Schizophrenia Research Forum - A Catalyst for Creative Thinking

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


Transcript

Identifying Phenotypes and Endophenotypes in Schizophrenia (Psychosis) Research

Participants: Mayada Akil (NIMH), Irving Gottesman (University of Minnesota), Carrie Bearden (University of California, Los Angeles), Jeremy Blank (University of California at Davis MIND Institute), Monica Calkins (University of Pennsylvania), Cameron Carter (University of California at Davis Medical School), Sufen Chiu (University of California at Davis Medical School), Michael Coleman (McLean Hospital), Wim Crusio (CNRS UMR, Talence, France; Genes, Brain and Behavior), Danielle Dick (Washington University), Steve Doochin (NARSAD), Patricia Estani (Neuropsychiatric Medical Center SMC, Argentina), Anne Gibbs (McLean Hospital), Heather Hain (Xenogen Biosciences), Hakon Heimer (Schizophrenia Research Forum), Olga Krastoshevsky (McLean Hospital), Mark Lenzenweger (SUNY-Binghamton), Deborah Levy (McLean Hospital), Connie Lieber (NARSAD), Angus MacDonald (Psychology, University of Minnesota), Maureen Martin (St. Louis University), Paul H. Patterson (California Institute of Technology), Greg Price (University of Western Australia), Ed Scolnick (Broad Institute), Jiajun Shi (University of Chicago), Nico Stanculescu (Schizophrenia Research Forum), Cenk Tek (Yale University), Gunvant Thaker (Maryland Psychiatric Research Center), Annamari Tuulio-Henriksson (National Public Health Institute, Helsinki), Irwin Waldman (Emory University), Felicia Widjaja (University of California at Davis MIND Institute), Qing Xu (Weill Medical College of Cornell University). Note: Transcript has been edited for clarity and accuracy. _______________________________________________________

Nico Stanculescu
Welcome, Irv!

Irving Gottesman
Can everyone read this text or only you?

Nico Stanculescu
Everyone.

Angus MacDonald
We're just really quiet.

Nico Stanculescu
Hahahaha.... Hello, Mayada, and welcome, Deborah!

Mayada Akil
Hi, everybody. Great to see so many people already in the "waiting" room.

Hakon Heimer
Hello to all!

Mayada Akil
Hey, Hakon. Should we get this thing started?

Hakon Heimer
Let's give a couple more minutes for late arrivals.

Mayada Akil
Okay.

Hakon Heimer
Feel free to chat amongst yourselves. Hi, Irv!

Mayada Akil
Hi, Gunvant. Nice to see you here.

Irving Gottesman
I concur with Mayada that we can start to make the best use of our one hour of "live" chatting in this chat room.

Hakon Heimer
Let's start off by having everybody in the "room" type his or her name and institution. I'm Hakon Heimer, editor of the Schizophrenia Research Forum.

Mayada Akil
Mayada Akil, NIMH.

Mark Lenzenweger
Mark F. Lenzenweger, SUNY-Binghamton.

Angus MacDonald
Angus MacDonald, Psychology, University of Minnesota.

Deborah Levy
Deborah Levy, McLean Hospital.

Paul Patterson
Paul H. Patterson, California Institute of Technology.

Wim Crusio
Wim Crusio, editor in chief, Genes, Brain and Behavior.

Edward Scolnick
Ed Scolnick, Broad Institute.

Irving Gottesman
Irv Gottesman, University of Minnesota.

Heather Hain
Heather Hain, Xenogen Biosciences.

Felicia Widjaja
Felicia Widjaja, University of California at Davis MIND Institute.

Patricia Estani
Patricia Estani, researcher at Neuropsychiatric Medical Center, SMC, Argentina.

Hakon Heimer
Thanks so much to all who started us off with commentary. We even had a late comment a few minutes ago. If you want to read it, don't hit "back" on your browser; just open another window.

