We report the results of a meta-analysis of genome-wide association scans for multiple sclerosis (MS) susceptibility that includes 2,624 subjects with MS and 7,220 control subjects. Replication in an independent set of 2,215 subjects with MS and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P=1.59×10-11), IRF8 (P=3.73×10-9) and CD6 (P=3.79×10-9). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio =1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency =0.02; odds ratio =1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is associated with higher mRNA expression of interferon-response pathway genes in subjects with MS.
De Jager PL, Jia X, Wang J, Bakker PIW, Ottoboni L, Aggarwa NT, Piccio L, Raychaudhuri S,Tran D, Aubin C, Briskin R,Romano S, International MS Genetics Consortium, Baranzini SE, McCauley JL, Pericak-Vance MA, Haines JL, Gibson RA, Naeglin Y, Uitdehaag B, Matthews PM, Kappos L, Polman C, McArdle WL, Strachan DP, Evans D, Cross AH, Daly MJ, Compston A, Sawcer SJ, Weiner HL, Hauser SL, Hafler DA, Oksenberg JR. Nature Genetics. 2009 July, Volume 41(7): p776ff
Comment by Jean-Marc Burgunder
A genetic background leading to susceptibility to develop multiple sclerosis (MS) upon exposure to environmental influence has been postulated since many years. New technologies and approaches from molecular genetics now allow working to solve this intriguing question and improve our understanding of interactions between genetic and environmental factors. For this large number of well-defined cases with the specific phenotype under investigation are needed and subtle variations (for example single nucleotide polymorphisms, SNP) in the genetic coding, which by themselves do not lead to any disease, are assessed. This has been done in a number of studies, which need to be replicated. In the landmark study by De Jager a metaanalysis of several studies searching for statistical association of SNP with MS using the whole genome sequence (genome wide association study, GWAS) has been performed, followed by a replication study in a separate cohort. Furthermore, a profound analysis of the expression and function of the gene with statistically associated SNP was performed in order to try to better understand the molecular underpinning of the disease and suggest novel therapies based on a clearer picture of what happens at the molecular level.
For such investigations a large number of well-defined cases are needed. The meta-analysis presented in the De Jager paper has included more than 2500 cases and more than 7200 controls from 5 studies using three different genotyping platforms. In the replication sample more than 2000 cases and control each from 4 US and 2 UK sites were added and genotyped with a uniform technology. Such large numbers are needed in order to get strong enough statistical power in order to be able to draw strong conclusions on SNP association with the phenotype under scrutiny. The loci with the highest statistical association level where then selected for the replication study. Finally from the replication analysis of 180 high-quality SNPs already reported associations in MHC (HLA DRB1*1501 HLA B*4402) and other genes (CLEC16A, IL2RA and IL7R) were confirmed. Several new SNP were identified with genome wide (TNFRSF1A, IRF8 and CD6) evidence and a range of additional ones with suggestive evidence, which will need confirmation in other studies.
The IRF8 locus contains the genetic information for an important transcription factor, which mediates the response to type I interferons. It was therefore interesting and important to get a step further from the statistical association to examine the mechanisms, by which a modulated function of the gene represented by the variable SNP may be involved in the molecular mechanism of the disease, thus possibly explaining the higher susceptibility of carrier of this specific SNP to suffer from the disorder. To do so, the authors have assessed the expression profiles in peripheral blood mononuclear of 240 persons suffering from different MS types and stages. Using a specific pathway analysis software, they were able to show that interferon response genes expression was upregulated in a coordinate fashion dependent upon a specific allele of IRF8.
Such studies provide strong evidence of an association of specific gene variation with disease susceptibility. This opens up opportunities for the search for rational therapies based on an improved understanding to the multiple molecular mechanisms involved in the disease. However, at the same time, the complexity of the findings with a number of different genes involved, the variation of each one of which being putatively associated with large molecular networks, is a clear evidence that such therapies are not going to involved single molecules but a whole array of interventions.
Jean-Marc Burgunder is Professor of Neurology in Bern, Switzerland and Chair of the EFNS Scientist Panel on Neurogenetics.