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Online Discussions

Updated 10 January 2006 E-mail discussion
Printable version

Live Discussion: Identifying Phenotypes and Endophenotypes in Schizophrenia (Psychosis) Research


Irv Gottesman

Mayada Akil

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Irving Gottesman (University of Minnesota) and Mayada Akil (NIMH) led our first live discussion on 10 January 2006. You can also read Dr. Gottesman's introductory text, as well as well as a brand new Genes, Brain, and Behavior paper coauthored with Todd Gould of NIMH (Gould and Gottesman, 2006). We welcome your comments on the live discussion materials and the transcript.
View the full text of Irv Gottesman and Todd Gould's (NIMH) well-known American Journal of Psychiatry endophenotype paper from 2003 (Gottesman and Gould, 2003), and see citation from David Braff's group on prepulse inhibition and facilitation (Hsieh et al., 2005).

Our thanks to Genes, Brain and Behavior for free access to Gould and Gottesman (2006): Psychiatric endophenotypes and the development of valid animal models, and to the American Journal of Psychiatry for free access to the Gould and Gottesman (2003) pdf: The Endophenotype Concept in Psychiatry: Etymology and Strategic Intentions.

See also the related SRF news story on a paper by Greg Price and colleagues describing a multivariate electrophysiological endophenotype, with commentary by Danielle Dick, Robert Freedman, and Elvira Bramon, along with a response by Price and Assen Jablensky.

Postscript: We would like to direct readers to the January issue of Schizophrenia Bulletin, which has a number of articles devoted to endophenotypes and schizophrenia research, edited by guest editor David Braff.

View Transcript of Live Discussion — Posted 23 February 2006

View Comments By:
Paul Patterson — Posted 2 January 2006
Elaine Chaika — Posted 6 January 2006
Michael Owen — Posted 6 January 2006
Patricia Estani — Posted 7 January 2006
Deborah Levy — Posted 8 January 2006
Edward Scolnick — Posted 8 January 2006
Daniel Weinberger — Posted 9 January 2006
Margit Burmeister — Posted 9 January 2006
David A. Hay — Posted 10 January 2006
Irwin Waldman — Posted 10 January 2006
Kurt Salzinger — Posted 14 January 2006
Ritushree Kukreti — Posted 30 January 2006


Background
by Irving Gottesman

Welcome to this experimental and still-evolving discussion in cyberspace. Our objective is to host a lively exchange of ideas among researchers pursuing a better understanding of the serious afflictions of the human mind, with the goal of amelioration sooner, rather than later, by optimizing strategies. In our live discussion in January, a few well-informed users of the endophenotype strategy will kick off the chat from the introductory paragraphs, with remarks, raising and answering questions, and providing further discussion points.

The endophenotype concept has reemerged as an important tool in neuropsychiatric research strategies after a long latency since its introduction to psychopathology by Gottesman and Shields (1972) and its reawakening (e.g., Gottesman and Gould, 2003). A quick peek into PubMed reveals more than 614 articles mentioning the concept, and all but 17 since January 1999. This emergence is due to many factors, including the limited reproducibility of genetic and neurobiological studies directed toward etiologies of the disorders in the DSM and an improved appreciation for the complex relationships between genes and behavior.

Endophenotypes are not discernible to the unaided eye or ear—they are not the signs or symptoms of medical practice. The prototype of an endophenotype that Gottesman and Shields had in mind 35 years ago was the role played by an abnormal glucose tolerance test, after glucose challenge to the phenotypically normal co-twins and close relatives of Type 1 diabetics, in identifying those at greatest genetic risk in the context of a multifactorial (polygenic) threshold model of etiology. Disease heterogeneity is often guaranteed, rather than simplified, through our current (DSM) diagnostic system; inherent benefits of endophenotypes include more specific disease concepts and process definitions. Endophenotypes for psychopathology can be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological in nature. Heritability and stability (independent of state) represent key components of any useful endophenotype. Importantly, they characterize an approach that reduces the complexity of symptoms and multifaceted behaviors resulting in units of analysis that are more amenable to being modeled in the laboratory (e.g., cell culture or animal studies). There exists a need for increased collaboration between clinicians and basic scientists, mediated by the conceptual framework embedded in the endophenotype story (depicted in Figs. 1 and 2 below in a very condensed format), the net result of which should be to improve diagnosis, classification, and treatment on one end, and to increase the construct relevance of preclinical/animal models on the other. Although focused on schizophrenia for this Schizophrenia Research Forum chat (Braff and Freedman, 2002; Egan and Goldberg, 2003; Lenzenweger, 1999; Hsieh et al., 2005), the endophenotype strategy is being applied to bipolar disorder (Glahn et al., 2004; Hasler et al., 2006; Lenox et al., 2002), major depression (Hasler et al., 2004; Ogden et al., 2004), ADHD (Waldman, 2005), childhood onset schizophrenia (Skuse, 2001; Sporn et al., 2003), coronary artery disease (Rodin et al., 2005 [.pdf]), autism (Belmonte et al., 2004), alcohol dependence (Dick et al., 2005), and other complex, genetically influenced conditions. Hopefully, the discussion to follow will clarify how the still-evolving definition of an endophenotype makes it distinct from broader terms such as biomarkers or biological markers—as well as from the undefined term, intermediate phenotype. Improvements in defining and deploying the concept are needed and welcomed.

