Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses

Polymorphisms in CACNA1E and Camk2d are associated with seizure susceptibility of Sprague-Dawley rats.

Seizures are associated with high intracellular calcium levels. However, conditions characterized by high intracellular calcium levels, such as stroke or traumatic brain injury, do not always evoke epilepsy. We hypothesized that polymorphisms in calcium-related genes CACNA1E and Camk2d contribute to the individual variability in seizure susceptibility. The distribution of one single nucleotide polymorphism (SNP) in the CACNA1E and one in the Camk2d gene was determined in Sprague-Dawley rats that were subjected to amygdala kindling or hyperthermia-induced seizures. The pre-kindling afterdischarge threshold was significantly lower in rats with the CACNA1E GG genotype (45.2+/-6.7microA) than in the GT genotyped animals (79.3+/-53.7microA). Among hyperthermia treated rats, the Camk2d G allele was more frequent among rats that did not display behavioral seizures during hyperthermia (67%) than in animals that did show behavioral seizures during hyperthermia (52%, chi(2)(1)=3.847, p=0.05). SNPs in CACNA1E and Camk2d genes are associated with the individual variability in seizure susceptibility in two experimental seizure models

Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10−4). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10−8), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals

Erratum: Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk (Cell (2019) 178(1) (262), (S0092867419306798), (10.1016/j.cell.2019.06.016))

(Cell 175, 1679\u20131687.e1\u2013e7; November 29, 2018) It has come to our attention that in preparing the final version of this article, the authors inadvertently misspelled the last name of author Charlotte E. Teunissen as \u201cCharlotte E. Theunissen.\u201d This error has been corrected in the article online. In the Editorial Note (Cell 178, 262, June 27, 2019), the editors refer to the original version of the published manuscript. That version contained a misspelled name, and as that has now been corrected, we are updating the Editorial Note as well

Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses