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, which did detect evidence for linkage (Myles-Worsely et al., 1999).

References:
Myles-Worsley M. Coon H. McDowell J. Brenner C. Hoff M. Lind P. Bennett P. Freedman R. Clementz B. Byerley W. Linkage of a composite inhibitory phenotype to a chromosome 22q locus in eight Utah families. Am J Med Genet. 1999 Oct 15;88(5):544-50. Abstract

View all comments by Robert Freedman

  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 (Paunio et al., 2004), but also in finding genes involved in other psychiatric problems. The use of electrophysiological endophenotypes has been critical in the identification of several genes related to alcohol dependence in the Collaborative Study of the Genetics of Alcoholism (COGA); importantly, association with these genes and alcohol dependence has already replicated in independent studies, a difficult feat in the area of psychiatric genetics. (See Dick et al., 2005, for a review of the utility of endophenotypes in gene identification efforts in COGA).

This paper by Price and colleagues provides a very nice extension of endophenotypic studies in schizophrenia, as it assessed multiple electrophysiological endophenotypes in its sample and integrated information across these measures to form a multivariate composite endophenotype. This represents an important advance over the standard model of individually studying single endophenotypes in isolation. The finding that the four commonly studied endophenotypes measured across participants in this study are largely uncorrelated is particularly interesting, and perhaps somewhat surprising. That these measures could be combined to create a multivariate composite that was more closely related to diagnosis than any individual feature represents a very interesting result. The utility of this composite endophenotype for gene identification remains to be seen, but this paper clearly suggests that the use of multivariate endophenotypes in genetic studies is an interesting future direction for study. In addition, the predictive accuracy of the multivariate endophenotype, while necessitating replication in independent samples, also has interesting implications for the current NIH movement to identify clinically relevant biomarkers to improve the diagnosis and classification of psychiatric disorders.

References:
Dick, D. M., Jones, K., Saccone, N., Hinrichs, A. L., Wang, J. C., Goate, A., Bierut, L., Almasy, L., Schuckit, M., Hesselbrock, V., Tischfield, J. A., Foroud, T., Edenberg, H. J., Porjesz, B. and Begleiter, H. (2005, December, Epub ahead of print). Endophenotypes Successfully Lead to Gene Identification: Results from the Collaborative Study on the Genetics of Alcoholism. Behavior Genetics.

Gottesman II, Shields J. (1972) Schizophrenia and Genetics; a Twin Study Vantage Point. Academic Press, Inc., New York.

Paunio, T., Tuulio-Henriksson, A., Hiekkalinna, T., Perola, M., Varilo, T., Partonen, T., Cannon, T. D., Lonnqvist, J. and Peltonen, L. (2004). Search for cognitive trait components of schizophrenia reveals a locus for verbal learning and memory on 4q and for visual working memory on 2q. Human Molecular Genetics 15: 1693-1702.

View all comments by Danielle Dick

  I recommend the Primary Papers

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” of the relevant endophenotypes should be simpler than that of the clinical phenotype of schizophrenia appears to be unwarranted and need not be a defining criterion of an endophenotype (see Michael Owen’s contribution to the SRF endophenotype discussion). Further, the seeming paradox of little correlation among the individual endophenotypes and the increase in relative risk when they are combined is compatible with their variable individual expression being offset by an upstream latent trait (see Deborah Levy’s comment in the SRF endophenotype discussion ).

In our experience, the main advantage of multivariate or composite endophenotypes is twofold, that is, (a) allowing a substantial increase in effect size, relative risk and, consequently, power for genetic analysis; and (b) providing tools for reducing the notorious heterogeneity of schizophrenia by parsing the broad clinical phenotype into relatively homogeneous subtypes that may have a distinct genetic basis. In the Western Australian Family Study of Schizophrenia, our research group systematically phenotyped, over the last 8 years, 388 members of 112 families with one or more affected members and over 150 population controls for multiple neurocognitive, neurological, electrophysiological, and personality features. By analyzing the whole-genome scan of these families using a composite neurocognitive endophenotype, which integrates performance measures across several domains, we recently demonstrated (Hallmayer et al., 2005) that a distinct subset of schizophrenia families (including ~30 percent of the probands in our sample) shares a pervasive cognitive deficit linked precisely (lod score 3.32) to the locus on 6p24-22 previously reported by Straub and colleagues (Straub et al., 1995) in a large sample of Irish multiplex schizophrenia families. Further genetic analyses of the Western Australian cohort will aim to explore the potential contribution of the multivariate electrophysiological endophenotype to a refined subclassification of schizophrenia.

