Comprehensive follow-up of the first genome-wide association study of multiple sclerosis identifies KIF21B and TMEM39A as susceptibility loci

Jacob L McCauley, John P. Hussman

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numberddp542
Pages (from-to)953-962
Number of pages10
JournalHuman Molecular Genetics
Volume19
Issue number5
DOIs
StatePublished - Mar 1 2010

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Genome-Wide Association Study
Multiple Sclerosis
Single Nucleotide Polymorphism
Odds Ratio
Genome
Inborn Genetic Diseases
Central Nervous System
Inflammation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Comprehensive follow-up of the first genome-wide association study of multiple sclerosis identifies KIF21B and TMEM39A as susceptibility loci. / McCauley, Jacob L; Hussman, John P.

In: Human Molecular Genetics, Vol. 19, No. 5, ddp542, 01.03.2010, p. 953-962.

Research output: Contribution to journalArticle

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