Figure 1. Biological markers (A.K.A. subclinical traits, vulnerability markers) may be primarily environmental, epigenetic, or multifactorial in origin. For this reason, criteria useful for the identification of endophenotypes—a special subset of such markers for studies in psychiatric genetics—have been proposed, adapted, and refined over time (see Gottesman and Gould, 2003; Hasler et al., in press; Leboyer et al., 1998; Lenox et al., 2002; Shields and Gottesman, 1973). Current criteria for an endophenotype, to be distinguished from biological markers, are designed to direct clinical research in psychiatry toward genetically and biologically meaningful conclusions.

Figure 2. Endophenotypes are characterized by simpler neurobiological and genetics antecedents than are psychiatric disorders. The schizophrenia phenotype, as an example, is associated with a number of candidate genes and chromosomal regions, the influence of which can be observed at the levels of either behavior or endophenotypes. Endophenotypes, located closer to genes in the pathway from genes to behaviors, have fewer genes associated, and thus are more amenable to genetic investigations and studies in model systems. This skeleton (genes to endophenotypes to behaviors), allowing for epigenetic, "environmental," and purely stochastic influences upon clinical observations, can be applied to other diseases with complex genetics using the input of disease-specific candidate genes/regions, SNPs, and endophenotypes (Gottesman, 1997; Gottesman and Gould, 2003; Hasler et al., in press; Manji et al., 2003; Sing et al., 1996; Sing et al., 1994). © 2005 I.I. Gottesman and used by permission.

References:

Only three short papers (Gottesman and Gould, 2003; Gould and Gottesman, 2005; Hsieh et al., 2005 have been selected as a starting background to the discussion. A suggested Reading List with more relevant items follows.

Belmonte MK, Cook EH Jr, Anderson GM, Rubenstein JL, Greenough WT, Beckel-Mitchener A, Courchesne E, Boulanger LM, Powell SB, Levitt PR, Perry EK, Jiang YH, DeLorey TM, Tierney E. Autism as a disorder of neural information processing: directions for research and targets for therapy. Mol Psychiatry. 2004 Jul;9(7):646-63. Review. Abstract

Braff DL, Light GA. The use of neurophysiological endophenotypes to understand the genetic basis of schizophrenia. Dialogues Clin Neurosci. 2005; 7(2):125-35. Abstract

Braff DL, Freedman R. (2002) Endophenotypes in studies of the genetics of schizophrenia. In Davis, K.L., Charney, D.S., Coyle, J.T. and Nemeroff, C. (eds), Neuropsychopharmacology: the fifth generation of progress. Lippincott Williams and Wilkens, Philadelphia, pp. 703-716.

