Unraveling interconnected paths to disease

Image courtesy of Zach Rivera, iStockphoto

Most common diseases arise from a complex interplay among gene variants, environment, and lifestyle habits, yet how these spheres of influence operate — individually and together — remains one of biomedicine’s most formidable mysteries. Some insights could be close at hand, though, thanks to a new NIH plan called the Genes, Environment, and Health Initiative (GEI). The first crop of awards under this initiative, announced last week, will fund a variety of both genetically and environmentally focused studies of human disease. Supporting the genetics arm of the effort, researchers at the Broad Institute will team up with scientists nationwide, conducting genome-scale analyses to pinpoint common genetic variants that underlie disease.

A central focus of the GEI is to identify the genetic risk factors that contribute to common diseases, such as heart disease, lung cancer and type 2 diabetes. Its core method of choice is a new systematic approach for quickly scanning the human genome for disease-related differences. Known as genome-wide association (GWA), the method springs from recent progress over the past five years to build enabling genomic resources and technologies for human genetics. Researchers in the Broad Institute’s Program in Medical and Population Genetics and Genetic Analysis Platform have contributed to many of these advances, including genome-scale maps of human genetic variants, high-density genotyping arrays to measure these variants, and analytical and statistical methods.

Though GWA is a newfound capability, dozens of papers published in the last 18 months have shown it to be a robust technique for uncovering slight differences in the genetic code — called single nucleotide polymorphisms or SNPs — that reproducibly alter a person’s susceptibility to disease. Several of these groundbreaking studies were led by Broad Institute scientists, uncovering new insights into the biological basis of type 2 diabetes, Crohn’s disease, prostate cancer, rheumatoid arthritis, multiple sclerosis and other conditions.

To foster its genomic work, the GEI has named the Broad Institute a genotyping center. Researchers at the institute will partner with other GEI-supported investigators to provide expertise in the latest GWA technologies and analysis methods. Broad scientists will also develop analytical, statistical and informatics capabilities by working together with disease investigators at the second genotyping center, the Center for Inherited Disease Research at the Johns Hopkins University, and with scientists at the GEI coordinating center at the University of Washington in Seattle.

The scientists at the Broad Institute who will contribute to the GEI effort include principal investigator Stacey Gabriel, director of the Genetic Analysis Platform and the National Center for Genotyping and Analysis; co-investigator David Altshuler, director of the Program in Medical and Population Genetics; Marcia Nizzari, director of informatics development for the Program in Medical and Population Genetics; Kristin Ardlie, director of the Biological Samples Platform; project manager Daniel Mirel; and Mark Daly, Steve McCarroll, Finny Kuruvilla, and Josh Korn, who will lend expertise in the analysis of GWA data.

“In just the past year, genome-wide association has uncovered novel insights into the genetic basis of prostate cancer, Crohn’s disease, type 2 diabetes, and many other common human diseases,” said principal investigator Stacey Gabriel. “By collaborating with researchers throughout the GEI network, we will help apply that method to a wide range of other important illnesses and medical conditions.”

A genome-wide study led by Frank Hu of the Harvard School of Public Health is among the first to get underway at the Broad Institute. Hu and his colleagues will examine how genes and lifestyle influence susceptibility to type 2 diabetes. New findings related to the disease were reported earlier this year from a genome-wide study led by the Diabetes Genetics Initiative of the Broad Institute, Lund University, and Novartis. A number of genetic regions, including several novel ones, were unearthed, though many others likely remain to be found.

A second major aspect of the GEI — an exposure biology program — involves the development of tools for measuring various environmental or behavioral stressors, from cigarette smoke and gasoline exhaust to anxiety and exercise. Once such exposures can be reliably detected, scientists can then begin to dissect how they conspire with genetic risk factors to promote disease.