Knight Group: Functional Genomics of Immunity

Our research aims to understand how genetic variation impacts genes critical to mounting an appropriate immune response and may contribute to susceptibility to infectious, inflammatory and autoimmune diseases. There is a wide spectrum of genetic variation modulating inter-individual differences in immune response with functional consequences ranging from severe primary immunodeficiency disorders to risk of multifactorial traits involving inflammation and immunity. Our discovery that non-coding regulatory variants are major drivers of diversity in the immune response transcriptome identifies an important mechanism for this.

The disease relevance of regulatory variants is highlighted by genome-wide association studies (GWAS) in which the majority of reported associations have been found to involve non-coding variants. To take forward the results of GWAS and translate into potential clinical benefit, we now need to define causal regulatory variants, resolve their mode of action and identify the specific modulated genes and pathways which may be therapeutic targets.

Our goal is to leverage recent advances in human genetics to improve understanding of biological process in immune disease pathogenesis, validate drug targets and advance opportunities for precision medicine.

Local and distant associations with gene expression in human monocytes (Science 2014)Our work combines bioinformatics with functional genomic approaches studying genetic variants in primary cells in disease relevant contexts and establishing mechanism. This includes analysis of allele-specific gene expression, expression quantitative trait mapping and detailed characterisation of how sequence diversity modulates the epigenetic and genetic control of gene expression.

We have established translational programmes in the genomics of sepsis as part of the UK Genomic Advances in Sepsis study and in ankylosing spondylitis together with new initiatives in response to the COVID-19 pandemic.

Resolving heterogeneity in sepsis (Lancet Respir Med 2016)We aim to promote use of genomics for drug target identification and validation, public engagement with genomics and implementation of genomic medicine in the clinic through education, training and a multidisciplinary team approach.