Mayada Akil
Welcome, everybody. This is the first live discussion on SRF and I am excited to be part of it. I selected this topic for the first discussion, and from the attendance today it appears to be one that many people are thinking about. Our guest of honor is Irv Gottesman, who is the leading authority on the use of endophenotypes in psychiatry. Some of his frequently cited papers have been posted on the site prior to this discussion.

Irv wondered about any reactions that people may have had to issues raised by the comments posted. There were questions of strategy raised, as well. For example, what makes strategic sense, given the current state of the science in our hunt for schizophrenia genes: to characterize endophenotypes and have them lead us to susceptibility genes or to search for as many risk genes for schizophrenia as possible, then focus on understanding their biology and characterize the phenotypes associated with them?

Angus MacDonald
I wanted to follow up on one of Michael Owen's comments that I believe Deborah also addressed. It was the issue of sampling, and whether the ease of recruitment in the general population was an additional advantage. Irv, what are your thoughts? Are individual differences in an endophenotype in the general population (and their link to polymorphisms therein) useful for understanding schizophrenia?

Irving Gottesman
Absolutely, Angus. The entire human and various animal species (see the article on animal models and endophenotypes by Todd Gould and myself from Wim Crusio's journal posted on the discussion page) are our oysters.

Mark Lenzenweger
I think ease of recruitment in the general population is not only an advantage in terms of ease/efficiency; it is necessary in that it allows us to specify base rates of deviance on the endophenotypes, allows us to evaluate the predictive power of an endophenotype (i.e., clinical status) conditioned on endophenotype deviance, and therefore evaluate P(S|E), where S = schizophrenia and E = endophenotype deviance. Most research still takes the form P(E|S) and this does not address the real question regarding the utility of endophenotypes, namely, how well do they detect schizophrenia liability?

Deborah Levy
One problem with studying endophenotypes in the general population is that one is not selecting for schizophrenia genes. In contrast, studying families of schizophrenics is selecting for schizophrenia genes.

Mayada Akil
Ed, do you care to comment on the strategy question I raised earlier, particularly in the context of recruitment issues being raised now?

Edward Scolnick
I wonder if someone would like to list the known general genetic causes of a varying clinical phenotype based on known medical genetics, not psychiatric medical genetics.

Mayada Akil
What do you mean by a varying clinical phenotype?

Edward Scolnick
There are many examples of varying phenotypes of known genetic diseases in medical genetics (see preliminary comment).

Irving Gottesman
I would point to the work of Charlie Sing and colleagues at Michigan on the genetic and molecular epidemiology of coronary heart disease (see citations in the Gottesman and Gould, 2003 background text from the American Journal of Psychiatry.

Deborah Levy
Irv, could you elaborate?

Irving Gottesman
Ed, Debbie, Mark, the endophenotype strategy gives us the resolution that permits the best of three worlds—encouraging the study of features of probands (index cases of patients), of their normal relatives, and members of the general population, and, it is cost-efficient to start, in the case of multifactorial threshold diseases, with probands—index cases and their unaffected relatives.

Mayada Akil
Is there an expectation that critical genes for schizophrenia have a detectable impact on the endophenotype?

Irving Gottesman
God willing.

Mayada Akil
If you have recently joined the discussion, please identify yourself and your institution. Thanks.

Jiajun Shi
Jiajun Shi, University of Chicago.

Deborah Levy
That would seem to be the point of using endophenotypes in linkage studies; because they are so much more prevalent than schizophrenia in family members, it is easier to detect the effect of a gene on the endophenotype than on schizophrenia. Irv?

Irving Gottesman
Yes, Debbie, that has been the strategy of the Finnish group (Leena Peltonen, Tiina Paunio, Ty Cannon) and David Glahn in Texas with bipolar and Irwin Waldman with ADHD.

Angus MacDonald
Mayada raises another interesting issue, which I think of as the distinction between endophenotypes as markers and endophenotypes as mechanisms. Is the identification of mechanisms more helpful in "filling in" the gap, rather than simply showing a correlation? We have argued that there may be more value added in mechanisms as compared to markers (MacDonald and Carter, 2002).

