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

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 × 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.

Genetic Basis of Common Human Disease: Insight into the Role of Missense SNPs from Genome-Wide Association Studies

“…For example, in a Crohn’s locus on chr1: 200.68–201.08 Mb, Franke et al [47] suggested two candidate genes, C1orf106 and KIF21B (kinisin family member 21B). KIF21B has been suggested as associated with multiple sclerosis [73,74] and inflammatory bowel disease [1], but no functional relevance to Crohn’s has been identified. We found two rare (maf < 5%) high impact missense SNPs in this gene, but because of uncertainty in the LD data we cannot ascertain whether these could generate the observed marker signal.…”

CD6 gene polymorphism rs17824933 is associated with multiple sclerosis in Indian population

“…The associated SNP (rs1132200) within this gene causes a nonsynonymous amino acid change (alanine-threonine) at position 487 in the protein. Genome-wide association study on two independent data set identifies TMEM39A as susceptibility loci (rs1132200, P = 3.09 × 10 −8 OR = 1.24) for MS.[27] In a recent study on replication of TMEM39A (rs1132200) in 2863 Spanish MS patients and 2930 controls identified this gene as susceptibility gene for MS ( p M-H = 0.001, OR M-H [95% CI] =0.84 [0.75–0.93]). [28] Our data showed nominal association for rs1132200 ( P = 0.023, OR = 1.41, CI = 1.05–1.91).…”

The Kinesin KIF21B Regulates Microtubule Dynamics and Is Essential for Neuronal Morphology, Synapse Function, and Learning and Memory

“…Micro-duplications in the chromosomal region 1q32.1, including the Kif21b gene, have been described in individuals with delayed motor and cognitive development (Olson et al, 2012). Additionally, polymorphisms in the Kif21b gene have been identified as a susceptibility locus for Multiple Sclerosis (MS) Goris et al, 2010; International Multiple Sclerosis Genetics, 2010). More recently, KIF21B enrichment was linked to accelerated neurodegeneration in MS and Alzheimer´s disease (AD).…”