References:
Hallmayer JF, Kalaydjieva L, Badcock J, Dragovic M, Howell S, Michie PT, Rock D, Vile D, Williams R, Corder EH, Hollingsworth K, Jablensky A. Genetic evidence for a distinct subtype of schizophrenia characterized by pervasive cognitive deficit. Am J Hum Genet. 2005 Sep;77(3):468-76. Epub 2005 Jul 12. Abstract

Price GW, Michie PT, Johnston J, Innes-Brown H, Kent A, Clissa P, Jablensky A. 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. 2005 Dec 17; [Epub ahead of print] Abstract

View all comments by Greg Price
View all comments by Assen Jablensky

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 markers can better distinguish Alzheimer disease from other forms of dementia and can improve predictions about drug efficacy (Cacabelos et al., 2004).

As for the low correlations among P300, MMN, P50, and antisaccades, maybe this is not all that surprising. These tasks are very different in nature; P50 and MMN are passive, whilst P300 and antisaccades require the participant’s cooperation. In addition, they probably reflect very diverse neural processes from brain gating (P50) to response inhibition (antisaccades) and sustained attention and memory (P300) (Freedman et al., 1997; Maccabe et al., 2005; Umbricht and Krljes, 2005; Bramon et al., 2005). I would argue that highly correlated endophenotypes would be less useful in practice. It would take extra work to measure them, yet they would provide redundant information. Surely a multivariate endophenotype must include a number of independent, hence low to moderately correlated markers. The lack of correlations between ERP components found by Price et al. should not be an obstacle and may be an advantage.

This article has implications for the growing field of early detection of psychosis. A combination of endophenotypes using EEG, structural and functional imaging, and neuropsychological techniques as well as clinical information like family history and symptom dimensions may ultimately improve our accuracy discriminating patients from controls. If such a multivariate measure was developed, it would make sense to investigate its use in identifying people with high risk of developing psychosis (Pantelis et al., 2003; Yung et al., 2004; Brockhaus-Dumke et al., 2005), who could benefit from early therapeutic interventions.

So far there is no individual endophenotype fulfilling all the criteria outlined by Gottesman and Gould (2003). For example, the P300 waveform is one of the most heritable, yet its estimated heritability is around 60 percent only (Van Beijsterveldt et al., 2002). MMN is very reliable (Hall et al., 2004), but its heritability is only starting to be investigated (Hall et al., in press). There is a large overlap in performance between patients and controls for most if not all endophenotypes described. Thus, a combination of selected markers could at least theoretically get closer to the ideal endophenotype, one that can discriminate accurately between high and low liability to psychosis. The influence of schizophrenia-related genes like COMT, CHRNA7, or DISC1 has only been investigated for a few individual endophenotypes like cognitive function, P50 and P300 waveforms, and brain morphometry (Egan et al., 2001; Freedman et al., 2001; Blackwood et al., 2004; Ohnishi et al., 2006; Bramon et al., 2006). The findings from Price and colleagues open new, exciting possibilities using multivariate endophenotypes to try to understand the role of putative candidate genes in psychosis.

References:

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Blackwood DH, Muir WJ. Clinical phenotypes associated with DISC1, a candidate gene for schizophrenia. Neurotox Res. 2004;6(1):35-41. Review. Abstract

Bramon E, Dempster E, Frangou S, McDonald C, Schoenberg P, Maccabe JH, Walshe M, Sham P, Collier D, Murray RM. Is there an association between the COMT gene and P300 endophenotypes? Eur Psychiatry. 2006 Jan 13; [Epub ahead of print] Abstract