Mark Lenzenweger
It is true that when testing endophenotypes in the general population, one is not conditioning on schizophrenia gene(s). However, the way we think of endophenotypes is that they are predictive of the schizophrenia gene(s), and we should probably test this assumption. Most clinical research on endophenotypes takes the form P(E|S), when it really should take the form P(S|E), where S = schizophrenia liability and E = deviance on endophenotypes.

Mayada Akil
I think Ed's point is that the same genes may produce different phenotypes, adding another level of complexity.

Irving Gottesman
Mayada, that is why they are called complex diseases, but especially when dealing with the more common diseases like schizophrenia, diabetes, heart, etc., versus the Mendelizing disorders that Ed pointed to in his originally posted comment. The lessons learned from research on the Mendelian disorders listed in OMIM over the years by Victor McKusick and colleagues do not readily transfer to research on the more ambiguous field of multigenic, threshold diseases (see King RA, Rotter JI, Motulsky AG, eds. The Genetic Basis of Common Diseases. New York, Oxford University Press, 2002).

Paul Patterson
Deborah, there is at least some evidence that the endophenotype of schizophrenia that runs in families may be different from that in schizophrenia caused by maternal infection. Thus, studying families only may restrict the endophenotypes one sees.

Deborah Levy
An endophenotype can have different causes in different groups; the rationale for studying families is that it is likely that the endophenotype has the same cause in the same family.

Carrie Bearden
Dr. Patterson, if the goal of the endophenotype concept is to ultimately identify underlying genes, would there be value in studying endophenotypes in "schizophrenia caused by maternal infection" (assuming this is a different, "environmental" mechanism rather than something more complex like gene-environment interaction).

Deborah Levy
How does one know whether maternal infection "caused" schizophrenia, as opposed to being correlated with the later development of schizophrenia?

Gunvant Thaker
In regard to maternal infection, endophenotypes can still be a useful tool to study gene/environment interaction.

Paul Patterson
Deborah, "caused" may not be the best term; maternal infection increases the risk for schizophrenia in the offspring. If it is true that the endophenotype of schizophrenia arising from interaction between susceptibility genes and maternal infection is different from schizophrenia arising from genes and some other factor, this would have major implications for pathophysiology, genetics, and for the role of environmental factors.

Deborah Levy
I am not sure at this point if we know that cases of schizophrenia associated with maternal infection are not influenced by genes. Perhaps genetic predisposition increases vulnerability to the effects of maternal infection.

Mayada Akil
Deborah, it is also possible that viral infections change gene expression.

Patricia Estani
The most useful thing that I take from the endophenotype concept is that it allows the researcher to design simpler experiments in the field of behavioral science, making clinical research as experimentally clear as the basic animal models are.

Cameron Carter
I would like to echo Angus's statement that an endophenotype may not just increase our power to identify an association between genetic risk and specific genetic variation; it may also provide important data and insights into how the expression of that genetic variation leads to disordered cognition, that is, the mechanisms linking genes to neurons to systems to behaviors.

Irving Gottesman
Right on, Cameron. Study of our Figure 2 in the intro material will reveal provisions for many of the complications to the complexities many of you are raising, even before "epigenetic" notions (see, e.g., Wong et al., 2005; Petronis, 2004).

Mayada Akil
Okay, Irv. Are endophenotypes less complex than the disorder itself?

Deborah Levy
When you say less complex, do you mean more Mendelian?

Mayada Akil
Yes, I do. My question is, are we exchanging one genetically complex phenomenon for another?

Irving Gottesman
Yes, Mayada, but they are not ipso facto simple. This is the task for the current generation of researchers to add to their work list. And Debbie, everything is Mendelian, but the impact on the phenotype from a dominant gene or a pair of recessives at one locus is humongous, compared to the often subtle or unnoticed effect of an allele in a multigenic system underlying a non-Mendelizing but definitely genetically influenced disease such as schizophrenia or bipolar disorder. Again, I would refer you to the Bible of complex diseases (The Genetic Basis of Common Diseases).

Deborah Levy
Using endophenotypes in both ways would be important to pursue.

