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Price GW, Michie PT, Johnston J, Innes-Brown H, Kent A, Clissa P, Jablensky AV. A multivariate electrophysiological endophenotype, from a unitary cohort, shows greater research utility than any single feature in the Western Australian family study of schizophrenia. Biol Psychiatry . 2006 Jul 1 ; 60(1):1-10. PubMed Abstract

Comments on Paper and Primary News
Comment by:  Robert Freedman
Submitted 9 January 2006 Posted 9 January 2006

Combined endophenotypes have frequently been raised as a possibility for the analysis of heritability in schizophrenia. They present practical as well as theoretical challenges. Practically, accurate determination of multiple phenotypes taxes the capability of both the laboratory and the subject. For example, among the endophenotypes in the Price et al. paper, some, like P50 suppression, require the subject to passively hear the sounds, without attempting to place significance on the first or second sound. Otherwise, the response to the second sound is enhanced. However, P300 paradigms often require that each sound be attended to carefully, to discern which are targets. Theoretically, if endophenotypes are proposed to be more closely related to a specific neuronal mechanism and its genetic determinants, then do multiple phenotypes represent different or overlapping sets of genes? Is combination of the endophenotypes implicitly endorsing an overlap hypothesis? If so, would larger correlation coefficients be expected? We have had experience with one such composite phenotype,...  Read more

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Comment by:  Danielle Dick
Submitted 9 January 2006 Posted 9 January 2006
  I recommend this paper

Although the concept of endophenotypes was first applied to the field of psychiatry by Gottesman and Shields in 1972, it has only been more recently that the utility of the endophenotype concept in psychiatry has been realized. Renewed enthusiasm for endophenotypes was likely brought about, in part, by the difficulties encountered in gene identification efforts for psychiatric disorders, despite considerable evidence for their heritability. Other fields have a longer history of using more readily quantifiable risk components to identify susceptibility genes for disease; for example, cholesterol levels, blood pressure, and body fat have been analyzed to identify genetic risk factors influencing cardiovascular disease. It is incredibly exciting to see this strategy also proving fruitful in the area of psychiatric genetics. This has been true not only in regard to schizophrenia, as nicely illustrated by an analysis of cognitive trait components of schizophrenia that yielded higher lod scores than analyses of diagnosis (  Read more

View all comments by Danielle Dick

Primary News: A Multivariate Electrophysiological Endophenotype—Are Four Waves Better Than One?

Comment by:  Greg PriceAssen Jablensky
Submitted 18 January 2006 Posted 20 January 2006
  I recommend this paper

We appreciate the SRF focus on our article (Price et al., 2005) and the comments by Robert Freedman, Danielle Dick, and other contributors to the general topic of endophenotypes. A couple of points raised call for a brief response.

Freedman’s query whether by combining several endophenotypes we implicitly assume that “overlapping sets of genes” are involved can be answered in the affirmative. It is now generally accepted that no 1:1 relationship exists between genes and phenotypes in the polygenic (or oligogenic) disorders. Similarly to the multiple interrelated neural systems, the sets of susceptibility and modifier genes operate as complex interacting networks that functional genomics is only now beginning to understand and tease out (see Liu et al., 2002; Jablensky, 2004). In this context, the requirement that the “genetic architecture”...  Read more

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View all comments by Assen Jablensky

Comment by:  Elvira Bramon
Submitted 20 February 2006 Posted 20 February 2006

Price and colleagues propose the use of a combination of multiple endophenotypes in schizophrenia research. Their article shows that their multivariate endophenotype provides the best method to distinguish affected from unaffected individuals with higher sensitivity and specificity than any individual measure of MMN or P300 amplitudes, P50 ratio or antisaccades.

At this stage, the article by Price et al. still awaits replication, but there are precedents where multiple rather than individual measures have improved the accuracy of tests. In pharmacogenetics, haplotypes are known to be more useful than individual single nucleotide polymorphisms in predicting clinical response as well as side effects to antipsychotics (Arranz et al., 2000; Malhotra et al., 2004) or antidepressants (Kirchheiner et al., 2004). A battery of multiple biological...  Read more

View all comments by Elvira Bramon
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