Publications

Below is an overview of full IMSGC publications, with IMSGC as author (type I publications as defined in Charter). An up-to-date list of all publications involving IMSGC as (co-)author can be found here.

Nature 2023: MS Severity GWAS

We conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF–ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue.

Science 2019: Genomic map

We analyzed genetic data of 47,429 MS and 68,374 control subjects and established a reference map of the genetic architecture of MS. This map includes 32 variants within the extended Major Histocompatibility Complex (MHC), 200 autosomal susceptibility variants outside the MHC, and one chromosome X variant.

Nature Communications 2019: Pathways

We conducted a cell-specific pathway analysis of the latest GWAS in MS. Our analysis identifies pan immune cell as well as cell-specific susceptibility genes in T cells, B cells and monocytes. Additionally, genotype-level data from 2,370 patients and 412 controls were used to compute intra-individual and cell-specific susceptibility pathways that offer a biological interpretation of the individual genetic risk to MS.

Cell 2018: Low-frequency variants

We showed in 68,379 cases and controls that up to 5% of MS risk heritability is explained by low-frequency variation in gene coding sequence. We identified three novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFNγ biology, and NFκB signaling.

PMID: 3 0343897

Neuron 2016

We counter the claim that the low-frequency variant NR1H3 p.Arg415Gln is sufficient to cause MS in certain individuals and determines a patient’s likelihood of primary progressive disease. No evidence for this was found in a 13‑fold larger patient collection.

Nature Genetics 2015: HLA

We analyzed high-density SNP data in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk. Among new and previously identified class II risk alleles and class I protective alleles, we find evidence for two interactions involving pairs of class II alleles.

PLoS Genetics 2013

Using SNP data from genome-wide studies, we identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1.

Nature Genetics 2013: ImmunoChip

Using the ImmunoChip custom genotyping array and combining these data with previous GWAS data, we identified 48 new susceptibility variants, leading to 1150 established MS risk variants at 103 discrete loci outside the major histocompatibility complex.

Brain 2013

Five previously reported loci with strong, but sub-genome-wide significant evidence for association with MS risk were evaluated in a large and independent data set of ~ 20,000 subjects. Our study provides compelling evidence that these five loci are genuine MS susceptibility loci.

American Journal of Human Genetics 2013

We merged nominal statistical evidence of association and physical evidence of interaction to conduct a protein-interaction-network-based pathway analysis (PINBPA) on two large genetic MS studies comprising a total of 15,317 cases and 29,529 controls. We found that products of genome-wide significantly associated genes are more likely to interact physically and belong to the same or related pathways.

Annals of Neurology 2011

We meta-analyzed 2,529,394 unique SNPs in 5,545 cases and 12,153 controls and identified 3 novel susceptibility alleles: rs170934(T) at 3p24.1 (OR, 1.17; p = 1.6 × 10(-8)), rs2150702(G) on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10(-8)), and rs6718520(A) on chromosome 2p21 (OR, 1.17; p = 3.4 × 10(-8)).

Nature 2011: GWAS

In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the Major Histocompatibility Complex region (MHC) we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci.

Genes and Immunity 2011

We studied 1470 MS cases and performed a genome-wide association study of more than 2.5 million single-nucleotide polymorphisms to identify loci influencing disease severity, measured using the MS severity score (MSSS). We conclude that the genetic architecture of disease severity is likely polygenic and comprised of modest effects, similar to what has been described for MS susceptibility.

PLoS One 2011

Variants in TNFRSF1A and in the vicinity of IRF8 were confirmed to be associated in these independent cohorts, which supports the role of these loci in etiology of multiple sclerosis. The variant in CD6 reached genome-wide significance after combining the data with the original meta-analysis.

Genes and Immunity 2010

Seven single-nucleotide polymorphisms (SNPs) with suggestive evidence of association with MS were analyzed in a replication study that includes 8,085 cases and 7,777 controls. Three loci exceeded genome-wide significance in the joint analysis: RGS1, IL12A and MPHOSPH9/CDK2AP1. Within the MPHOSPH9/CDK2AP1 locus, the risk allele correlates with diminished RNA expression of the cell cycle regulator CDK2AP1.

Nature Genetics 2010

In this Letter to the Editor, we counter that the rs10492972[C] variant of KIF1B increases susceptibility to multiple sclerosis.

American Journal of Human Genetics 2010

We demonstrate a polygenic component to MS susceptibility and suggest that the risk alleles identified to date represent just the tip of an iceberg of risk variants likely to include hundreds of modest effects and possibly thousands of very small effects.

Human Molecular Genetics 2010

We present a substantially more comprehensive follow-up of the first genome-wide association screen performed in MS. We find considerable evidence for a number of novel susceptibility loci including KIF21B and TMEM39A.

Nature Genetics 2009

We report the results of a meta-analysis of genome-wide association scans for MS susceptibility. We replicated new MS susceptibility loci at TNFRSF1A, IRF8 and CD6 in an independent cohort.

Genes and Immunity 2009

We tested seven single nucleotide polymorphisms (SNPs) that are known to be associated with type I diabetes in a large MS data set consisting of 2369 trio families, 5737 cases and 10,296 unrelated controls. Two of these seven SNPs showed evidence of association with MS. These findings lend support to the notion of autoimmune susceptibility genes.

The Lancet Neurology 2008

We perform a more extensive analysis of three markers in IL7R and IL2RA in an additional 20,708 individuals.

New England Journal of Medicine 2007: First GWAS

Using genetic information from both family trios and unrelated case and control subjects, we identified three variants in IL7R and IL2RA as heritable risk factors for MS.

American Journal of Human Genetics 2005: Linkage

To provide a definitive linkage map for multiple sclerosis, we have genotyped the Illumina BeadArray linkage mapping panel in a data set of 730 multiplex families of Northern European descent.