Genomics England Research Registry ID: 431
Registered: 20/08/2020
Expert Summary
The circadian clock is known to affect multiple aspects of health and disease, but the impact on rare diseases is relatively unknown. We have proposed “Chronomic medicine” as a sub-discipline within genomic medicine that looks for the contribution of the circadian clock to common and rare disease. We have identified likely rare diseases to be the best candidates for chronomic medicine based on diurnally varying patho-physiology. Long QT syndrome (LQTS) and Brugada Syndrome (BrS) are Inherited Arrhythmia Syndromes associated with an increased risk of sudden cardiac death but both the underlying electrocardiographic phenotypes and risk of arrhythmic events demonstrate unexplained diurnal and seasonal oscillations. We will identify common variants in the circadian cis elements upstream of rare disease associated genes that are known to have circadian expression in arrhythmia genes. 50% of the PanelApp genes for ICAs are predicted to oscillate over the course of the day. In a pilot study we have identified an enriched variant in the located in a circadian E-box motif upstream of SCN5A. This variant had previously been thought to modulate arrhythmias. We will identify enrichment of other common variants in circadian promoter motifs in the cohort and establish the mechanism for circadian regulation of the promoters in the canonical arrhythmia gene.
We will look at the enrichment of chronotype markers in the rare disease cohort, starting with the inherited cardiac arrhythmia diseases. These markers are commonly used to determine the phase of individuals sleep pattern, and they are increasingly being associated with health parameters. Our pilot data have revealed several chronotypes enriched and linked to Long QT Syndrome. This will allow us to identify the key diseases that are more prevalent in people with morning or evening chronotypes.
This project will allow us to identify at what level the circadian clock influences these diseases, and pace the way for applying this method to other rare diseases.
Lay Summary
Why do some diseases have symptoms at particular times of day? All people have a biological clock that synchronises their body with the daily cycle of day and night. This is called the circadian clock. The effects of your circadian clock being out of synch with the environment can be seen most obviously with the phenomena of jetlag. However, the circadian clock is important for the correct functioning of all the cells in your body.
We are working to identify how the circadian clock affects people with rare diseases. We call this merging of genomic medicine and chronobiology “chronomic medicine”. We are looking at different ways that this can happen.
Different groups of people are genetically programmed to do things earlier or later in the course of the day. This is called a person’s chronotype. People may be familiar with the popular terms used to describe this – “morning lark” and “night owl”. An increasing number of indicators of health and disease are becoming associated with a person’s chronotype. We are identifying which genetic diseases are associated with chronotype, and the likelihood of getting a severe coronavirus infection.
The circadian clock is found within every cell, but controlling different genes depending on the tissue or organ under observation. There is a master clock in the brain that synchronises the rest of the body with hormones that rise and fall every day. The genes that control this clock can also cause diseases for example sleep disorders. However, whether these genes cause other diseases in different tissues is unexplored.
Around 40% of the genes in your body change what they do over the course of a day. The bit of a gene that contains this information for controlling a gene contains activity across a gene is called a promoter. Within this promoter are elements that make the activity of that gene oscillate across the day. Many diseases show different severity in different people, and at different times of day. We have found differences in these regions in people with rare genetic diseases which show time of day effects have which might explain why the gene behaves differently.
We have worked to identify candidate diseases for prioritisation for chronomic medicine. Our previous work has identified inherited cardiac arrhythmia syndromes as good candidate diseases. We are looking at whether these diseases, such as Long QT syndrome, have more people with early or late chronotypes, and whether this is associated with the severity of the disease. We have identified some changes in the promoters of a key gene in Long QT Syndrome that may control whether changes in levels of that gene change over over a day that are very common in people with arrhythmias, but not in other people. We are studying how these variants affect the daily timing of these important disease genes, and how they might affect the expression of the gene like a dimmer switch.
This project is identifying how our relationship with the day night cycle impacts rare diseases. It will lead to possible routes for new non-invasive therapies, by optimising the time of day that existing therapies are given.
Chronomic Medicine Group 