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

ABSTRACT 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 The UK Biobank is the largest whole-exome sequencing project to date, with marked power to detect associations from a limited number of rare, functional variants. Our study will leverage current knowledge of interferon biology and genotype-phenotype correlations in Mendelian diseases of type I interferon to test biologically plausible hypotheses. The UK Biobank includes phenotypes from multiple sources, which improves classification accuracy for several health outcomes such as stroke and dementia. We will carefully select genes and variants with strong evidence of biological relevance to optimize the power of our analyses, which is particularly relevant for less common phenotypes in the UK Biobank such as systemic lupus erythematosus. We will increase the specificity of predicted loss-of-function variants by using stringent sample quality control and filtering criteria.