Studies

The primary aim of our research is to identify genetic factors that are relevant to multiple sclerosis (MS). Genetic factors that influence the risk of developing the disease, determine how severe the disease will be and affect how it will respond to treatment. Searching for these factors is challenging because the human DNA code, the genome, is so very large. Fortunately advances in technology have allowed us to establish the whole DNA sequence in almost 7,000 patients. Our plan is to compare these sequences to the equivalent data that is being generated from hundreds of thousands healthy volunteers, in projects such as the UK Biobank and Our Future Health.

DNA is made up of four chemicals known as bases that are joined together in a long string. The four chemicals are Adenine, Cytosine, Guanine and Thymine, usually abbreviated to A, C, G and T. The order of the bases in the string is known as the DNA sequence, and example of a piece of DNA might be "...AACTGGACTGTGA...". This sequence is a code that allows cells to make the proteins they need. In total there are 3 billion bases in the human genome, that is the human DNA sequence is 3 billion bases long. If the DNA from any two individuals is compared, then on average 99.9% of the sequence is identical. The differences determine the genetic make-up of an individual and some of these are important to MS. In some parts of the data small runs of sequence are repeated, for examples "...ACTAACTGCTGCTGCTGTTAG...". In this example the motif "CTG" is repeated 4 times. There are thousands of positions in the genome where these so called "short tandem repeats" (STRs) occur and interestingly the number of repeats sometimes varies, so some people may carry longer repeats than others. At some sites, it is known that if the number of repeats becomes very large it can cause diseases that cause neurological problems very similar to MS.

In this project we will use the latest analysis methods to calculate the number of repeats carried at each of 170,000 STR sites in the genome. We will then compare MS and controls and see if the number of repeats in any way predisposes to the development of MS or the severity of the disease. We will also look for rare unusual errors in the sequence and see if these are more common in MS. Using related analysis methods, we can also look for larger errors in the sequence, regions where the sequence is missing (deletions), repeated (duplications) or runs in the opposite direction (inversions).

Multiple sclerosis (MS) is an example of what doctors refer to as an autoimmune disease. In these conditions, white blood cells from the immune system mistakenly attack specific parts of the body. In the case of MS the abnormal immune attack is directed against the central nervous system (CNS), and results in damage to the brain and the spinal cord. In the initial stages the disease patches of inflammation develop at random places of the CNS that result in temporary neurological symptoms, such as blurred vision, imbalance, double vision, weakness and tingling. These transient upsets are known as relapses. As well as these fluctuating symptoms the majority of patients also develop a relentless worsening disability that is known as progression.

Over the last 20 years, through extensive international collaborative efforts we have identified a range of genetic factors that influence the risk of developing MS, and more recently have identified a single genetic risk factor influencing the severity of the disease. The studies to date have used methods that have only allowed us to look at certain selected sites in the human genome, with this new project we are undertaking on CYNAPSE we will be able to look at very nearly the whole sequence. We will also be able to consider types of genetic factors, such as STRs that have not been looked at before. This new project will greatly expand our knowledge of the genetic architecture underlying MS. In turn this will enable us to understand the development of the disease, its highly variable clinical course and its unpredictable response to treatment. We believe that in the longer term this knowledge will enable the development of rational treatments that are both safe and effective.

The molecular pathology of human genetic disease study aims to understand how genetic factors can predispose to inherited conditions. Working with individuals and families with rare conditions, we use advanced genomic techniques to identify genetic alterations that cause a range of disorders such as inherited predisposition to tumours and epigenetic developmental disorders. Identifying the genetic alterations that cause a disorder and relating these to how an individual is affected by the condition can enable us to design medical services for early detection and, in the long-term, lead to novel approaches to treatment.

Rare diseases are, by definition, rare but with >7,000 known rare diseases, collectively they affect a significant number of people (~1 in 17). Historically, the diagnosis of rare diseases has often been delayed and treatment options limited. However, about 80% of rare diseases have a genetic basis and advances in genomic technologies leading to the deployment of exome and genome sequencing in clinical practice is enabling faster diagnosis and providing insights into potential therapeutic approaches for some disorders. In this research, we study the genomes of individuals with rare diseases to gain insights into the genetic basis of both rare and, often also common, diseases. Through this research we have developed specific genetic tests that allow earlier diagnosis of rare conditions and so improve the management of those affected by or at risk of the disorder (e.g. by scanning for early stage tumours in high-risk individuals with an inherited predisposition to cancer).

We would like to try to find out more about the different causes of gastric (stomach) cancer to improve how we screen for them and how we treat people affected by them. We particularly wish to identify those families who fit the criteria for Hereditary Diffuse Gastric Cancer (HDGC). Some people have a family history of gastric cancer and do not have the mutation in the CDH1 gene, so for these families we would like to search for new genes that can help us understand the disease better. We hope that this will enable local genetic centres to provide more accurate advice to families who have a history of gastric cancer and may be undergoing clinical genetic testing.

Diffuse Gastric Cancer (DGC) is highly aggressive and associated with an extremely poor prognosis. Germline CDH1 mutations confer a high lifetime risk of developing hereditary diffuse gastric cancer (HDGC). Cambridge is the only UK reference centre for HDGC and we have one of the largest cohorts of CDH1+ families worldwide, but we have an even larger number of HDGC families where no CDH1 mutation has been identified. We have previously conducted germline whole exome sequencing (WES) in 39 individuals from 22 families without known CDH1 mutations (Fewings et al., 2018 Lancet Gastroenterol Hepatol). In this study mutations in known and plausible genes were identified in probands from six families, but the majority of families remained unexplained. WGS is superior to WES as it gives more uniform and complete coverage, reducing issues relating to sequence (GC) content or capturing design and enrichment. In addition to improved coverage of the coding exome, WGS can also be used to identify pathogenic variation in non-coding regions and structural/copy number variants in the genome. We have completed germline WGS in five individuals from the family in our cohort with the strongest history of DGC where no causative mutation has been identified. We would like to analyse these data in detail to use as a pilot for WGS studies in additional CDH1 negative HDGC families.

Pulmonary Arterial Hypertension (PAH), or high blood pressure in the lungs, is a rare condition affecting younger people that shortens life. Patients with severe PAH die of heart failure. Although the cause of this disease is usually unknown, in about 15-20% of cases there is a mutation in a gene that controls how blood vessels grow and function. The gene is called BMPR2. Although mutations in BMPR2 are a major risk factor for PAH, not everyone with a mutation will develop the disease. Other factors are likely to contribute. In this study, we aim to recruit patients in the UK with a rare form of PAH and their first-degree family members and follow them up for several years. We hope to discover new mutations for this disease, to determine what environmental or biological factors lead to poor outcome and so improve risk stratification, and to understand the triggers that lead to disease.

Understanding the cause of Pulmonary arterial hypertension (PAH) could help find targets for treatments and improve risk scores (and thus give patients more accurate prognoses). This will help the people affected by PAH who can experience shortened lives as patients with severe PAH die of heart failure.