Irwin Waldman
I think that several points raised before the live chat—namely by Michael Owen, Deborah Levy, and Ed Scolnick—bear mention, in particular the contrasting emphasis on using endophenotypes to find genes for complex psychiatric phenotypes versus using endophenotypes to elaborate the various disorders that risk-inducing genes may code for.

Also, although there is the notion that endophenotypes are genetically less complex than manifest disorders, I don't think we know this for any endophenotypes or complex psychiatric disorders.

Wim Crusio
Irwin, even if endophenotypes may be as genetically complex as schizophrenia itself, performing linkage studies using more detailed phenotypical information may increase your power. There are several successful examples from animal work (e.g., Moisan et al., 1996).

Irwin Waldman
I agree with you, Wim. It may simply be that the use of a continuous phenotype, or in some cases, one with better psychometric properties, could entail increases in power.

Patricia Estani
I think this problem is not only genetics or simplifying genetics. The endophenotype concept must simplify our concepts of behavioral approaches to schizophrenia. I think that the appropriate combination of biology and behavior must occur in the study of schizophrenia.

Deborah Levy
At this point, we can ask whether the observed data about an endophenotype (rate in schizophrenics, rate in siblings of schizophrenics, rate in the general population) are consistent with simpler genetics.

Gunvant Thaker
Mayada and Debbie, it depends on the endophenotype; if the measure is "elemental," then it is more likely that it's less complex and controlled by a small number of genes. There are physiological measures in cardiology controlled by a single gene.

Mayada Akil
Irv, so let me play devil's advocate here and say, why not find the risk genes for schizophrenia through genome scans first, then focus on understanding their biology and let that lead us to the phenotypes?

Deborah Levy
Why not let the endophenotypes help to clarify the biology?

Carrie Bearden
This is a really valuable point ("complexity" of endophenotypes); as Irv points out in his paper, subgroups based on symptoms, etc., don't really "count" as endophenotypes. Do we need to know more about the genetic architecture of other candidate endophenotypes (e.g., working memory) before going forward with large-scale genetics investigations?

Cameron Carter
Mayada, with regard to the "simple" point, I like to think of behavioral endophenotypes as being microbehaviors, whose measurement can be refined and distinguished from nonspecific, generalized deficits that can result from poor motivation or poor test-taking skills, and that are supported in the brain by more or less discrete circuits whose biological characteristics and molecular architecture may be understood and used to constrain molecular genetic theories of etiology in schizophrenia.

Angus MacDonald
Mayada's comment reflects Michael Owen's comment that endophenotypes may only be useful once we've got associations with schizophrenia to play with. But my heart lies with Irwin's and Wim's point about power.

Deborah Levy
How, then, would you handle the false negative problem?

Mark Lenzenweger
The use of the quantitative phenotype not only can increase power, but in using a quantitative approach (particularly with ratio scale characteristics), one achieves greater precision (not just increased power), and one moves away from "ratings" approaches, such as those that characterize all symptoms assessments.

Mayada Akil
I think the two strategies are not mutually exclusive, by the way.

Angus MacDonald
Additionally, the endophenotype is more amenable to translational (animal) studies (as Patricia pointed out—I believe Moldin addresses this point in Moldin, 1994). Thus, it can be more readily studied with microarrays and knockouts.

Qing Xu
Genetic study of schizophrenia patients cannot identify the direct causal factor(s) that happened transiently during neurogenesis. Therefore, it is crucial to build a network first with those genetically identified genes and relate them to the endophenotypes by the evaluation of animal models.

Irving Gottesman
I suggest that endophenotypes be optimistically as well as logically perceived as relatively less complex than the diseases themselves. Hypertension genes in rats were easier to identify than the other genes involved in coronary disease.

Mayada Akil
Angus, you make an excellent point. The question of gene networks affecting a certain phenotype is important if one is to pursue the biology in knockout mice.

Patricia Estani
Nobody has yet discussed the general and conceptual point of view that the classifications of schizophrenia have failed in that they are so phenomenological. I think that this discussion must be theoretical and conceptual, too.

