eMERGE publications highlight large-scale genomics research using electronic medical records
Range of studies show new gene-disease links
By Steven Benowitz
Associate Director of Communications, Extramural Research Program
A series of nearly 20 papers published online in 2014 highlights research on the use of DNA biorepositories and electronic medical records (EMRs) to better understand the underlying genomics of disease. Many of the studies point to new associations of genetic variants with a number of conditions and disorders, such as obesity and asthma. The papers, which appear in the journal Frontiers in Genetics, were co-authored by members of the Electronic Medical Records and Genomics (eMERGE) Network. eMERGE is supported by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH).
The major goal of eMERGE is to better understand disease risk and susceptibility and, ultimately, improve patient care. eMERGE researchers hope to reach this goal by combining a patient's data and disease characteristics with his or her genomic information collected from stored tissue specimens in biorepositories.
"These studies are based on data from across the eMERGE Network," said Marylyn Ritchie, Ph.D., director of the Center for Systems Genomics at Pennsylvania State University in University Park and one of three co-editors who organized the series. "Many are focused on understanding some aspect of the genetic architecture of different traits, conditions and diseases. They examine the genome in many different ways, and include large patient data sets and diverse ancestries."
Some of the papers explore research methods or offer reviews of previously published research in specific areas of study, while others report new findings. One review addresses how research results are returned to physicians and patients in the eMERGE Network. Another examines ways that the genetic makeup of individuals from different populations and ancestries across the network can be harnessed in large genomic discovery studies.
Several studies aimed to show the usefulness of electronic medical records in genomic research studies to understand gene-disease associations. A large number of samples in eMERGE tissue repositories have been genotyped - that is, the individual's genetic make-up has been determined. With that information in hand, researchers performed genome-wide association studies (GWAS) to test hundreds of thousands of genetic variants across the genomes in people with or without a particular disease or condition to determine potential associations between genetic variants and disease. Some scientists also carried out phenome-wide association studies, or PheWAS, which examined potential links between a particular genetic variant and many disorders and conditions. A phenome is an individual's complete set of physical traits.
Such studies focused on the potential roles of variants in a number of disorders, and included:
- Genetic variants of FTO, an obesity-related gene. An electronic medical record-based, phenome-wide association study of more than 24,000 adults uncovered new disease associations for genetic variants of FTO, a gene related to obesity in adults. Joshua Denny, M.D., associate professor of biomedical informatics and medicine at the Vanderbilt University School of Medicine in Nashville, Tennessee, and his colleagues found obesity-related FTO variants associated with fibrocystic breast disease and non-alcoholic liver disease. They also showed that non-obesity related FTO variants had potential ties to non-inflammatory disorders of the cervix and chronic periodontitis, a gum disease.
In another study, John Harley, M.D., Ph.D., Bahram Namjou, M.D., and their team at Cincinnati Children's Hospital Medical Center (CCHMC) examined data from more than 5,000 samples of children of European ancestry from the EMRs of two large universities. The investigators showed a high rate of overweight and obese children (28 percent) was associated with the same variants in FTO as in adults.
- Genetic variants and juvenile rheumatoid arthritis. Using data from the same group of more than 5,000 samples of children, Drs. Harley, Namjou and their co-workers confirmed several known associations between genetic variants and juvenile rheumatoid arthritis, asthma and other disorders. Dr. Harley, director of the Center for Autoimmune Genomics and Etiology at CCHMC, also found examples of other such associations, including between variants near the PLCL1 gene and speech and language development delay. Variants close to the IL5-IL13 gene were linked to a type of esophagitis, an inflammatory condition in the esophagus.
- Genes that increase negative side effects of certain chemotherapy drugs. Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at Children's Hospital of Philadelphia (CHOP), and his co-workers used genomic data from samples in a biorepository to predict defective alleles (one member of the gene pair) in the gene that codes for an enzyme, thiopurine methyltransferase (TPMT). TPMT metabolizes thiopurines, a class of chemotherapy drugs. In certain individuals with "loss of function" (LOF) variants, the body's bone marrow may be suppressed after chemotherapy treatment - a potentially severe side effect of the drugs. LOF variants can alter and even curtail a gene's activities. Researchers identified two drug-metabolizing variants tied to three TPMT alleles. The findings are important early steps toward developing screening methods for individuals who are at risk for severe side effects from taking thiopurine drugs, Dr. Hakonarson said.
- Genes that play a role in fat metabolism. Dr. Hakonarson also led a study that examined LOF variants in a gene, PCSK9, which plays a role in fat metabolism. Those with LOF variants in this gene may have low cholesterol - a protective effect. These variants can be used to predict which individuals will have low cholesterol. "A large dataset like that in eMERGE studies can be used to confirm these predictions by looking at lipid and cholesterol levels in patient EMRs and estimating who has a potentially favorable or unfavorable lipid profile," he noted.
Dr. Hakonarson heads one of two eMERGE pediatric sites. Along with CHOP, there is a joint program at CCHMC and Boston Children's Hospital. The pediatric group wants to use the EMR databases and biorepositories to conduct studies aimed at uncovering variants that contribute to childhood disorders such as asthma, autism, attention deficit hyperactivity disorder, obesity and more. Ultimately, investigators would like to be able to use this information to improve risk assessment and treatment for these and other disorders.
"eMERGE will continue to be a centerpiece for where genomic science should go," said Dan Roden, M.D., assistant vice chancellor for personalized medicine at the Vanderbilt University School of Medicine in Nashville. "If we are going to implement genomic medicine broadly, we have to be able to effectively couple genetics with electronic medical records."