Journal Article

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

Zarzycki, Onigiusz, Wong, Garrett, Buck, Dorothea, Cimpean, Maria, Hadjigeorgiou, Georgios, Cusi, Daniele, Lindén, Magdalena, Panteliadis, Ioannis-Pavlos, Gourraud, Pierre-Antoine, Baker, Amie, Kockum, Ingrid, Benedetti, Maria D., Lage, Kasper, Manrique, Clara P., Andlauer, Till F. M., Stewart, Graeme, Agliardi, Cristina, Salvetti, Marco, Martinelli, Vittorio, Fitzgerald, Kate, Galimberti, Daniela, Esposito, Federica, Harbo, Hanne F., Guillot-Noel, Lena, Spurkland, Anne, Ban, Maria, Gasperi, Christiane, Vecchio, Domizia, Thørner, Lise Wegner, Montalban, Xavier, Compston, Alastair, Replogle, Joseph, Sospedra, Mirela, Lee, Michelle H., Lathrop, Mark, Hillert, Jan, Saarela, Janna, Dubois, Bénédicte, McCauley, Jacob L., Lathi, Ellen, Santaniello, Adam, Dardiotis, Efthimios, Beecham, Ashley H., Schaefer, Cathy, Olsson, Tomas, Li, Taibo, Keenan, Brendan, Weiner, Howard, White, Charles, Korn, Thomas, Brandes, Aaron, Pongratz, Viola, Mancini, Nicasio, An, David, Madireddy, Lohith, Comabella, Manuel, Zuccalà, Miriam, Comi, Giancarlo, Isobe, Noriko, Lill, Christina M., Sawcer, Stephen, Hakonarson, Hakon, Calabresi, P

2019

Overview

The genetics underlying who develops multiple sclerosis (MS) have been difficult to work out. Examining more than 47,000 cases and 68,000 controls with multiple genome-wide association studies, the International Multiple Sclerosis Genetics Consortium identified more than 200 risk loci in MS (see the Perspective by Briggs). Focusing on the best candidate genes, including a model of the major histocompatibility complex region, the authors identified statistically independent effects at the genome level. Gene expression studies detected that every major immune cell type is enriched for MS susceptibility genes and that MS risk variants are enriched in brain-resident immune cells, especially microglia. Up to 48% of the genetic contribution of MS can be explained through this analysis. Science , this issue p. eaav7188 ; see also p. 1383 A genomic map of multiple sclerosis identifies putatively affected immune genes. 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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science,American Association for the Advancement of Science (AAAS)
• Subject: Adaptive systems / Anatomy / Annotations / Architecture / Astrocytes / Autoimmune diseases / Brain / Case-Control Studies / Cell Cycle Proteins - genetics / Central nervous system / Chromosome Mapping / Chromosomes / Chromosomes, Human, X - genetics / Consortia / Data analysis / Enrichment / Gene expression / Gene Frequency / Gene mapping / Genes / Genetic Loci / Genetics / Genome-Wide Association Study / Genomes / Genomics / Genotypes / GTPase-Activating Proteins - genetics / Heritability / Human health and pathology / Humans / Immune system / Individualized Instruction / Inheritance Patterns / Life Sciences / Loci / Lymphocytes / Lymphocytes B / Lymphocytes T / Major Histocompatibility Complex / Microglia / Microglia - immunology / Multiple sclerosis / Multiple Sclerosis - genetics / Myeloid cells / Natural killer cells / Nervous system / Neurons / Perturbation / Pluripotency / Polymorphism, Single Nucleotide / Prevention / Protein interaction / Proteins / Quantitative Trait Loci / Replication / RESEARCH ARTICLE SUMMARY / Risk / RNA-Seq / Statistical Significance / Statistics / Stem cells / Transcriptome / Young adults