Genome-Wide Association Studies in Rare Neurological Diseases

Genome-wide association studies (GWAS) are a widespread and purposeful tool to reveal associations between genotypes and phenotypes, even when individual genetic differences only have small phenotypic effects. In this thesis, an overview of the steps standardly involved in these analyses is given. Using the examples of GWAS in two rare neurological diseases with complex multi-factorial etiology which have been published in meaningful journals, the application in medical research is presented. The first disease is the most common subtype of autoimmune encephalitis, an immune-mediated inflammatory brain disease, with antibodies against the N-methyl-ᴅ-aspartate (NMDA) receptor. The second disease is multiple system atrophy (MSA), a neurodegenerative condition from a group of diseases called “synucleinopathies”. Anti-NMDA receptor encephalitis as well as MSA lack known variants associated with the respective disease so far. This thesis reveals new potentially involved SNPs in the pathogenesis of anti-NMDAR encephalitis and MSA passing the genome-wide significance threshold or are very close to this threshold respectively. The suggested risk loci from the GWAS are also supported by eQTL data in different tissues and immune cells, as well as immunohistochemical analyses for MSA. This makes them a good starting point for uncovering pathomechanisms, which could lead to an improvement in therapy, prevention, and diagnosis in the long term.

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