Researchers have made great progress in understanding the causes of relatively rare, single-gene disorders such as cystic fibrosis and muscular dystrophy. The hunt for genetic factors in common diseases, however, such as cancer or diabetes, has been a long, costly, and, until quite recently, often futile.
That is about to change. Genome-wide association studies, the latest in a series of powerful new research approaches that meld state-of-the-art genomic technologies with the rigorous methods of epidemiology, have begun identifying numerous genes involved in many common diseases. To speed up the application of these technologies and lay a solid groundwork for translating the results into improved medical care, the National Human Genome Research Institute (NHGRI) recently established the Office of Population Genomics. NHGRI is one of the 27 institutes and centers that make up the National Institutes of Health (NIH), the nation's premier biomedical research agency.
"Our goal is to apply these rapidly evolving genomic technologies to existing population-based studies, or develop new studies, as needed, to improve our overall understanding of how genetic variants modify human health and disease. Genome-wide association studies are a critical first step in identifying the genetic basis for common diseases," said Teri Manolio, M.D., Ph.D., who directs the new office located within NHGRI's Office of the Director.
Genome-wide association studies are powerful because they combine state-of-the-art genomic technologies with traditional epidemiologic research approaches, such as those that identified smoking and high blood pressure as risk factors for heart disease half a century ago. Early findings from genome-wide studies have identified genetic variants contributing to prostate cancer, breast cancer, diabetes, obesity, eye diseases and a host of other conditions. In the future, physicians and scientists could use such tools to give patients individualized information about their risks of developing certain diseases and potentially, a tailored prevention plan to reduce these risks.
"We are witnessing an avalanche of exciting results from these kinds of studies as they uncover subtle and previously unsuspected genetic factors contributing to health and disease," said NHGRI Director Francis S. Collins, M.D., Ph.D. "Research groups who have been doing the tough clinical work of recruiting and examining large numbers of people at risk for these diseases can now use genomic technologies to shine a bright light on the entire genomic landscape of their patients. The findings will enhance how we predict, diagnose and ultimately design personalized prevention and treatments for our patients."
Studies so far have just scratched the surface. For example, early studies have identified genes that were not previously suspected to be related to specific conditions, such as genes related to inflammation as risk factors for eye diseases or genes related to cell growth as possible causes of heart disease. Some studies have pointed to areas of the genome that lack identifiable genes, but which must contain some critical genetic controls. Considerable work is still needed to determine how these genes or non-gene-containing stretches of DNA function to influence disease risk and how best to apply this knowledge in the clinic.
To conduct a genome-wide scan, researchers collect groups of people with disease and compare their genetic material to people without the disease, usually 1,000 or so participants in each group. Then, using a laboratory technique, the researchers scan the entire genome of each individual for some 500,000 to 1 million subtle genetic variations called single nucleotide variations, or SNPs. These variations, or SNPs, are similar to changing a single letter in a word. The change can be neutral and not change the meaning of the word - theater or theatre, for example - or it can produce a shift in meaning that is either subtle or substantial.
Such studies, with thousands of participants producing millions of individual pieces of data, require the development of sophisticated analytical tools to sort out real signals from random differences or chance findings that cannot be replicated by other researchers. Considerable work is needed to understand how these variations alter gene function and what their implications are in large and diverse groups of people over time. To accomplish this, geneticists and epidemiologists will need to collaborate closely to identify risk factors involved in the health and illness of large populations.
Key questions related to these findings are whether genetic variants associated with an increased disease risk act differently in the presence of environmental exposures such as diet, stress or allergens. Some of the variants related to eye disease, for example, have appeared to increase risk more strongly in persons who are obese or who smoke, suggesting targeted approaches that may lead to more effective, personalized disease prevention.
To address these challenges, the Office of Population Genomics will promote cross-disciplinary research and training in epidemiology and genomics to make sure that the latest technological innovations, which are used to assess the structure and function of the genome, are evaluated in large numbers of people representative of the U.S. population as a whole. Such studies will ensure that the effect of these variants in the entire population, and in important subgroups such as those defined by race or socioeconomic status, will be clearly defined so that resources can be devoted to variants of the greatest public health importance.
Dr. Manolio, who is also the Senior Advisor to the Director, NHGRI, for Population Genomics, has extensive training and experience in clinical medicine, traditional epidemiology, human genetics and genetic epidemiology. She began her career with the National Heart, Lung, and Blood Institute (NHLBI) at NIH, where she gained a wealth of experience working on large population studies such as the Cardiovascular Health Study and the well-known NHLBI Framingham Heart Study.
Recognizing the potential for extending the genomic revolution beyond small groups of patients or families to large populations, Dr. Manolio expanded her training to human genetics and began examining known genetic variants related to heart, lung and blood diseases in existing NHLBI population studies. The possibility of extending these findings to other common conditions, and utilizing the advances in one field to enhance another, drew her to NHGRI in late 2005.
