ederal science officials on Thursday announced the launch of a $260 million program to identify rare gene variants that raise or lower people’s risk of developing such common conditions as heart disease, stroke, diabetes, and autism — the latest Big Science effort to mine DNA sequences for medical breakthroughs.
Four genome hubs won $40 million to $80 million each, spread over four years, to form the Centers for Common Disease Genomics, the National Institutes of Health said. They are the Broad Institute in Cambridge, Mass.; Washington University in St. Louis; Baylor College of Medicine in Houston; and the New York Genome Center in New York City.
Together, the centers will sequence the full genomes of about 150,000 to 200,000 people, some with a disease and some without it. That would have broken the bank just a few years ago, but is now feasible because it costs about $1,000 to sequence and analyze a single human genome.
By comparing how genomes in the two groups differ, scientists hope to understand how genomic variants — essentially spelling differences in the DNA — cause or prevent cardiovascular, metabolic, and neuropsychiatric disorders, including asthma, epilepsy, and inflammatory bowel disease.
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They hope the project will do much more than add to the growing list of “disease risk genes” that DNA-testing companies sell reports on. That information can be confusing or frustrating, since the elevated risk from any particular gene variant is often tiny, leaving people at sea about how worried they should be that their diabetes risk is, say, 9 percent above average.
Instead, discovering all the DNA variants that cause or prevent disease will, scientists hope, let physicians predict more accurately how someone’s disease will unfold and how severe it will be, reveal how the same gene can have different effects in different ethnic groups, and perhaps lead to treatments.
“The time is right for a very large-scale human genome sequencing program” to untangle “the genetic and environmental causes of common diseases,” Dr. Eric Green, director of the NIH National Human Genome Research Institute, told reporters. “The kind of information that can come out of this is overwhelmingly medically important.”
A big reason for the large numbers of people who need to be sequenced reflects a surprise discovery about genetics. “Although a lot of genes were implicated in diseases, they didn’t make much difference in the likelihood of getting a disease,” said geneticist Dan Koboldt of the McDonnell Genome Institute at Washington University.
For instance, although mutations in the BRCA1 and BRCA2 genes raise the risk of breast and ovarian cancer more than 600 percent, most disease-related gene variants raise risk by just a few percent.
Scientists therefore are looking not for common gene variants with tiny effects — those are unlikely to yield drug targets — but rare ones that pack a punch.
“These variants might be found in only 1 out of 100 or 500 or more people,” said Dr. Sekar Kathiresan, who will help lead the Broad’s work. “That’s why we need to look at thousands of people,” perhaps 25,000 with a particular disease and 25,000 without it. In one 2015 study that Kathiresan led, sequencing the genomes of some 10,000 people located a variant that’s present in only 1 in 200 people but quadruples their risk of having a heart attack at a young age.
If the search for common-disease genes works, scientists hope, the variants should show not only how diseases develop but how to stop or treat them. Maybe an immune-system gene will turn out to be involved in heart disease or autism, inspiring new ways to treat or prevent it. “That’s the goal of this,” Koboldt said: “To develop new therapeutics.”
For all the billions of dollars spent on human genome mapping and sequencing — in mega-projects with names like the International HapMap Project, the 1,000 Genomes Project, and the granddaddy of them all, the Human Genome Project — the medical payoff has been slim, critics say.
That reflects how long it takes to develop a drug based on a gene. It was a decade from the discovery of the PCSK9 gene associated with cholesterol levels to the arrival of Praluent from Regeneron and Repatha from Amgen, both of which target that gene to lower “bad” cholesterol — and that was considered lightning fast.