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As New Breed of Sequencing Takes Root, NIHM Program Encourages Fresh Approaches


Fledgling next-generation sequencing firms and high-end genotyping practitioners may find serious funding and a way to prove themselves if they qualify to take part in a new research program from the US National Institute of Mental Health.

"I would imagine that all those technology companies are very interested in using the [program announcement] because this can provide a proof of concept," Thomas Lehner, chief of the Genetic Basis of Mental Disorders Program at NIMH, told Pharmacogenomics Reporter. "If they have new technologies that allow for high-throughput sequencing, genotyping, or whatever it is, they can use it as a platform to show that their technology can be used as a tool to deep-sequence the genome for relatively little cost," or otherwise find genetic risk factors for the disorders, he said.

The program announcement for NIMH's "Deep Sequencing and Haplotype Profiling of Mental Disorders" explicitly encourages researchers using new sequencing technologies, experimental large-scale SNP-typing technologies, and other innovative approaches to apply for grants to study factors contributing to mental disorders.

In light of the recent acquisition of next-generation sequencing company Agencourt by Beckman Coulter, and the distribution deal between Roche Diagnostics and 454 Life Sciences [see related story], last week's NIMH announcement adds fuel to the rising fire of competition among companies and researchers seeking to create new genetic and genomic technologies.

The NIMH program promotes research and innovative technologies to understand seven mental disorders: anorexia nervosa; attention deficit hyperactivity disorder; autism and related autism spectrum disorders; depression; bipolar disorder; obsessive compulsive disorder; and schizophrenia. The program announcement, number PA-05-106, can be found here.

Because of the structure of the funding system, the NIMH makes no restrictions on funding; all such decisions are handled by peer review. "We understand that large-scale studies can be very expensive," said Lehner. But the program announcement uses the amount of $2.5 million over three years — the maximum duration — as an example of a large direct grant of this type, he said.

The due dates for applications are Feb. 1, June 1, and Oct. 1 for Cycles I, II, and III of the program, which should allow enough time for Solexa, Helicos, 454 Life Sciences, and other novel sequencing-technology companies with plans to produce working platforms within the year. Information on other important dates can be found here.

Due to the dearth of replication of genetic findings in the field, there is no sense among researchers that small studies have shown conclusively which genomic factors are important to the disorders, Lehner said. "In fields like ours, we should look beyond smaller studies," because many of the field's problems stem from sacrifices in study design caused by the complexity of mental disorder phenotypes and genetic models, he said. "I was trying to get some form of standardization by taking money out of the equation" to encourage large, innovative, collaborative studies.

To avoid some of the problems associated with small studies, the program focuses on the use of samples from the Center for Collaborative Genetics Studies, a repository established by NIMH containing DNA, cell lines, phenotypic data, clinical information, and genotyping data from a "large number of fully consented individuals" with mental disorders, along with samples from controls, according to the program announcement. "No new data collection efforts will be supported through this PA," although researchers can use their own data in conjunction with CCGC samples, the document says.

Despite disagreements in the field about the utility of association studies, the program announcement encourages innovative study designs. "I wanted to leave flexibility in [the program] to use different approaches, all using technologies that are high throughput to look more-or-less globally at the whole genome or a large number of genetic regions" to understand the disorders," said Lehner.

So far, response to the PA has been enthusiastic. Lehner has been getting several calls a day asking about technical and mundane details, such as the types of collaborations allowed, or what is considered high throughput. "I have no opinion on that — it's peer reviewed," he said.

When asked whether he expected next-generation sequencing companies to apply for the grants, Lehner said, "I would very much hope so. It depends on how well they set up collaborations with other researchers in the field."

The announcement also encourages the use of: existing SNP-typing platforms; identification and analysis of tag SNPs in genome-wide analysis; genome-wide haplotype analysis with novel statistical methods; innovative analytical approaches such as admixture designs; identification and analysis of clinical sub-phenotypes in large-scale genotyping studies; experimental technologies for SNP-typing; analysis of genomic structure; new bioinformatics tools; and the integration of computational and experimental components, "such as comparative sequence analysis of candidate genes with model organisms."

Applicants will learn the priority score assigned to their applications one week after the assigned date of their review, and they will receive a summary of the reviewer's comments within eight weeks of that date, according to the announcement.

— Chris Womack ([email protected])

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