Cold Spring Harbor Laboratory plans to use four Illumina Genome Analyzers to support research at the new Stanley Center for Psychiatric Genomics, which was created last week with a $25 million gift from the Stanley Medical Research Institute.
In a statement announcing the gift, CSHL said that the goal of the center is to “unambiguously diagnose patients with psychiatric disorders based on their DNA sequence in 10 years time.” [In Sequence 06-26-07]
An important step in reaching that goal, according to CSHL professor Dick McCombie, is fine-grained sequencing of large candidate regions of the human genome in order to home in on the variations that underlie psychiatric disorders.
McCombie told In Sequence last week that sequencing will be “complementary” to other genomic and genetic approaches at the center like association mapping, SNP arrays, and copy number variation analysis.
Nevertheless, he noted, “I think the technology has reached the point where sequencing can play a major role in looking at the variation that underlies some of these disorders.”
While genomic tools such as microarrays are commonly used in psychiatric research, sequencing technology is only now reaching the point where it is a cost-effective alternative.
The goal of the center is to “look at all the genetic variability, not just the variability of SNPs,” McCombie said. “We want to actually look at the affected people and look at how they differ from non-affected people, and we think it’s important not just to look at exons, so that means that the sequencing requirement goes up dramatically.”
With the advent of next-generation sequencing instruments, he said, “we feel that we can do that now in a cost effective way with the new technology. It was always possible, but it was just hideously expensive.”
Others in the field agree that the time is ripe for a sequencing-based approach to psychiatric genomics.
“Historically, because there was no way to do sequencing,” researchers performed association studies to identify biomarkers linked to a phenotype, said Jon McClellan, an associate professor of psychiatry at the University of Washington and co-author of a paper published recently in the British Journal of Psychiatry suggesting that schizophrenia is caused by multiple rare alleles.
However, he noted, “markers can only take you so far. They’ll help you narrow down [the genetic component of the disease] and get closer to where the error is, but as you get closer you need to do sequencing to figure out what the exact error really is.”
McClellan said that his lab does some sequencing, as well as other studies. “People already do sequencing, but it’s just that as the technology continues to get better and better it becomes much more efficient, and hopefully more cost-effective, so that you can do more cases or get the information back much quicker than you used to be able to.”
McCombie said the center’s four Illumina sequencers, which will be installed by the end of the month, will provide enough throughput to “let us move very quickly on this.”
While the group plans to evaluate other new sequencing technologies as they are commercialized, “we feel quite confident that we can do this project on the Illumina/Solexa platform, and are going ahead with that assumption until we see something that makes us think that we can do it better and cheaper with another platform,” he said.
Candidate Regions Under Discussion
The CSHL researchers plan to sequence large candidate regions that have already been associated with psychiatric disorders via other genetic approaches such as SNP arrays or copy number analysis, McCombie said. He declined to provide details on specific regions under study, citing the early phase of the initiative.
“We’re looking at millions of bases, but the precise regions are still under active discussion,” he said.
We feel that we can do that now in a cost effective way with the new technology. It was always possible, but it was just hideously expensive.”
Likewise, the number of patient samples that will be required is still unclear. “It’s going to vary depending on the loci that we’re looking at,” McCombie said. “There will be different studies with different numbers of patients. … Whether it’s 100 or 500 or a thousand is going to depend on the precise study and what we’re looking for.”
One short-term challenge for the CSHL team is the development of a “front end” for the Illumina system to accurately extract target genomic regions from patient samples for sequencing.
“If you’re sequencing a thousand bases from a thousand people, that’s pretty straightforward. You do a thousand PCR reactions,” McCombie said. “If you’re sequencing several million bases from a thousand people, that can be done with long-range PCR — and, in fact, we’re looking at that as one option — but it requires it to be done in an industrial-scale process much different than you would do it on smaller loci.”
He said his lab is looking at “a number of different ways to essentially pull these regions of the genome out, because the sequencing’s still not at the point where you would just sequence the entire genome.”
McCombie said that he and CSHL colleague Greg Hannon have been working on this particular problem for more than a year, underscoring the fact that many activities planned for the psychiatric genomics center are already underway at various groups around the lab. “This gift is going to let us really scale these efforts up and coalesce them a bit,” he said.
As for the center’s long-term goals, McCombie said that the aim is “to have in 10 years a wide range of sequence-based diagnostics for these disorders so that we can begin to eliminate the ambiguity from the diagnostics of this and to really begin to understand the molecular pathology of [these disorders] and use that information to move ahead therapy.”
The University of Washington’s McClellan agreed that CSHL’s 10-year goal is realistic.
“I think in 10 years we’re going to know enormously more than we know now, and we will almost assuredly at that point have figured out some, and hopefully many genes, where errors in those genes are related to psychiatric illness,” he said.
“That doesn’t mean we’ll have them all figured out in 10 years, but hopefully we’ll have a lot more than we do now, and the more genes that are identified that are clearly connected to an illness, it makes the whole field move ahead much quicker,” he said.