The GRAMS Study: An Approach to Bridging Genomic Data and Deep Phenotyping to Understand Familial Multiple Sclerosis

Multiple Sclerosis (MS) is an inflammatory autoimmune disorder, which affects ca. 2.8 million people worldwide and the prevalence is rapidly increasing. Research over the past decades has clarified aspects of MS pathophysiology and enabled effective treatment and disease management. However, the origins of the disease are still far from clear because of its inherent complexity and multifactorial character. The interaction between genetic and environmental influences is evident, and despite substantial progress in elucidating its molecular and genetic architecture, a comprehensive understanding of how these factors converge to shape individual disease trajectories remain limited. Existing data collections have provided valuable insights into clinical and imaging markers but often lack the depth and multidimensionality needed to capture psychiatric, cognitive, and social dimensions of the disease. To address this gap, the GRAMS study was established as a deep-phenotyping cohort integrating genetic, psychological and environmental information within a single harmonized framework. The cohort currently includes 600 participants, primarily individuals with MS but also unaffected family members. Phenotyping covers a broad range of domains, ranging from social and medical history to psychological and neuropsychological assessments, cognitive measures, and detailed physical and neurological examinations. On the genetic side, SNP array data were generated for the full cohort, and whole-genome sequencing was conducted in a subset of 85 individuals. The focus of the present work is the integration of these multidimensional data sources and the development of a sustainable resource for future research that reflects the complexity of MS in a real-world clinical population. Initial steps toward data integration and quality control demonstrate that the cohort can serve as a foundation for comprehensive analyses across phenotypic and genetic layers. However, given the current relatively small sample size, genetic results are preliminary and not suited for interpretation at this stage. Taken together, the GRAMS database provides first a proof-of-concept for the present approach and delivers the initial steps towards an integrated deep-phenotyped and genotyped resource. It introduces a multilayered framework supporting future research and as well as the ultimately needed larger-scale investigations on disease heterogeneity and more individualized approaches to MS.