Reverse Mendelian randomization separates causes from early proteomic biomarkers of glioma

Background/Objectives: Glioma represents the largest entity of primary brain tumours in adults, with an overall survival of less than 20% over 5 years. Glioblastoma is the most frequent and aggressive glioma subtype. At present, there are few well-established pre-clinical predictors for glioma incidence. Due to the availability and size of prognostic studies in glioma, we utilised a Mendelian randomization framework to identify non-causal protein biomarkers which are associated with early-onset of glioma in the European population. Methods: We generated polygenic risk scores (PRS) for glioma (n=12,496), glioblastoma (n=6,191), and non-glioblastoma (n=5,819) cases. We used reverse Mendelian randomization (MR) to examine the relationship between the genetic liability of glioma and 1,463 and 90 proteins were measured using an Olink panel (UKBB, n=35,571 and SCALLOP, n=21,758), additionally 4,907 and 2,994 aptamers were assayed using SOMAscan assays (deCODE n=35,559 and INTERVAL, n=3,301). We further performed a forward cis-MR and colocalization analysis leveraging the circulating protein markers in risk of glioma, glioblastoma and non-glioblastoma. Results: Reverse MR identified 161 unique proteins associated with the PRS of glioma, 79 proteins associated with the PRS of glioblastoma, and 11 proteins associated with the PRS of non-glioblastoma. Enrichment analyses identified a proportion of plasma proteins to be associated with the PRS of glioma to be correlated with response to external stimulus. A group of plasma proteins linked to the PRS of glioma and glioblastoma were related to the immune system process. Forward MR of the putative relationships were found to have little or no evidence of association on the causal pathway. Candidate markers ETFA, RIR1 and BT3A1 are evidenced in glioma risk. Conclusion: Our findings identify a high genetic liability to glioma is associated with the immune system processes. Non-causal plasma biomarkers identified through PRS associations could indicate novel non-causal biomarkers of early glioma development. ### Competing Interest Statement JWR is employed at Boehringer Ingelheim for unrelated research. The other authors have no conflicts of interest to declare. ### Funding Statement LJA and KMK are funded by Cancer Research UK (grant number C30758/A29791); ZAT is funded by Southmead Hospital Charitable Funds: Brain tumour bank and research fund 8036. KMK is funded by Innovate [grant number 10027624]. GH is supported by the Wellcome Trust and Royal Society [208806/Z17Z] and the Medical Research Council (MRC) Integrative Epidemiology Integrative Epidemiology Unit (IEU) at the University of Bristol [MC\_UU\_00032/01]. This work was supported by Cancer Research UK [grant number C18281/A29019 and C18281/A30905]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data available in the supplementary materials.