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Policy Brief: A $2 Billion Proposal for Research in Neuropsychiatric Disease

29 March 2010. Just as SRF has finished posting our look at the state of schizophrenia genetics (see SRF related news story), eight prominent geneticists and neurobiologists (including three Nobel laureates) have added a timely postscript by laying out their vision of how best to move forward with research in schizophrenia and other neuropsychiatric diseases. Their proposal, set forth in a policy piece in the March 25 issue of Science, calls for a $2 billion international effort over the next 10 years, with half to go to sequencing 100,000 complete personal genomes and half to be used to integrate genomic findings with neurobiology.

No one would argue that a significant influx of research funds earmarked for neuropsychiatric disease is warranted. As lead author Huda Akil, University of Michigan, Ann Arbor, and her colleagues point out, the top three diseases (schizophrenia, depression, and autism) add up to the leading cause of disability in North America and Europe, with the cost in lost earnings estimated at $200 billion per year in the U.S. alone. Yet there have been no major advances in prevention or treatment in 20 years or more.

The lack of results stems partly from the complexity of the problem. Schizophrenia and other neuropsychiatric disorders result from disruption of neural circuits, Akil and colleagues write, but because the development and function of circuits is so complicated, there are likely many routes to disease. That leads Akil and colleagues to call for a turn away from approaches like genomewide association. “Starting from a diagnosis and searching broadly for genetic causes that are commonly shared across all affected individuals is not likely to succeed....” they write. Instead, they espouse an approach of whole-genome sequencing that can detect private mutations and take into account the genetic and neurobiological heterogeneity of these disorders. The National Institutes of Mental Health is already moving in that direction, funding some whole-genome sequencing for psychiatric disorders, but the vision of Akil and coauthors would dramatically escalate current efforts. (For more discussion on the pros and cons of this shift in focus, see SRF Genetic series, Part 4.)

The second billion-dollar project, aimed at the integration of genetics with the latest techniques for studying circuit function in humans and in experimental animal models, seems less clear-cut than the genomic goal. An important component appears to be the production of animal models based on yet-to-be-discovered human genes.

The article gives the views of eight individuals. Now we would like to hear what the rest of you think. What is there to like about this proposal? What possible pitfalls do you as researchers and SRF readers see?—Pat McCaffrey.

Reference:
Akil H, Brenner S, Kandel E, Kendler KS, King MC, Scolnick E, Watson JD, Zoghbi HY. The future of psychiatric research: genomes and neural circuits. Science. 2010 Mar 26;327(5973):1580-1. Abstract

 
Comments on News and Primary Papers
Primary Papers: Medicine. The future of psychiatric research: genomes and neural circuits.

Comment by:  David J. Porteous, SRF Advisor
Submitted 29 March 2010 Posted 29 March 2010

This Perspective is important, not least because of the collective scientific authority and policy influence of the coauthors. But it will also be controversial and there will be dissenters who will need winning over or convincing.

When the Human Genome Project was first mooted, there were passionate dissenting voices, arguing against such a costly investment, but in hindsight only the most blinkered would deny the all-pervasive and positive impact on biomedical science. Be in no doubt, however, that we have just reached the end of the beginning in terms of genome capacity and impact. Next-generation sequencing will change everything, again. Already, the power of complete genome sequencing in related members of an affected family has been demonstrated for genetic heterogenous conditions, such as Charcot-Marie-Tooth neuropathy (one proband sequenced completely and affected and unaffected relatives tested for all possible causal variants; see Lupski et al., 2010), and Miller syndrome/primary ciliary dyskinesia (one family of...  Read more


View all comments by David J. Porteous

Comment by:  Michael Owen, SRF Advisor
Submitted 30 March 2010 Posted 30 March 2010

By and large, I agree that this is how the big picture looks.

Regarding the genetics: I disagree that we now know that “private” mutations are responsible for disease in many cases. This is conjecture, since no pathogenic point mutations have yet been identified. Moreover, a number of the rare pathogenic variants that have been identified to date (CNVs) are not private, and I see no reason to suppose that the situation will be different for point mutations. However, I very much agree that the focus is going to have to be on very large samples to get full traction on the genetics. Some people think that as we move to sequencing over the next few years, the focus should shift away from very large samples to studies of families. However, given the findings from linkage, where single families with cast iron linkages are extremely rare, and the huge statistical challenges to identifying association with individually rare variants, the samples required will be just as large as those that will be required to identify common risk variants by GWAS, i.e., tens of thousands. So the...  Read more


View all comments by Michael Owen
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