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Massive genomics project unveils schizophrenia results

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Virginia Hughes
10 November 2009

Fine print: Analysis of thousands of samples has revealed six genetic variants associated with schizophrenia.

The Psychiatric GWAS Consortium, a massive international project aimed at finding common variants in five psychiatric disorders, has released its first batch of analyses, identifying several significant common variations associated with schizophrenia. The results were presented Sunday at the World Congress of Psychiatric Genetics in San Diego.

Founded in 2007, the consortium plans to perform statistically rigorous meta-analyses of data from genome-wide association studies, which compare the genetic make-up of thousands of cases with that of healthy controls. So far, the team has focused on studies of people with only European ancestry. By combining data sets, the scientists hope to increase statistical power and find previously unknown associations.

"We believe this is the largest biological experiment ever conducted in psychiatry," says Patrick Sullivan, chair of the consortium's depression group, and professor of genetics and psychiatry at the University of North Carolina, Chapel Hill.

With nearly 22,000 of the 69,000 samples contributed so far by 68 institutions, the schizophrenia arm of the project is the largest of the five. The data amassed from people with depression, attention deficit hyperactivity disorder and autism, however, have not yet yielded interesting genetic associations.

The researchers have identified six variants associated with schizophrenia. Smaller studies had previously found three of these, in chromosomal regions 6p, 18q and 11q. The other three — in chromosomal regions 7p, 8q and 10q — are new.

"No sample in our collection by itself yielded a genome-wide significant result. This is important. So, combining the samples was really fundamental," says Pablo Gejman, head of the schizophrenia working group, and director of the Center for Genetics in Psychiatry at NorthShore University HealthSystem Research Institute in Evanston, Illinois.

The autism arm, which includes 3,282 cases and 3,282 controls, did not find regions with genome-wide significance in people with the disorder. The statistics turned up some modest peaks of association for about 30 genes, "none of which are smoking guns for autism above and beyond what we're already seeing in terms of the autism [genome-wide association] studies," says Richard Anney, research fellow in psychiatry at Trinity College in Dublin.

Anney took note of one potentially interesting smaller peak on chromosome 9, however, which includes the nuclear factor 1 B-type (NF1B) gene. Mice that lack NF1B show abnormal brain and axon development1.

NF1B also regulates the expression of cell adhesion molecules2, which have been implicated in previous studies of autism. "[NF1B] is the kind of gene that we'll pay attention to as we go through these analyses," Anney says.

In the next wave of the project, the consortium plans to add many more samples and perform complex analyses to pinpoint variants shared by multiple disorders.

References:


  1. Mason S. et al. Mol. Neurobiol. 39, 10-23 (2009) PubMed

  2. Wang W. et al. J. Neurosci. 27, 6115-6127 (2007) PubMed

Comments

Name: Mike Thomas Orr
11 November 2009 - 9:39PM

if this is the "largest biological experiment ever conducted in psychiatry" , then it is definitely the LARGEST FAILURE EVER OCCURRED IN PSYCHIATRY.
The pompous attitude does not help.
The same people last summer (in a Nature paper) claimed that there are hundreds or even thousands of common variants that affect disease risk. If indeed it is true that after checking the DNA of 22000 people they only found six variants that are associated with the disease (it is not even clear if they reach genome-wide significance), of which only three are new, then we are faced with a colossal waste of time and money. These results are trivial and provide no biological insight.
I wonder if they check another 22000 people, would the same variants show up? I seriously doubt that.

Name: Alan Packer
13 November 2009 - 4:45PM

The previous comment reflects a view, commonly held in some quarters, that the search for common variants in neuropsychiatric disease has been an umitigated failure (Nicholas Wade of the The New York Times famously labeled some work published earlier this year as “a historic defeat, a Pearl Harbor of schizophrenia research”).

That’s catchy, but I think a more balanced perspective is in order. To begin with the Psychiatric GWAS Consortium’s meta-analysis, of the 22,000 genotypes analyzed, only about 9,000 are from cases, and an additional 31,000 samples soon to be added should boost the power of the study to detect many additional novel risk variants. The six loci discovered thus far are indeed genome-wide significant, and history shows that the vast majority of variants that reach such a statistical threshold do hold up over time. It should also be noted the Nature paper referred to by the commenter is not directly comparable to the meta-analysis being undertaken by the GWAS Consortium. The International Schizophrenia Consortium’s findings reported in Nature used a novel statistical approach to ask whether common variants en masse contribute to the risk of schizophrenia and bipolar disorder. They found that the answer was yes, but their analysis probably included many variants with effect size too small to be detected by the meta-analysis undertaken by the GWAS Consortium.

Finally, how does the commenter know that “these results are trivial and provide no biological insight”? Each identified locus implicates new candidate genes and new biological hypotheses, which can then be followed up. If he knows that these are going to dead-ends, I’d like to know how.

Name: Mike Thomas Orr
13 November 2009 - 9:49PM

I agree with Alan Packer that " a ..balanced perspective is in order" when evaluating the relative contribution of rare and common variation in common complex psychiatric disorders. Therefore pompous statements such as the "largest biological experiment ever conducted in psychiatry" do not help.
Indeed, it is very likely that common variation is contributing to the genetic risk of schizophrenia and other CNS disorders. For example there are several hundred of genes that control the basic structure of synaptic circuits or the communication between neurons in synapses. Variations is such genes are very likely to affect the risk of schizophrenia, to the same extend that they will modulate the risk of any other CNS disorder.
My argument is twofold:
1. Genetic association studies have failed (and will fail) miserably to identify most if not all of these common variants
2. The biological insight offered by a variant that affects, for example, basic synaptic transmission is trivial (schizophrenia is a disease of the brain and brain is all about synaptic transmission).

Also:

1. Although it is true that the analysis in the Nature paper is not directly comparable to the meta-analysis being undertaken by the GWAS Consortium, the argument is loud and clear: there are many-probably thousands- of common variants that contribute to the disease risk. It is equally clear that GWAS failed to identify the vast majority of them. When the vast majority of common variants will go undetected and when the biological insight from the very few that may be identified is likely to be trivial, does it worth the effort and the millions of dollars from philanthropists or tax-payers to pursue this approach?

2. Alan also argues that history shows that the vast majority of variants that reach such a statistical threshold do hold up over time. However, he fails to point out that this has been true for diseases with straightforward quantifiable phenotypes. As a matter of fact the historical lessons from psychiatric genetics are a source of pessimism. One has to consider the "Neuregulin' fiasco, which is probably the reason for the change of heart by Nicholas Wade of the The New York Times, who for many years was uncritically presenting this gene as the Rosetta stone of psychiatry from the pages of this newspaper.

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