Dr. Manolio's staff, all epidemiologists, have first-hand experience in the types of research championed by the Office of Population Genomics. Emily Harris, Ph.D., has training in epidemiology and genetics. Dr. Harris has conducted research in the genetic epidemiology of cancer, heart disease, mental health disorders, and iron overload disorders at institutions as varied as Johns Hopkins University, the National Cancer Institute, and Kaiser Permanente in Portland, Ore. Erin Ramos, Ph.D., M.P.H., has training in both public health and genetics. Her research has focused on the identification of genetic risk factors for late-onset Alzheimer's disease. Lucia Hindorff, Ph.D., M.P.H., has training in epidemiology and genetics and has worked on the genetic epidemiology of heart and blood vessel diseases. Jeffery Struewing, M.D., M.S., has more than 15 years of experience conducting family and population-based studies of breast and ovarian cancer at the National Cancer Institute.
The Office of Population Genomics currently leads a number of NIH-supported and NIH-affiliated genome-wide association studies. These include the Genes, Environment and Health Initiative (GEI) and the Genetic Association Information Network (GAIN), which are studying more than a dozen health conditions in large-scale population samples, such as coronary heart disease, lung cancer, psoriasis, pre-term birth, diabetes and mental illnesses.
Data from the genome-wide association studies will be deposited in the database of Genotype and Phenotype (dbGaP) [ncbi.nlm.nih.gov], at the National Center for Biotechnology Information, a part of the National Library of Medicine at NIH, which will manage the vast amount of genetic, medical and environmental information. To encourage rapid research advances, and in keeping with the principles pioneered by the Human Genome Project, all data generated through these initiatives will be made available to researchers, consistent with NIH's Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies (GWAS). The data-sharing policy ensures that the privacy of individual research participants and correct uses of their data are maintained.
Besides helping to shape the focus and direction of genome-wide association studies such as GEI and GAIN, the Office of Population Genomics is developing several other efforts. For example, one program (Epidemiologic Investigation of Putative Causal Genetic Variants-Study Investigators (U01)) will support in-depth, epidemiological investigations of genetic variants identified in genome-wide association and similar studies as probable contributors of public health significance. Examining the relationship of such variants to other observable traits, such as body size measures, hormone levels, x-ray findings and other measures can help to determine the function and impact of these variants in the population as a whole.
"The idea of adding genetic tools to epidemiological investigations of health and disease is not new, but to be able to apply them on such a large scale is a fantastic research opportunity," said Dr. Harris. "It presents both the epidemiology and research communities the chance to get a more complete picture of the complex interactions of genetic and environmental factors involved in health and disease."
Another program, PhenX (consensus measures for Phenotypes and eXposures) will support the development of a basic standardized "tool kit" to uniformly measure physical characteristics, or "disease phenotypes," and environmental exposures in existing and future genome-wide association studies. This would make it possible to combine and compare data across several different studies, refining estimates of risk and extending them to other population groups. For example, researchers could observe whether a particular set of genetic factors acted similarly or differently in people with more than one health condition, such as those with both obesity and diabetes, or with high blood pressure and high cholesterol.
The office has also developed a program (Genome-Wide Studies in Biorepositories with Electronic Medical Record Data (U01)) to use several existing well-characterized biorepositories, which collect and store biospecimens such as DNA, linked to electronic medical records for genomic research. The participating biorepositories will collaborate to develop best practices for evaluating and incorporating electronic medical record data and genomic information to ascertain the risk and potential modifiers of diseases in large, diverse populations.
The Office of Population Genomics also plays an active role in building collaborations with other NIH institutes and centers conducting genomic research. For the past two years, the office has organized and led an annual NIH-wide symposium on the application of genomics to population-based studies being conducted across NIH. The office, in partnership with the Society for Epidemiological Research, also organized and conducted a day-long seminar for traditional epidemiologists in June 2007, Genome-Wide Association Studies for the Rest of Us and has made the video archive of those sessions available through NHGRI's Web site (genome.gov). They also provided an epidemiology training seminar, "Designing Geneticists," for geneticists attending the annual American Society of Human Genetics meeting in October 2007.
Another focus of the office is fostering collaborations with agencies and groups outside of NIH, such as the Centers for Disease Control and Prevention and the U.S. Food and Drug Administration (FDA). In this case, genome-wide association studies could be used to target the genetic variants and environmental factors associated with adverse drug reactions as has recently been demonstrated for blood thinning drugs, such as warfarin, and drugs for HIV/AIDS, such as abacavir.
"Genome-wide association studies targeting the genetic and environmental factors associated with how a drug is processed by the body could improve genetic tests that would help patients avoid dangerous and costly adverse drug reactions," said Dr. Manolio. "NHGRI is excited by the potential of these powerful studies to identify the small number of people who have a significant increased risk of adverse effects of a particular drug. We hope these studies will ultimately lead to more targeted, personalized medicine, making the one-size-fits-all system we live with now a distant memory."
More information and a complete list of activities and funding opportunities are available from the Office of Population Genomics Web site at www.genome.gov/PopulationGenomics. More information on genome-wide association studies is also available at www.genome.gov/20019523/GenomeWide-Association-Studies-Fact-Sheet.
Last Reviewed: February 26, 2012