TY - JOUR
T1 - Comprehensive follow-up of the first genome-wide association study of multiple sclerosis identifies KIF21B and TMEM39A as susceptibility loci
AU - McCauley, Jacob L.
AU - Hussman, John P.
PY - 2010/3
Y1 - 2010/3
N2 - Genome-wide association studies (GWASs) have proven highly effec tive, 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 × 10-10, odds ratio (OR) = 1.22] and TMEM39A (rs1132200, P = 3.09 × 10-8, 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.
AB - Genome-wide association studies (GWASs) have proven highly effec tive, 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 × 10-10, odds ratio (OR) = 1.22] and TMEM39A (rs1132200, P = 3.09 × 10-8, 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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U2 - 10.1093/hmg/ddp542
DO - 10.1093/hmg/ddp542
M3 - Article
C2 - 20007504
AN - SCOPUS:77950544633
VL - 19
SP - 953
EP - 962
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 5
M1 - ddp542
ER -