Broad Institute awarded grants to propel studies of common, rare diseases
The Broad Institute and its collaborating institutions have received two major grants from the National Human Genome Research Institute (NHGRI) that will support the use of genome sequencing and analysis to identify the genes and genetic variation that underlie both rare and common diseases. The funding will support two state-of-the-art centers — the Center for Mendelian Genomics (CMG) and the Center for Common Disease Genomics (CCDG)—involving scientists from the Broad Institute, in the greater Boston area, and across the world.
“Recent advances in genome sequencing and analysis are making it possible to systematically unravel the genetic basis of disease,” said Eric Lander, director and president of the Broad Institute and a principal investigator of the CCDG. “And, knowing the genes is the critical foundation for understanding the underlying biological mechanisms and identifying potential targets for treatment.”
Daniel MacArthur, co-director of the Broad’s Program in Medical and Population Genetics, and Heidi Rehm, Clinical Director of the Broad’s Clinical Research Sequencing Platform, are the principal investigators of the institute’s Center for Mendelian Genomics. They will work together with leading scientists at institutions in the Boston area and throughout the country, including Boston Children’s Hospital, Massachusetts Eye and Ear Infirmary, and Rockefeller University.
The Broad’s Center for Common Disease Genomics will be led by four scientists: Broad director Eric Lander; Mark Daly, co-director of the Broad’s Program in Medical and Population Genetics; Stacey Gabriel, director of the Broad’s Genomics Platform; and Sekar Kathiresan, director of the Broad’s Cardiovascular Disease Initiative.
Tackling rare diseases: the Broad’s Center for Mendelian Genomics
Rare, inherited diseases are often the work of single, errant genes. These so-called Mendelian disorders — single-gene diseases, such as cystic fibrosis, Huntington’s disease, and many others, — have been studied for decades. Remarkably, of the roughly 20,000 genes in the genome, fewer than 20% have so far been linked to any disease. In the last five years, major advances in genomic technology, especially in sequencing whole genomes and whole exomes (the portion of the genome that codes for proteins), have given rare disease research an important boost. Still, significant challenges remain.
“Although we can sequence the whole human genome, the biggest limitation is in interpreting the genetic variation that we find,” said Daniel MacArthur, who is also a group leader within the Analytic and Translational Genetics Unit (ATGU) at Massachusetts General Hospital and an assistant professor at Harvard Medical School. “In each patient, we find on average three to five million genetic variants, and figuring out which variants cause disease is incredibly challenging.”
With $13.4 million of funding from the NHGRI over four years, the Broad’s new Center for Mendelian Genomics will seek to address these and other challenges. Specifically, center investigators will focus on a handful of key areas. These include improving the technologies for genome sequencing and, importantly, genome analysis, enabling researchers to uncover genetic variants that have so far eluded detection and to interpret variants that have yet to be deciphered. As part of their technology development goals, the scientists will also work to further improve sequence quality — decoding exomes and genomes as accurately and as cheaply as possible.
To reach these goals, MacArthur, Rehm and their colleagues will need to work at the appropriate scale — that is, sequence a sufficiently large number of patient genomes. The researchers aim to decode roughly 10,000 exomes and 7,000 whole genomes over the four-year period. They will focus on a handful of rare disease areas, including muscle, heart, neurodevelopmental, and retinal diseases, in addition to other types of rare diseases.
“Having done a lot of clinical interpretation for patients, my frustration over many years is that we cannot diagnose the causes of disease in most of the rare disease patients we test,” said Heidi Rehm, who is also the Chief Laboratory Director of the Laboratory for Molecular Medicine at Partners Personalized Medicine and an associate professor at Harvard Medical School. “This opportunity is about finding the causes of diseases so that we can improve diagnostics and therapeutics for patients.”
Collaboration is essential to the researchers’ success. Because many diseases are exceedingly rare, it is unlikely that one investigator will be able to collect a sufficient number of patient samples to reliably pinpoint disease genes. For this reason, Rehm, MacArthur and their colleagues have built an international network of collaborators with large sample collections and deep clinical expertise. The Broad’s CMG will also work together with the three other NHGRI-funded centers at Yale University; University of Washington; and a joint center at Baylor College of Medicine and Johns Hopkins University.
Data sharing is also critical for rare disease research. In order to accelerate the discovery of genes that underlie disease, the Broad’s Center for Mendelian Genomics has established a robust framework for center researchers to share their data. A centerpiece of the data-sharing policy involves a new project, called Matchmaker Exchange, which networks together or federates existing genetic databases, allowing researchers to query not only their own data but also the data in other databases to determines whether there are patients with matching profiles. Importantly, data is only discoverable by an investigator with a matched case.
“We feel pretty strongly that it is in the best interests of both the patients and, in fact, the researchers to put the data out there in a way that it can be combined and strengthened, and get these discoveries made sooner,” said Rehm.
A comprehensive approach to common diseases: the Broad’s Center for Common Disease Genomics
Common diseases, such as heart attack, diabetes, and psychiatric disease, represent a major burden on society. Hundreds of millions of people worldwide suffer from these conditions. Unlike rare diseases, which typically stem from mutations in a single gene, common diseases emerge from mutations in multiple genes, sometimes tens or even hundreds of them. And genetic influences are not the only contributors. Lifestyle and environment can also play a role, too.
Beginning about a decade ago, advances in genomic technologies catalyzed efforts to systematically reveal the genes involved in common diseases. Now, as technologies have further evolved, the Broad’s Center for Common Disease Genomics, together with other NHGRI centers, will seek to use whole genome sequencing to create a comprehensive catalog of the genetic variation associated with disease.
The grants awarded under this program mark the latest effort in the NHGRI’s long-running Genome Sequencing Program. The Broad Institute has been a grantee in this program since its earliest phase, the Human Genome Project.
To begin their work as a CCDG, Kathiresan, Gabriel, Daly, Lander, and their colleagues, awarded $80 million over four years, will focus on a handful of diseases in three core areas, including cardiovascular disease, inflammatory disease, and neuropsychiatric disease. Specific diseases in these core areas include early heart attack, stroke, inflammatory bowel disease, asthma, autism, and epilepsy.
“These are really exemplar diseases,” said Kathiresan, who is also the director of preventive cardiology at Massachusetts General Hospital and an associate professor at Harvard Medical School. “Although they are all common diseases, they have important differences — some have significant environmental influences, some occur early in life, some later in life. These differences suggest that the diseases we have chosen will have quite different genetic architectures.”
By assembling a complete genetic picture of these exemplar diseases, the investigators will provide a paradigm for tackling other common diseases. In the coming years, additional diseases will be chosen for study.
The centers will work collaboratively to dissect the genetics of the selected diseases, and seek to gather roughly 25,000 samples for each disease from investigators around the world. They will use genome sequencing to build a comprehensive view of the genomic variation associated with each disease, covering all types of genomic variation and all frequency levels, from the most common to the most rare.
For Kathiresan, who has studied the genetics of heart attack for the last decade, this work signifies a sort of finish line. “We started with candidate gene studies, then moved to common variants and genome wide association studies, and then, most recently, leveraged exome sequencing, he said. “Now, with whole genome sequencing, we can begin to complete the story, and that is incredibly exciting.”