Using long-read sequencing for translational health research

Biography

Nathalie Kingston has a PhD in Immunology from the University of Strathclyde. She joined the University of Cambridge to carry out research work in autoimmune and infectious diseases before transferring to the Wellcome Sanger Institute for a position in Scientific Administration and becoming the Director’s Executive Assistant.

Nathalie joined the NIHR BioResource for Translational Research over 10 years ago and in 2017 was appointed Director. She is responsible for the day-to-day operations of the NIHR BioResource, the delivery of its operational strategy, and maintaining relationships with all external stakeholders. BioResource has enrolled over 300,000 participants and delivered major programmes with direct impact on clinical care.

Dr Kathy Stirrups leads the NIHR BioResource Samples team, which is responsible for the bio-banking of samples from new participants for future research studies. She also oversees the feasibility and provision of samples to research groups according to the project specification and manages bespoke projects such as WGS or RNA sequencing to assess the translation of these techniques into health systems. Kathy has held a number of academic and small biotech roles specialising in bio-banking and sequencing.

Abstract

The NIHR BioResource is trialling the use of long-read sequencing (LRS) in three large-scale translational health research projects. The Rare Disease project aims to increase diagnostic yield in participants with undiagnosed genetic disorders. In a previous short-read whole-genome sequencing (WGS) project on 8,000 participants, the diagnostic rate was 20% across 15 different rare diseases. LRS technology should improve detection and resolution of structural variants and repetitive sequence elements and add epigenetic methylation signatures. The UK Eating Disorders Genetics Initiative (EDGI) is a sub-study within the NIHR BioResource Mental Health theme and the largest study of eating disorders in the UK. Eating disorders have a 45% (binge eating) to 60% (anorexia nervosa) genetic heritability and have no drugs to target their core symptoms. By selecting cases with quantitatively extreme phenotypes that are likely to be enriched for rare variants, we hypothesise that LRS will capture novel repeat and structural variants and epigenetic variance, highly likely to contribute to the genetic component of the disease and provide new biological insights. The Genes and Cognition study is a cross-theme recallable cohort of over 21,000 participants tested with cognitive profiling in 2021 and 2024. The study will help determine age-related penetrance of known genetic risk factors for neurodegenerative disease and dementia. Heritability of dementia is between 58–79% with 75 putative risk loci identified, but polygenic risk scores only account for approximately 20% of the heritability. Analysis of structural variants and methylation status could improve understanding of age-related cognitive decline and prediction.