Irwin Waldman
A point that has not yet been discussed is the use of both the disorder and the endophenotype in molecular genetic studies. We recently have explored this in some of our work, and found stronger associations between childhood ADHD and the dopamine receptor D4 and adrenergic receptor 2A genes in children with ADHD who show deficits on putative endophenotypes related to executive functions.

Deborah Levy
A bivariate phenotype composed of schizophrenia and an endophenotype could be much more powerful than either alone.

Wim Crusio
Irwin, that was actually what I was hinting at before. Endophenotypes may increase the amount of information that we have by being quantitative, by being measured more precisely, or by combining the information from several variables (be they endophenotypes or schizophrenia itself).

Irwin Waldman
I agree, Wim, and they can be even more useful to the extent that they reflect some component of the etiological contribution of a candidate gene that the diagnosis does not itself reflect (or reflects only very imperfectly).

Wim Crusio
Absolutely.

Mayada Akil
Is anyone doing this kind of work in schizophrenia?

Deborah Levy
The Psychology Research Laboratory at McLean Hospital is currently undertaking linkage studies of a bivariate phenotype comprising schizophrenia and each of several endophenotypes (eye tracking dysfunction, thought disorder, and craniofacial dysmorphology).

Angus MacDonald
Got to run. Best to all. Fun new medium for hashing out these issues.

Irving Gottesman
Last few threads—we are in the phase of discovering reasonable endophenotypes by engaging in the various strategies in the citations posted. Cf. Winston Churchill during WWII regarding the end of the beginning but not yet the beginning of the end.

Deborah Levy
Let's hope we get to the middle game.

Patricia Estani
I would like to remark that the endophenotype concept must be used in behavioral research because it can reduce the phenotypical manifestations of the disease and make the research more clear. Thus, in studies of behavior and neuropsychology, the concept can simplify the experimental designs.

Mayada Akil
One other issue I would like to raise for discussion. If the goal is to understand the biology of schizophrenia as opposed to merely identify the genes, don't endophenotypes have a critical role?

Deborah Levy
Absolutely.

Mayada Akil
There is tension now between the use of endophenotypes and large genetic screens using diagnoses (maybe with HapMap). Strategically, it is worth considering: Should we as a field be doing both?

Deborah Levy
They seem to be complementary approaches.

Carrie Bearden
Yes, there are some great examples of that in the area of dyslexia (combining categorical and quantitative phenotypes).

Patricia Estani
What are the examples of dyslexia work?

Carrie Bearden
Patricia, I was thinking of work by Pennington and colleagues looking at various quantitative phenotypes of reading disability (nicely reviewed in Fisher and DeFries, 2002).

Mayada Akil
We have a couple of minutes left. Any last comments, thoughts, or questions are welcome.

Patricia Estani
In behavioral science, not only in the field of research but also in the field of clinical diagnosis, we need to review our concepts in order to create new classifications based on concepts like endophenotypes.

Gunvant Thaker
Regarding large genetic screens, the endophenotypic approach is particularly useful for genes with small effects on a heterogeneous disease.

Deborah Levy
Is it possible that a gene has a large effect on an endophenotype and a smaller effect on schizophrenia?

Mayada Akil
Good question, Deborah.

Irving Gottesman
Yes, to Debbie's last question. To all participants, thank you for your energy and provocations. Although I do not play speed chess, I feel as if I just participated in its equivalent for discussing endophenotypes with a varied audience. Do read the intro and suggested references.

Mayada Akil
Thank you all very much for participating. This was thought-provoking and fun. I see why teenagers are addicted to chat rooms. Those who have not had a chance to, please check out the comments on the site posted before the discussion.

Hakon Heimer
Those who have other engagements, thanks so much for joining in this first experiment.

Annamari Tuulio-Henriksson
I hope this chat will appear soon again; I was too late this time!

Hakon Heimer
Annamari, I think there will be an endophenotypes discussion, Part Deux.

Annamari Tuulio-Henriksson
Great!

