genes previously reported as exhibiting ALS-specific copy number variation, only four exhibited copy number variation in this study. Potentially interesting novel loci, including EEF1D, a translation elongation factor involved in the delivery of aminoacyl tRNAs to the ribosome (a process which has previously been implicated in genetic studies of spinal muscular atrophy) were identified but must be treated with caution due to concerns surrounding genomic location and platform suitability. Conclusions and Significance : Interpretation of CNV association findings must take into account the effects of filtering and combining CNV calls when based on early genome-wide genotyping platforms and modest study sizes.
DOI Link: 10.1371/journal.pone.0008175
ISSN: 1932-6203
Links: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0008175
http://hdl.handle.net/2381/7387
Type: Article
Rights: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
This paper was published as PLoS One, 2009, 4 (12), e8175. It is available from http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0008175#abstract0. Doi: 10.1371/journal.pone.0008175
Appears in Collections:Published Articles, Dept. of Health Sciences

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