An Atlas of Clinical Associations Mapping to Variants within Protein Structures
Each human genome consists of approximately 6 billion pairs of DNA, represented by combinations of nucleotides known as A, T, C, and, G. Only a fraction of this genome represents genes, units of As, Ts, Cs, and Gs that instruct the cell to make something like a protein. We know from rare genetic diseases like sickle cell anemia that a single change in the DNA sequence can cause disease by altering the protein's function. In general, the DNA sequences of genes that result in protein products are thought to be very important and, when altered, could be a cause of severe disease or death early in life or make a person more susceptible to developing a chronic disease later in life.
The genomics community now has the ability to sequence genomes, which gives us the complete catalog of a person's As, Ts, Cs, and Gs. While we have a good idea of where genes are located in these sequences, we do not understand how a single change of an A, T, C, or G within the gene will impact the making of or function of the gene's protein. We also do not have an understanding if these changes within the protein-important sequences will make people more susceptible to disease and, if so, which ones.
We expect the UK BioBank dataset will provide us with a list of DNA changes in protein-important sequences that possibly predispose people to specific common diseases. The UK BioBank is one of the only studies available to us that has DNA sequences in protein-important regions of the genome on people who have also provided health-related data and blood for laboratory measurements for important markers of health such as cholesterol levels. We have developed a new way to screen all the As, Ts, Cs, and Gs to identify which changes might be bad for the protein. Using our new method, we will screen the UK BioBank sequences for these changes and test whether or not these sequence changes are more frequent among UK BioBank participants with diseases compared to healthy UK BioBank participants. Results from this study will help the scientific community better understand which genetic changes are important for common human diseases and may provide us with clues as to how to better prevent, diagnose, and/or treat them.