Irving Gottesman
Good afternoon, good night, and good luck. See you all at Part Deux.

Mayada Akil
Hakon, will people be able to post comments on the chat later?

Hakon Heimer
Mayada, absolutely; the background text stays up, as do all the comments, and the ability to comment on the text or the transcript.

Mayada Akil
I want to close by thanking Irv Gottesman for his time, expertise, and grace. Also for great background reading.

Patricia Estani
Good night, from Argentina.

Wim Crusio
Thanks to all, greetings from France!

Hakon Heimer
And I want to thank Mayada and Irv for all their time in getting our inaugural chat going. We'll work out any bugs for the next chat.

Mayada Akil
Au revoir.

Irving Gottesman
Thank you, Mayada and Hakon, for letting me be the special child of the day.

Carrie Bearden
This was fun and extremely informative. Thanks, everyone!

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 curious if others have followed up on this report on subsets of schizophrenia and risk: Parental transmission (genetic) is prominent in periodic catatonia cases, while mid-gestation infection is prominent in the systemic catatonia phenotype (Stober et al., 2002). Is the distinction between periodic and systemic catatonia made in the USA? Could differential endophenotypes tell us something about the causes of schizophrenia?

View all comments by Paul PattersonComment by:  Elaine Chaika
Submitted 6 January 2006
Posted 6 January 2006

Gottesman's noting of the importance of eye-tracking dysfunction in schizophrenics seems very on-target to me. In an early paper, "A unified explanation for the diverse structural deviations reported for adult schizophrenics with disrupted speech," (Chaika, 1982), later summarized in my 1990 book Understanding Psychotic Speech: Beyond Freud and Chomsky (Chas. C. Thomas, Springfield, Ill; pp 44-5; 190-1), I showed that the speech syndrome long identified uniquely as schizophrenic, when diagrammed, shows the same pathway deviations that the eye-tracking dysfunction manifests. Both the saccades and spiky type movement (of visual tracking) are analogous to schizophrenic utterances. The saccades show lack of focusing ability, a deficit in tracking. The spiky type movement represents perseverations in associative pathways. It should also be noted that the initial utterances of speech-disordered schizophrenics, such as responses to questions, are usually correct. However, they veer off the track quickly. While these references are old, so far as I can see, the ideas are still pertinent and valid.

View all comments by Elaine ChaikaComment by:  Michael Owen, SRF Advisor
Submitted 6 January 2006
Posted 6 January 2006

Irv Gottesman and colleagues are to be congratulated on their lucid and thoughtful championing of the use of endophenotypes in schizophrenia research. Like many, I agree that this would appear to have massive face validity, given that it is clear that the clinical diagnosis of schizophrenia is syndromic and relies upon the detection and measurement of symptoms and signs that are to a large extent heterophenomenological in nature. However, I believe that there are a number of issues that need to be carefully considered before genetics researchers rush headlong into the widespread use of endophenotypes. To my mind, the most important of these are as follows.

1. How well do currently advocated endophenotypes really satisfy the criteria laid out clearly by Gould and Gottesman? In particular, it is often not clear to the outsider just how state-independent most of the measures proposed really are, with the potential for contamination not just by fluctuations in course and drug treatment, but also by factors such as smoking.

2. How much inter-laboratory variation is there for many of the methods espoused? Are there generally agreed upon protocols for eliciting deficits in potential endophenotypes such as PPI and P50 in schizophrenia? How good is the inter-relater reliability?

3. Is the genetic architecture of endophenotypes really going to be any simpler than that of schizophrenia? Ten years ago there were many people around who seemed to believe that the use of endophenotypes would allow schizophrenia to be decomposed into a set of single-gene deficits. This does not appear to have held up, and I wonder whether it is really likely to. If people are going to consider using endophenotypes in gene-finding studies, then I think the crucial question is as follows: Is the genetic architecture of the relevant endophenotype simpler than that of the genetic architecture of schizophrenia, to a sufficient degree to offset the greater difficulty in collecting large samples?

