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

Abstract

Background: 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: 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 93160. We expect to disseminate our results in a peer-reviewed journal and at an international cardiovascular conference.

Keywords: UK Biobank; dementia; genetics; inflammation; interferonopathy; lupus; stroke; type I interferon; variants.

Figure 1.. Graphical summary of the study methodology.

This summary illustrates the three main steps of the study: i) genes of interest will be identified from a literature review and Gene Ontology, followed by clinical and functional filtering, ii) variants of interest will be included based on their clinical relevance and functional annotations, and iii) the association of variants and phenotypes will be tested with a rare variant genetic risk score and gene-level tests. Abbreviations: ICD, International Classification of Diseases; LOFTEE, Loss-Of-Function Transcript Effect Estimator; M-CAP, Mendelian Clinically Applicable Pathogenicity score; NCBI, National Center for Biotechnology Information; OMIM, Online Mendelian Inheritance in Man; OQFE, Original Quality Functionally Equivalent; pLOF, predicted loss-of-function; SKAT-O, optimal sequence kernel association test; VEP, Variant Effect Predictor. Created with BioRender.com.

Figure 2.. Overview of the interferon cascade.

Graphical overview of the main steps involved in interferon regulation and signalling. Endogenous nucleases (blue circle sectors) remove nucleic acids (red confetti) that can trigger interferon production. Abnormal accumulation of endogenous material through impaired regulation (box 1) and viral nucleic acids (not shown) can trigger interferon production through linkage to i) toll-like receptor sensors at the cell membrane surface (not shown) and at endosomes, and ii) cytoplasmic sensors (box 2). Interferons are sensed by cell surface receptors specific to types I (heterodimer with subunits IFNAR1 and IFNAR2), II (heterotetramer with two IFNGR1 and two IFNGR2 subunits) and III (heterodimer with subunits IFNLR1 and IL-10R2) ligands. Signal transduction and intracellular signalling through JAK-STAT activates the transcription of interferon-stimulated genes (box 3). Abbreviations: GAS, gamma-activated sequence; IFN, interferon; IRF, interferon regulatory factor; ISG, interferon-stimulated gene; ISRE, interferon-stimulated response element; TLR, toll-like receptor. Created with BioRender.com.

Figure 3.. Power calculations for gene-level tests with phenotypes of interest using SKAT-O.

The power calculation assumes an α=1.11x10 ^-5, a genetic sampling length of 2,962 bp, a MAF <0.1%, an empirical optimal correlation coefficient, and sample sizes observed in the UKB. Abbreviations: AD, Alzheimer’s disease; AF, atrial fibrillation; bp, base pairs; BrV, total brain (grey plus white matter) volume; CKD, chronic kidney disease; Dem, all-cause dementia; HipV, hippocampal grey matter volume (average); IBD, inflammatory bowel disease; ICH, intracerebral haemorrhage; IHD, ischemic heart disease; IS, ischemic stroke; MAF, minor allele frequency; PAD, peripheral artery disease; RA, rheumatoid arthritis; SAH, subarachnoid haemorrhage; SCTD, systemic connective tissue disorder; SLE, systemic lupus erythematosus; VascD, vascular dementia; WMHV, total white matter hyperintensity volume.