An interdisciplinary approach leveraging human genetic variation to identify novel mechanisms of liver disease and pregnancy sickness

A major aim of human genetics in both academic in industrial spheres is to translate a genetic association to a mechanistic understanding of the disease process or trait being studied. The rewards in achieving this are large – a detailed mechanistic understanding of how genetic variation affects a human characteristic is of broad interest as it is likely to inform our understanding of both fundamental biology and be of translational importance given its direct relevance to humans. The advent of next-generation sequencing and population biobanks have resulted in a large number of cohorts with detailed phenotyping and genotyping, leading to an exponential rise in robust human genetic associations. In spite of this success, the number of genetic associations where there is even a rudimentary understanding of its mechanistic basis remains small. Bridging this knowledge gap is essential to maximise biological insight from human genetics and to successfully translate genetic discoveries to therapeutics. Traditionally, genetic discoveries at population scale have been made by teams of statistical geneticists who are more likely to have undertaken training in epidemiology, statistics or related disciplines. In contrast, discovery of rare monogenic syndromes has been the purview of clinicians and clinician-scientists with foundational training in clinical medicine and human physiology. While these are not mutually exclusive groups, it remains true that research groups remain largely siloed by discipline. I posit that such demarcation of expertise and interests hinders translation in human genetics as a clear understanding of the evidence supporting a genetic association, plausible effector tissues, candidate mechanisms and experimental tractability are all essential to move from ‘marker to mechanism’. Here I present work that leverages state of the art human genetics approaches to prioritise causal hypotheses in metabolic and endocrine disease and test and refine these using studies in cells, mice and humans. Specifically, I performed functional characterisation of rare variants in the cholesterol sensing receptor LXRand undertook a functionally enriched human genetic association study. Using this approach, I demonstrated that loss of function mutations in LXR(Liver-X-Receptor-alpha) are a cause of hepatotoxicity in humans despite evidence of suppression of hepatic lipogenesis. Follow-up mechanistic studies in cells and mice provided evidence that damaging mutations in LXRcause profound fibrotic liver injury in mice supporting a novel causal role for competent hepatocyte cholesterol metabolism in human liver health. Next, large scale proteogenomic studies, biobanked samples from rare disease cohorts and cellular models were leveraged to provide insight into the causes and consequences of elevations in the poorly studied hepatokine Activin-C. Finally, in an examination of the role of GDF15 (Growth Differentiation Factor-15) in hyperemesis gravidarum we used observational epidemiology and rare and common genetic association studies to delineate the consequences of pre-natal and antenatal elevations in GDF15 on hyperemesis gravidarum risk identifying novel therapeutic opportunities in this previously poorly understood disease. This thesis highlights the advances that can be made by interdisciplinary teams dedicated to mechanistic discovery who use human genetics for hypothesis prioritisation. I reflect on challenges in the endeavour of interdisciplinary scientists translating discoveries in population genetics to the pathophysiology of human disease.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Lockhart, Sam

Advisor dc:contributor.advisor

• O'Rahilly, Stephen

• genetics
• metabolism
• liver disease
• fatty liver disease
• MASLD
• GDF15
• LXR-alpha
• LXRa
• NR1H3
• INHBC
• INHBE
• Pregnancy Sickness
• Hyperemesis Gravidarum

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/c0f64e7e-90d0-49b6-b929-ea7ba35bd20b/download
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.114549

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/377860