Etiological insights and therapeutic target prioritization in multiple sclerosis using multi-omics and population data

<p dir="ltr">Background: Multiple sclerosis (MS) is an immune-mediated chronic central nervous system disease, driven by inflammation and neurodegenerative processes, and characterized by demyelination and axonal injury. It affects nearly three million people worldwide, typically strikes young adults, and leads to progressive disabilities. Despite advances, the underlying causes and pathogenesis of MS remain elusive, limiting progress in early diagnosis and the development of effective treatments.</p><p dir="ltr">Aims: This thesis aimed to elucidate the etiology and pathogenesis and to translate these insights into therapeutic and diagnostic opportunities. Specifically, these studies aimed to investigate (1) whether elevated testosterone levels influence the risk of MS; (2) whether MS risk increases among individuals with relatives affected by other immune-mediated inflammatory diseases (IMIDs), and whether shared genetic architecture plays a role; (3) potential causal proteins underlying MS susceptibility and opportunities for drug discovery and repurposing; (4) potential causal proteins underlying MS progression and opportunities for drug discovery and repurposing; and (5) clinically actionable diagnostic biomarkers in cerebrospinal fluid (CSF) and plasma.</p><p dir="ltr">Methods: The combination of large-scale population-based observational studies with genome-wide cross-trait analyses was used to explore the links between polycystic ovary syndrome (serving as a proxy for elevated testosterone levels) and MS, as well as familial co-aggregation of MS with IMIDs. Multi-omics integrative analyses were conducted to identify potential causal proteins detected in plasma and the brain tissue for MS susceptibility and progression. Pathway annotation, protein interaction, and multi-omics verification analyses were performed to elucidate the underlying molecular mechanisms and provide evidence for drug development. Ultra-sensitive proteomic profiling technologies (Olink and NULISA) were applied to matched CSF and plasma samples to discover diagnostic biomarkers using multivariable linear regression. The diagnostic performances were evaluated.</p><p dir="ltr">Results: No evidence was found suggesting a causal role of elevated testosterone in MS risk, while increased MS risk was identified among individuals with first- degree relatives affected by IMIDs, and demonstrated a shared genetic basis between MS and IMIDs. Integrative analyses identified 18 proteins exhibiting putative causal links with MS susceptibility and six with progression. These proteins interacted with known MS drug targets and linked with drugs currently indicated for other conditions, underscoring their potential for drug discovery and repurposing. In the diagnostic biomarker identification study, 39 CSF proteins were significantly associated with MS, and seven plasma proteins showed nominal associations. Several CSF proteins demonstrated excellent diagnostic performance (AUC up to 0.98), while the plasma panel consisting of seven proteins achieved an AUC of 0.92, highlighting the potential of minimally invasive biomarkers.</p><p dir="ltr">Conclusions: The thesis established a translational pipeline linking observational findings with genetic and molecular insights, and ultimately providing evidence for clinical application, potentially advancing precise strategies for the prevention, treatment, and diagnosis of MS.</p><h3>List of scientific papers</h3><p dir="ltr">I. Exploring the relationship between polycystic ovarian syndrome, testosterone, and multiple sclerosis in women: A nationwide cohort study and genome-wide cross-trait analysis. <b>Yuan Jiang</b>, Carolyn E Cesta, Qianwen Liu, Elaine Kingwell, Pernilla Stridh, Klementy Shchetynsky, Tomas Olsson, Ingrid Kockum, Elisabet Stener-Victorin, Xia Jiang, Ali Manouchehrinia. Multiple Sclerosis Journal. 2024 Dec;30(14):1765-74.<br><a href="https://doi.org/10.1177/13524585241292802" rel="noreferrer" target="_blank">https://doi.org/10.1177/13524585241292802<br><br></a></p><p dir="ltr">II. Shared aetiology underlying multiple sclerosis and other immune mediated inflammatory diseases: Swedish familial co-aggregation and large-scale genetic correlation analyses. Qianwen Liu, <b>Yuan Jiang</b>, Thomas Frisell, Pernilla Stridh, Klementy Shchetynsky, Lars Alfredsson, Ingrid Kockum, Ali Manouchehrinia, Xia Jiang. Journal of Autoimmunity. 2024 Sep 1;148:103294.<br><a href="https://doi.org/10.1016/j.jaut.2024.103294" rel="noreferrer" target="_blank">https://doi.org/10.1016/j.jaut.2024.103294<br><br></a></p><p dir="ltr">III. Multi-omics integration prioritizes potential drug targets for multiple sclerosis.<b> </b><b>Yuan Jiang</b>, Qianwen Liu, Pernilla Stridh, Ingrid Kockum, Tomas Olsson, Lars Alfredsson, Lina-Marcela Diaz-Gallo, Xia Jiang. Proceedings of the National Academy of Sciences. 2025 Jul 1;122(26):e2425537122.<br><a href="https://doi.org/10.1073/pnas.2425537122" rel="noreferrer" target="_blank">https://doi.org/10.1073/pnas.2425537122<br><br></a></p><p dir="ltr">IV. Multi-omics integration provides biological insight and prioritizes potential drug targets in multiple sclerosis progression. <b>Yuan Jiang</b>, Jinyu Xiao, Ingrid Kockum, Pernilla Stridh, Qianwen Liu, Tomas Olsson, Lars Alfredsson, Xia Jiang. [Submitted]</p><p dir="ltr">V. Identifying diagnostic biomarkers for multiple sclerosis using multi-platform proteomic profiling of matched cerebrospinal fluid and plasma. <b>Yuan Jiang</b>, Cecilia Vuong, Mohsen Khademi, Fredrik Piehl, Tomas Olsson, Ingrid Kockum, Jesse Huang. [Manuscript]</p>