Phenotypes associated with genetic determinants of type I interferon regulation in the UK Biobank: a protocol

Introduction Type I interferons are cytokines involved in innate immunity against viruses. Genetic disorders of type I interferon regulation are associated with a range of autoimmune and cerebrovascular phenotypes. Carriers of pathogenic variants involved in genetic disorders of type I interferons are generally considered asymptomatic. Preliminary data suggests, however, that genetically determined dysregulation of type I interferon responses is associated with autoimmunity, and may also be relevant to sporadic cerebrovascular disease and dementia. We aim to determine whether functional variants in genes involved in type I interferon regulation and signalling are associated with the risk of autoimmunity, stroke, and dementia in a population cohort. Methods and analysis We will perform a hypothesis-driven candidate pathway association study of type I interferon-related genes using rare variants in the UK Biobank (UKB). We will manually curate type I interferon regulation and signalling genes from a literature review and Gene Ontology, followed by clinical and functional filtering. Variants of interest will be included based on pre-defined clinical relevance and functional annotations (using LOFTEE, M-CAP and a minor allele frequency <0.1%). The association of variants with 15 clinical and three neuroradiological phenotypes will be assessed with a rare variant genetic risk score and gene-level tests, using a Bonferroni-corrected p-value threshold from the number of genetic units and phenotypes tested. We will explore the association of significant genetic units with 196 additional health-related outcomes to help interpret their relevance and explore the clinical spectrum of genetic perturbations of type I interferon. Ethics and dissemination The UKB has received ethical approval from the North West Multicentre Research Ethics Committee, and all participants provided written informed consent at recruitment. This research will be conducted using the UKB Resource under application number 93,160. We expect to disseminate our results in a peer-reviewed journal and at an international cardiovascular conference. STRENGTHS AND LIMITATIONS OF THIS STUDY ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement BR is supported by the Centre for Clinical Brain Sciences of the University of Edinburgh (Rowling & Dr Hugh S P Binnie scholarship), the Canadian Institutes of Health Research (CIHR; Doctoral Foreign Study Award, DFD-187711), the Fonds de recherche du Québec - Santé and the Ministère de la Santé et des Services sociaux du Québec (joint clinician-investigator fellowship), and the Power Corporation of Canada Chair in Neurosciences of the University of Montreal (research scholarship). KR is supported by Health Data Research UK (Rutherford fellowship MR/S004130/1), and the Wellcome Trust-University of Edinburgh Institutional Strategic Support Fund. SM is supported by the Clayco Foundation for RVCL research. DM is supported by the Wellcome Trust (216767/Z/19/Z). RB is supported by an Association of British Neurologists Clinical Research Training Fellowship funded by the Guarantors of Brain. DH is supported by a Wellcome Trust Senior Research Fellowship (215621/Z/19/Z) and the Medical Research Foundation. WW is supported by the Chief Scientist Office of the Scottish Government (CAF/17/01), the UK Alzheimer's Society and the Stroke Association, the National Institute for Health and Care Research (NIHR) and the National Institutes of Health (NIH). Funding sources had no role in the design or conduct of the study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The UKB has received ethical approval from the North West Multicentre Research Ethics Committee, and all participants provided written informed consent at recruitment. This research will be conducted using the UKB Resource under application number 93,160. 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