Author： McCauley Jacob L. Zuvich Rebecca L. Beecham Ashley H. De Jager Philip L. Konidari Ioanna Whitehead Patrice L. Aubin Cristin Ban Maria Pobywajlo Susan Briskin Rebeccah Romano Susan Aggarwal Neelum T. Piccio Laura McArdle Wendy L. Strachan David P. Evans Denis Cross Anne H. Cree Bruce Rioux John D. Barcellos Lisa F. Ivinson Adrian J. Compston Alastair Hafler David A. Hauser Stephen L. Oksenberg Jorge R. Sawcer Stephen J. Pericak-Vance Margaret A. Haines Jonathan L.
Publisher： Oxford University Press
ISSN： 1460-2083
Source： Human Molecular Genetics, Vol.19, Iss.5, 2010-03, pp. : 953-962
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Abstract
Genome-wide association studies (GWASs) have proven highly effective, identifying hundreds of associations across numerous complex diseases. These studies typically test hundreds of thousands of variations and identify hundreds of potential associations. However, to date, follow-up attempts have generally only concentrated on just the few most significant initial associations, leaving the majority of true associations in any GWAS study without replication. Here, we present a substantially more comprehensive follow-up of the first genome-wide association screen performed in multiple sclerosis (MS), a complex genetic disease with central nervous system inflammation. We genotyped approximately 30 000 single-nucleotide polymorphisms (SNPs) that demonstrated mild-to-moderate levels of significance (P 0.10) in the initial GWAS in an independent set of 1343 MS cases and 1379 controls. We further replicated several of the most significant findings in another independent data set of 2164 MS cases and 2016 controls. We find considerable evidence for a number of novel susceptibility loci including KIF21B [rs12122721, combined P 6.56 1010, odds ratio (OR) 1.22] and TMEM39A (rs1132200, P 3.09 108, OR 1.24), both of which meet genome-wide significance. Both of these loci were overlooked in the initial replication, despite being among the top 3000 (1) SNP hits in the original screen.
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