Castellanos FX, Tannock R. Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat Rev Neurosci. 2002 Aug;3(8):617-28. Review. No abstract available. Abstract

Crusio WE. Flanking gene and genetic background problems in genetically manipulated mice. Biol Psychiatry. 2004 Sep 15;56(6):381-5. Review. Abstract

Dick DM, Jones K, Saccone N, Hinrichs A, Wang JC, Goate A, Bierut L, Almasy L, Schuckit M, Hesselbrock V, Tischfield J, Foroud T, Edenberg H, Porjesz B, Begleiter H. Endophenotypes Successfully Lead to Gene Identification: Results from the Collaborative Study on the Genetics of Alcoholism. Behav Genet. 2005 Dec 10;:1-15 [Epub ahead of print] Abstract

Doyle AE, Willcutt EG, Seidman LJ, Biederman J, Chouinard VA, Silva J, Faraone SV. Attention-deficit/hyperactivity disorder endophenotypes. Biol Psychiatry. 2005 Jun 1;57(11):1324-35. Review. Abstract

Egan MF, Goldberg TE. Intermediate cognitive phenotypes associated with schizophrenia. Methods Mol Med. 2003 ;77():163-97. Abstract

Gershon ES, Goldin LR. Clinical methods in psychiatric genetics. I. Robustness of genetic marker investigative strategies. Acta Psychiatr Scand. 1986 Aug;74(2):113-8. Abstract

Geyer MA, McIlwain KL, Paylor R. Mouse genetic models for prepulse inhibition: an early review. Mol Psychiatry. 2002;7(10):1039-53. Review. Abstract

Glahn DC, Bearden CE, Niendam TA, Escamilla MA. The feasibility of neuropsychological endophenotypes in the search for genes associated with bipolar affective disorder. Bipolar Disord. 2004 Jun;6(3):171-82. Review. Abstract

Gottesman II. Twins: en route to QTLs for cognition. Science. 1997 Jun 6;276(5318):1522-3. No abstract available. Abstract

Gottesman II, Erlenmeyer-Kimling L. Family and twin strategies as a head start in defining prodromes and endophenotypes for hypothetical early-interventions in schizophrenia. Schizophr Res. 2001 Aug 1;51(1):93-102. Review. Abstract

Gottesman II, Shields J. Genetic theorizing and schizophrenia. Br J Psychiatry. 1973 Jan;122(566):15-30. No abstract available. 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

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

Gould TD, Manji HK. The molecular medicine revolution and psychiatry: bridging the gap between basic neuroscience research and clinical psychiatry. J Clin Psychiatry. 2004 May;65(5):598-604. Review. Abstract

Hasler G, Drevets WC, Gould TD, Gottesman II, Manji HK. (in press) Toward constructing an endophenotype strategy for bipolar disorders.

Hasler G, Drevets WC, Manji HK, Charney DS. Discovering endophenotypes for major depression. Neuropsychopharmacology. 2004 Oct;29(10):1765-81. Review. Abstract

Hsieh MH, Swerdlow NR, Braff DL. Effects of Background and Prepulse Characteristics on Prepulse Inhibition and Facilitation: Implications for Neuropsychiatric Research. Biol Psychiatry. 2005 Sep 16. Abstract

Kirov G, O'Donovan MC, Owen MJ. Finding schizophrenia genes. J Clin Invest. 2005 Jun;115(6):1440-8. Review. Abstract

Leboyer M, Bellivier F, Nosten-Bertrand M, Jouvent R, Pauls D, Mallet J. Psychiatric genetics: search for phenotypes. Trends Neurosci. 1998 Mar;21(3):102-5. Review. Abstract

Lenox RH, Gould TD, Manji HK. Endophenotypes in bipolar disorder. Am J Med Genet. 2002 May 8;114(4):391-406. Review. Erratum in: Am J Med Genet 2002 Jul 8;114(5):592. Abstract

Lenzenweger MF. Schizophrenia: refining the phenotype, resolving endophenotypes. Behav Res Ther. 1999 Mar;37(3):281-95. Review. Abstract

Manji HK, Gottesman II, Gould TD. Signal transduction and genes-to-behaviors pathways in psychiatric diseases. Sci STKE. 2003 Nov 4;2003(207):pe49. Review. Abstract

Miguel EC, Leckman JF, Rauch S, do Rosario-Campos MC, Hounie AG, Mercadante MT, Chacon P, Pauls DL. Obsessive-compulsive disorder phenotypes: implications for genetic studies. Mol Psychiatry. 2005 Mar;10(3):258-75. Review. Abstract

Niculescu AB 3rd, Akiskal HS. Proposed endophenotypes of dysthymia: evolutionary, clinical and pharmacogenomic considerations. Mol Psychiatry. 2001 Jul;6(4):363-6. Review. Abstract

