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WCPG 2007—Putting Endophenotypes to the Test

Editor's Note: On Tuesday, 9 October 2007, at the World Congress on Psychiatric Genetics in New York City, Raquel Gur of the University of Pennsylvania chaired a session entitled simply, "Endophenotypes." We are grateful to Jennifer Barnett of University of Cambridge in England (and this year a visiting postdoctoral fellow at Massachusetts General Hospital), who filed the following report.

16 October 2007. Have endophenotypes advanced our understanding of the genetic basis of schizophrenia? This was the subject of an afternoon oral session on the Tuesday of the recent World Congress on Psychiatric Genetics meeting in New York. Four speakers presented data from studies employing a range of candidate endophenotypes in both animal and human research (see also SRF Live Discussion).

First up, Maartje Aukes from UMC Utrecht presented a study in which cognitive, psychophysical, and personality phenotypes were subjected to cosegregation analysis in 25 extended, multiplex families. Despite the common acceptance that such measures are highly heritable, only five of 14 measures showed moderate within-family correlations, resulting in heritabilities between 0.37 and 0.54. These five were prepulse inhibition, the personality trait openness, backward masking, spatial span, and verbal fluency. It was notable that many other popular candidates did not make this cut, including verbal memory, neuroticism, and the P50 signal. Furthermore, commingling and segregation analysis performed on the five heritable traits showed that a simple mode of transmission was likely for just two: openness and prepulse inhibition. These data provide food for thought for researchers hoping that endophenotypes will prove an easier way into the complex genetics of schizophrenia.

Dan Rujescu presented an array of results from his prolific translational research program at the University of Munich. His group have been screening for genetic candidates using as a model MK801, an NMDA receptor antagonist similar to PCP. The aim is to identify genes affecting a range of phenotypes in animals, which can then be moved into human genetic studies for replication. So far the approach has been used to identify genes involved in hippocampal function which appear associated with schizophrenia or cognitive function.

On a rather different tack, Clyde Francks from Oxford then described his work identifying and characterizing the effects of the LRRTM1 gene. This gene on chromosome 2 was originally identified by linkage studies back in 2002 and a haplotype appears associated with handedness. Recent studies in schizophrenia-affected families have shown paternal overtransmission of the same haplotype. Interestingly, there is no evidence for maternal overtransmission of this haplotype, and the association is not found in non-European populations such as Han Chinese.

The final presentation, by Michel Maziade from the Université Laval, Canada, showed results from a study of 44 kindreds in eastern Quebec who are densely affected with either schizophrenia or bipolar disorder. High-risk but currently unaffected offspring were assessed with a comprehensive neuropsychological test battery. Cognitive deficits were large, with effect sizes in the moderate to large range for measures including IQ, executive function, and verbal fluency. Interestingly, and in contrast to previous studies, the cognitive profiles of high-risk offspring of bipolar versus schizophrenia kindreds were almost identical in this sample.

Endophenotypes are potentially powerful, commented Mike Owen (Cardiff), but it is not yet clear that any of our candidates meet two crucial criteria: that they share genes with schizophrenia, and that they lie on the disease pathway. Some of what we propose as endophenotypes may instead be epiphenomena, as in the case of the LRRTM1 gene and lefthandedness. Lefthandedness certainly might, through cerebral asymmetry, share a genetic basis with schizophrenia, but is unlikely to lie on the disease pathway. To the extent that endophenotypes are used to identify new genes, this is fine. But if the aim is to understand the function of genetic variants associated with schizophrenia, then an endophenotype must lie on the disease pathway. Given the likelihood of substantial pleiotropy in genes involved in psychiatric disorder, it is difficult to see how this can be proven.

Nor is it yet known if endophenotypes will prove easier to genetically dissect than the diagnoses themselves. In fact, the cosegregation analysis presented by Dr Aukes suggests this is unlikely to be the case for the majority of our candidates. Possibly true, argued commentators from the audience, but this may be because we tend to use summary test scores reflecting multiple cognitive functions, rather than more simple cognitive or sensory processes. Moreover, smaller endophenotype studies may have two advantages over large case-control association approaches. First, there is a benefit in statistical power of studying quantitative traits over binary diagnostic categories. And second, they may provide more information about the biology, bringing us closer to the ultimate goal of diagnostic or treatment improvements.—Jennifer Barnett.

 
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