Bramon E, McDonald C, Croft RJ, Landau S, Filbey F, Gruzelier JH, Sham PC, Frangou S, Murray RM. Is the P300 wave an endophenotype for schizophrenia? A meta-analysis and a family study. Neuroimage. 2005 Oct 1;27(4):960-8. Abstract

Brockhaus-Dumke A, Tendolkar I, Pukrop R, Schultze-Lutter F, Klosterkotter J, Ruhrmann S. Impaired mismatch negativity generation in prodromal subjects and patients with schizophrenia. Schizophr Res. 2005 Mar 1;73(2-3):297-310. Abstract

Cacabelos R. Genomic characterization of Alzheimer's disease and genotype-related phenotypic analysis of biological markers in dementia. Pharmacogenomics. 2004 Dec;5(8):1049-105. Review. Abstract

Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6917-22. Epub 2001 May 29. Abstract

Freedman R, Coon H, Myles-Worsley M, Orr-Urtreger A, Olincy A, Davis A, Polymeropoulos M, Holik J, Hopkins J, Hoff M, Rosenthal J, Waldo MC, Reimherr F, Wender P, Yaw J, Young DA, Breese CR, Adams C, Patterson D, Adler LE, Kruglyak L, Leonard S, Byerley W. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):587-92. Abstract

Freedman R, Leonard S, Gault JM, Hopkins J, Cloninger CR, Kaufmann CA, Tsuang MT, Farone SV, Malaspina D, Svrakic DM, Sanders A, Gejman P. Linkage disequilibrium for schizophrenia at the chromosome 15q13-14 locus of the alpha7-nicotinic acetylcholine receptor subunit gene (CHRNA7). Am J Med Genet. 2001 Jan 8;105(1):20-2. Abstract

Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003 Apr;160(4):636-45. Review. Abstract

Hall M, Schulze K, Bramon E, Murray RM, Sham P, Rijsdijk F (In press): Genetic Overlap Between P300, P50 and Duration Mismatch Negativity. American Journal of Medical Genetics (Neuropsychiatric genetics).

Hall MH, Schulze K, Sham P, et al (2004): Test-retest reliability of ERP components of P300, P50 and duration mismatch negativity in monozygotic twins. Schizophrenia Research 67:129-129.

Kirchheiner J, Nickchen K, Bauer M, Wong ML, Licinio J, Roots I, Brockmoller J. Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry. 2004 May;9(5):442-73. Review. Abstract

Maccabe JH, Simon H, Zanelli JW, Walwyn R, McDonald CD, Murray RM. Saccadic distractibility is elevated in schizophrenia patients, but not in their unaffected relatives. Psychol Med. 2005 Dec;35(12):1727-36. Abstract

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Ohnishi T, Hashimoto R, Mori T, Nemoto K, Moriguchi Y, Iida H, Noguchi H, Nakabayashi T, Hori H, Ohmori M, Tsukue R, Anami K, Hirabayashi N, Harada S, Arima K, Saitoh O, Kunugi H. The association between the Val158Met polymorphism of the catechol-O-methyl transferase gene and morphological abnormalities of the brain in chronic schizophrenia. Brain. 2006 Feb;129(Pt 2):399-410. Epub 2005 Dec 5. Abstract

Pantelis C, Velakoulis D, McGorry PD, Wood SJ, Suckling J, Phillips LJ, Yung AR, Bullmore ET, Brewer W, Soulsby B, Desmond P, McGuire PK. Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet. 2003 Jan 25;361(9354):281-8. Abstract

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. 2005 Dec 17; [Epub ahead of print] Abstract

Umbricht D, Krljes S. Mismatch negativity in schizophrenia: a meta-analysis. Schizophr Res. 2005 Jul 1;76(1):1-23. Epub 2005 Jan 23. Abstract

van Beijsterveldt CE, van Baal GC. Twin and family studies of the human electroencephalogram: a review and a meta-analysis. Biol Psychol. 2002 Oct;61(1-2):111-38. Review. Abstract

Yung AR, Phillips LJ, Yuen HP, McGorry PD. Risk factors for psychosis in an ultra high-risk group: psychopathology and clinical features. Schizophr Res. 2004 Apr 1;67(2-3):131-42. Abstract

View all comments by Elvira Bramon