Petryshen TL, Kirby A, Hammer Jr RP, Purcell S, Singer JB, Hill AE, Nadeau JH, Daly MJ, Sklar P. Two QTLs for prepulse inhibition of startle identified on mouse chromosome 16 using chromosome substitution strains. Genetics. 2005 Jul 5; [Epub ahead of print] Abstract

Rodin A, Mosley TH, Clark AG, Sing CF, Boerwinkle E. Mining genetic epidemiology data with Bayesian networks application to APOE gene variation and plasma lipid levels. J Comput Biol. 2005 Jan 1;12(1):1-11. Abstract; .pdf

Shields J, Gottesman II. (1973) Genetic studies of schizophrenia as signposts to biochemistry. In Iversen, L.L. and Rose, S.P.R. (eds), Biochemistry and mental illness, Vol 1. Biochemical Society, London, pp. 165-174.

Sing CF, Haviland MB, Reilly SL. Genetic architecture of common multifactorial diseases. Ciba Found Symp. 1996;197:211-29; discussion 229-32. Review. Abstract

Sing CF, Zerba KE, Reilly SL. Traversing the biological complexity in the hierarchy between genome and CAD endpoints in the population at large. Clin Genet. 1994 Jul;46(1 Spec No):6-14. Review. Abstract

Skuse DH. Endophenotypes and child psychiatry. Br J Psychiatry. 2001 May 1;178():395-6. Abstract

Sporn AL, Greenstein DK, Gogtay N, Jeffries NO, Lenane M, Gochman P, Clasen LS, Blumenthal J, Giedd JN, Rapoport JL. Progressive brain volume loss during adolescence in childhood-onset schizophrenia. Am J Psychiatry. 2003 Dec ;160(12):2181-9. Abstract

Swerdlow NR, Geyer MA, Braff DL. Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology (Berl). 2001 Jul;156(2-3):194-215. Review. Abstract

Waldman ID. Statistical approaches to complex phenotypes: evaluating neuropsychological endophenotypes for attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005 Jun 1;57(11):1347-56. Abstract


Comments on Online Discussion
Comment by:  Paul Patterson
Submitted 2 January 2006 Posted 2 January 2006

I'm interested in the maternal infection risk factor, and...  Read more


View all comments by Paul Patterson

Comment by:  Elaine Chaika
Submitted 6 January 2006 Posted 6 January 2006

Gottesman's noting of the importance of eye-tracking...  Read more


View all comments by Elaine Chaika

Comment by:  Michael Owen, SRF Advisor
Submitted 6 January 2006 Posted 6 January 2006

Irv Gottesman and colleagues are to be congratulated on...  Read more


View all comments by Michael Owen

Comment by:  Patricia Estani
Submitted 7 January 2006 Posted 7 January 2006

The current and clinical classifications of schizophrenia...  Read more


View all comments by Patricia Estani

Comment by:  Deborah Levy
Submitted 8 January 2006 Posted 8 January 2006

I want to follow up on several comments made by Dr. Owen,...  Read more


View all comments by Deborah Levy

Comment by:  Edward Scolnick
Submitted 8 January 2006 Posted 8 January 2006

I suggest anyone participating in this discussion read...  Read more


View all comments by Edward Scolnick

Comment by:  Daniel Weinberger, SRF Advisor
Submitted 9 January 2006 Posted 9 January 2006

If we accept that schizophrenia genes, or for that matter...  Read more


View all comments by Daniel Weinberger

Comment by:  Margit Burmeister
Submitted 9 January 2006 Posted 9 January 2006

Regarding Mike Owen's point: "I think the crucial question...  Read more


View all comments by Margit Burmeister

Comment by:  David A. Hay
Submitted 10 January 2006 Posted 10 January 2006

Hi, Irv. Sorry I can't join your discussion but it will be...  Read more


View all comments by David A. Hay

Comment by:  Irwin Waldman
Submitted 10 January 2006 Posted 10 January 2006

It is worth noting that several researchers have...  Read more


View all comments by Irwin Waldman

Comment by:  Kurt Salzinger
Submitted 13 January 2006 Posted 14 January 2006

I was delighted to read the two Gottesman and Gould...  Read more


View all comments by Kurt Salzinger

Comment by:  Ritushree Kukreti
Submitted 30 January 2006 Posted 30 January 2006

The multifactorial etiology of schizophrenia makes it a...  Read more


View all comments by Ritushree Kukreti
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