Successful Replication of GWAS Hits for Multiple Sclerosis in 10,000 Germans Using the Exome Array

Abstract

Genome-wide association studies (GWAS) successfully identified various chromosomal regions to be associated with multiple sclerosis (MS). The primary aim of this study was to replicate reported associations from GWAS using an exome array in a large German study. German MS cases (n = 4,476) and German controls (n = 5,714) were genotyped using the Illumina HumanExome v1-Chip. Genotype calling was performed with the Illumina Genome Studio(TM) Genotyping Module, followed by zCall. Single-nucleotide polymorphisms (SNPs) in seven regions outside the human leukocyte antigen (HLA) region showed genome-wide significant associations with MS (P values < 5 × 10(-8) ). These associations have been reported previously. In addition, SNPs in three previously reported regions outside the HLA region yielded P values < 10(-5) . The effect of nine SNPs in the HLA region remained (P < 10(-5) ) after adjustment for other significant SNPs in the HLA region. All of these findings have been reported before or are driven by known risk loci. In summary, findings from previous GWAS for MS could be successfully replicated. We conclude that the regions identified in previous GWAS are also associated in the German population. This reassures the need for detailed investigations of the functional mechanisms underlying the replicated associations.

Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

“…We used linear mixed models to correct for population structure in 13 of these strata, estimated from the 16,066 common, synonymous coding variants present on the exome chip (i.e., variants with MAF > 5% in our samples). We included population structure-corrected summary statistics for the remaining cohort (from Germany), which has been previously described ( Dankowski et al., 2015 ). As expected, we saw a strong correlation between effect size and variant frequency, with rarer alleles exerting larger effects ( Figure S2 ).…”

Neuroimmunological Registries in Germany

“…In addition to the evaluation of baseline clinical data, large-scale genetic projects have already been significantly supported with DNA material of the cohort and successfully published [32,33]. Nine risk genes within the human leukocyte antigen (HLA) region and seven outside the HLA region were thus replicated within this German population [32].…”

Neuroimmunologische Register in Deutschland

“…Neben der Auswertung der klinischen Baseline-Daten konnten mithilfe der asservierten DNA bereits genetische Großprojekte maßgeblich unterstützt und erfolgreich publiziert werden [32,33]. So gelang die Replikation von neun Risikogenen innerhalb und sieben Risikogenen außerhalb der HLA-(Humanen Leukozyten-Antigen) Region in einer deutschen Population [32].…”

“…Neben der Auswertung der klinischen Baseline-Daten konnten mithilfe der asservierten DNA bereits genetische Großprojekte maßgeblich unterstützt und erfolgreich publiziert werden [32,33]. So gelang die Replikation von neun Risikogenen innerhalb und sieben Risikogenen außerhalb der HLA-(Humanen Leukozyten-Antigen) Region in einer deutschen Population [32]. In einer weiteren Untersuchung wurden vier neue Suszeptibilitätsgene identifiziert, die bisher nicht als Risikogene beschrieben waren und deren Genprodukte an der epigenetischen Regulation beteiligt zu sein scheinen [33].…”