Advocacy group Autism Speaks has announced a partnership with Chinese genomics institute BGI to sequence the whole genomes of 10,000 individuals in families of children with autism spectrum disorder.
The collaborators plan to complete the project over a two-year period, yielding the world's largest library of ASD genomes and effectively doubling BGI's current collection of 10,000 whole human genome sequences.
The effort will kick off with a 200-subject pilot combining 100 subjects from the Autism Genetic Resource Exchange and 100 Chinese subjects, which the partners hope will be finished by the end of the first quarter of 2012, according to Autism Speaks.
Previous whole-genome autism sequencing projects have been limited to relatively small numbers of subjects, while exome sequencing and other genome analyses have only tackled small percentages of the whole genome, Andy Shih, Autism Speaks' vice president for scientific affairs, told Clinical Sequencing News. Because of this, Autism Speaks considers this new whole-genome data, especially in such volume, integral to developing a deeper understanding of the genetic basis of the disorder, he said.
The organization hopes this more comprehensive picture of the genetic heterogeneity of ASD will accelerate the identification of autism-associated genes and pathways that can be used for diagnosis and prediction, and hasten the development of new treatments, said Shih.
"What has been exciting is that even with a limited approach [like exome sequencing or GWAS] we're really learning a lot about the genomic architecture of autism," he said. "I think that highlights the possibility that with a much [more comprehensive] picture, we may be able to develop drugs targeting some of these pathways to help our community."
Shih said this wealth of whole-genome data may also aid research into tests to diagnose autism, which could also impact treatment. "The mantra in the community is that earlier diagnosis will lead to early intervention, which will lead to better prognosis."
A few groups are already looking into sequencing-based autism tests. For example, Transgenomic announced earlier this year that it will develop a next-generation sequencing-based autism test with IP licensed from IntegraGen, which will analyze 95 genes to predict autism risk for a child with an older sibling already diagnosed with ASD (CSN 6/21/2011).
Last march, RainDance launched a panel to identify mutations associated with autism spectrum disorder. The company reported that the ASDseq panel offers 92 percent design coverage across 62 genes known to be associated with autism spectrum disorders (CSN 3/22/2011).
Shih said because of the genetic diversity of the autism spectrum, previous sequencing studies with smaller numbers of subjects and studies based on microarray analyses have not gotten the full picture of the disorder's genomic underpinnings. He said the expansion of whole-genome data that will come out of the 10,000-subject collaboration can only improve the ability to diagnose, predict, and treat the disease.
Having 10,000 whole genomes will "allow us to draw more generalizable conclusions," he said. "Especially if the current thinking is true that it's caused by potentially hundreds of rare variants, this is really the most comprehensive and systematic approach to solve the problem."
Shih said that Autism Speaks is funding the 200-subject pilot with $250,000 for the sequencing and an initial $200,000 to collect 100 samples from Chinese subjects. He said the plan is to complete the pilot by the end of the second quarter of 2012, though discussions are still open on the exact timeline.
After the pilot, Autism Speaks and BGI will work together to seek public and private funding for the next 9,800 whole genomes, he added. The 10,000 subjects are expected to include 2,000 multiplex families (parents plus at least two affected children) or simplex families (parents and one affected child) from the AGRE repository, totaling between 8,000 and 9,000 samples.
The remainder will be samples from China, Shih said. "So not only can we benefit from a huge amount of information, but we can also compare with similar information drawn from a different ethnicity, which is something I don't think has really been examined before now."
'Just Scratching the Surface'
Stephen Scherer, director of the Centre for Applied Genomics at the Hospital for Sick Children in Toronto, told Clinical Sequencing News that he considers the 10,000-genome project very exciting.
Scherer, along with several other teams, has been involved in investigating copy number variation and other genetic factors underlying autism using genotyping arrays. "We can now account for probably around 15 percent or so of families with autism," he said.
"But, that leaves the remainder."
"Indeed we are finding more variants, but I think all [the groups doing large autism sequencing studies] agree that we're just scratching the surface... So I think this announcement is really great because it's making a big investment."
The fact that the study is using whole-genome sequencing instead of exome sequencing also sets it apart from other work in the field, he said, noting that his own group is conducting an exome sequencing study of 1,000 Canadian autism patients.
"The new project will be whole genomes, so it will add a whole new dimension of data we don't have right now," he said. Furthermore, it will serve to "pilot other studies because obviously, [whole-genome sequencing] is where everyone will be going soon."
The 10,000-sample goal for the BGI collaboration reflects the group's hope to reach a threshold where it will "start to see more of the less-common variants," Shih said. The more complete a picture the sequencing gives, the more solid a platform researchers will have moving forward to investigate not only the genes themselves, but also the environmental factors at work in ASD.
"If we can get a really comprehensive picture of the genetic risk factors, it will open new avenues in environmental research as well," he said. "Hopefully we'll be able to deliver a strong genetic foundation to explore gene-environment interaction."
According to Shih, data will be housed first at BGI during the project. Then the partners will "decide together" how to provide access to the wider research community.
"AGRE's history is that we rapidly share data when it's useful for the community," he explained. "We will work with [BGI] to conduct preliminary analysis, and then try to publish findings as quickly as possible … Then hopefully with the collective wisdom of the community we can explore more information contained in those sequences."
Shih said that the AGRE sample collection has supported more than 100 publications so far. "We have hundreds of users that have taken samples from us and conducted high-quality research, and all of them," he said, "are potential stakeholders in using the outcome of the [10,000 whole-genomes] project."
"Nothing like this exists at the moment," he said, "so we are really trying to establish new ground here."
Autism Speaks hopes to refine the sequencing pipeline and analytical approaches through the pilot, "and then from there it is really just 'go' on BGI's part," said Shih.
BGI chairman Yang Huanming said in a statement that the institute has now sequenced over 10,000 whole human genomes to date.
This one project "essentially doubles their expertise in this area," Shih said. "It's going to be truly a huge undertaking."
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