Genome-wide association study of the white matter lesion volume in patients with multiple sclerosis

• Applicant: Dr. Christiane Gasperi
• Subject Area: Human Genetics ; Medical Informatics and Medical Bioinformatics
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 513308106

More than 230 genetic risk factors for multiple sclerosis (MS) have been identified over the last decades. At the same time, knowledge on how genetics shape the disease course and severity of MS is lacking. The disease course of MS is highly variable. While some patients experience benign, almost subclinical courses, others suffer from a highly active disease with frequent relapses and rapid disability progression. A number of different immunomodulatory therapies have been approved for the treatment of MS with different modes of action, efficacy and side effects. Currently, no reliable biomarker for the prediction of the individual disease course of patients with MS is available, which prevents an early stratification of patients regarding the risk for an aggressive disease course and thereby the identification of patients in need of highly effective treatments early in the disease course. A well-established marker of MS severity and progression is the number and volume of white-matter lesions. While genetic MS risk factors might influence the presentation of the disease in the central nervous system, the extent of demyelination and neurodegeneration in the individual patient is likely also shaped by genetic variants not influencing disease susceptibility. Identifying genetic variants influencing the development and persistence of these lesions can contribute to the development of prediction models for the patients’ disease course and stimulate the development of new therapeutic options. To date, no genome-wide association study (GWAS) on the white-matter lesion volume has been published. Likely, a reason for this lack of studies is that large samples of MS patients with available magnetic resonance imaging (MRI) and genotype data are required for such a project. Therefore, we propose to generate the most extensive existing dataset for genetic studies of white-matter lesions in patients with MS by genotyping patients from several European MS centers, leading to a dataset consisting of more than 6600 patients. Using these data, we plan to conduct multicentric GWAS meta-analyses with the following aims: First, identify common genetic variants associated with the white-matter lesion volume in patients with MS. Second, functionally annotate these variants and identify the genes influencing white-matter lesions. Third, analyze whether genetic variants associated with the white-matter lesion volume also affect other disease severity phenotypes like brain atrophy and disability scores. Fourth, generating a large, harmonized, multi-centric dataset that will stimulate and facilitate future research projects. Thereby, the planned project holds strong potential for the discovery of genes influencing MS disease severity. Knowledge of these genes will be the first step towards personalized prediction models of the MS disease course and novel MS-specific drugs. These innovations would ultimately improve the quality of life of patients with MS.

• DFG Programme: Research Grants
• Co-Investigators: Professor Dr. Bernhard Hemmer; Professor Dr. Mark Mühlau