4. Recent research on electrophysiological endophenotypes (Price et al., 2005) showed minimal correlation among four different endophenotypes (P50, P300, mismatch negativity, and antisaccades). This could reflect genetic heterogeneity, but the authors conclude it is more likely that the four features are stochastic expressions of a latent trait. The researchers then propose that a multivariate endophenotype based on all four might be optimal. This greatly increases the burden of phenotyping on the investigator, and I am not sure whether the increase in power for gene finding studies compared with use of clinical diagnosis is really sufficient (see above).

We need clear answers to the above and probably other questions before we can safely assume that we should be using endophenotypes to find novel genes for psychiatric disorders.

In my view, use of endophenotypes has much greater potential once risk genes, and preferably risk alleles, have been identified. This then allows the investigator to ask very specific questions about the functional consequences of a particular genetic risk factor in terms of altered brain function. We are starting to see a plethora of such studies based on cognitive and imaging endophenotypes, which I think offer an exciting way forward, but only once risk genes have been found. Studies of this kind are not without their problems and some discussion of these would also be helpful. There seem to be differences between laboratories in detailed imaging and cognitive methodology, and one wonders how well studies will replicate, though findings for COMT and prefrontal function seem encouraging. There are also potential concerns relating to multiple testing and these experiments should be based on very specific genetic and functional hypotheses. I know that many researchers are worried about the apparent ease with which positive findings have been obtained for anonymous SNPs in genes where risk alleles have not been clearly implicated.

View all comments by Michael OwenComment by:  Patricia Estani
Submitted 7 January 2006
Posted 7 January 2006

The current and clinical classifications of schizophrenia are completely phenomenological. These classifications are not useful for the research dissection of the variables implicated in the disease. New directions, such as those given by the idea of endophenotypes, must be used in the research of schizophrenia. The concept of endophenotype, as it is defined by Dr. Gottesman, is extremely important (Gottesman and Gould, 2003). The idea of endophenotype is a useful tool to design experimental approaches, not only in the field of animal research, but also in the clinical and genetic research of this disease.

In reply to the comment of Dr. Owen, I think that the concept delimited by Dr. Gottesman is clear and well defined. In this way, many factors, such as smoking, could affect an endophenotype, but a specific endophenotype is not altered by all factors in an easy way. In this sense, the concept is very robust and clear.

References:
Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003 Apr 1;160(4):636-45. Abstract

View all comments by Patricia EstaniComment by:  Deborah Levy
Submitted 8 January 2006
Posted 8 January 2006

I want to follow up on several comments made by Dr. Owen, who wrote, "Is the genetic architecture of the relevant endophenotype simpler than that of the genetic architecture of schizophrenia, to a sufficient degree to offset the greater difficulty in collecting large samples?"

I agree with Dr. Owen that this is a fundamental question. What has made it difficult to provide compelling evidence for the potentially simpler genetic architecture of endophenotypes? One cause is that existing methods to evaluate power (e.g., the elegant work of Risch) apply when a symmetrical ascertainment design is being used (probands are ascertained for having trait x and relatives are examined for recurrence on the same trait). In such a design, power is largely determined by relative risk (the “Risch λ”) (Risch, 1990). It has not been widely appreciated that studies of endophenotypes are based on an asymmetrical ascertainment design—probands are ascertained on the basis of schizophrenia and relatives are evaluated for recurrence on an endophenotype. Relative risk for the endophenotype is not a “Risch λ” and a different method for calculating power is required.

My colleagues, Steven Matthysse and Nancy Mendell, and I have recently developed methods complementary to those of Risch to evaluate power when an asymmetrical ascertainment design is used (Levy et al., 2005). To illustrate the usefulness of these methods, we evaluated power to detect linkage to one endophenotype (e.g., a certain kind of thought disorder). Power to detect linkage to this endophenotype is much higher than power to detect linkage for schizophrenia (and the sample size requirements are more modest by orders of magnitude). The primary reason is that the thought disorder phenotype has such a high recurrence risk in relatives of schizophrenics that using it to identify nonpenetrant gene carriers dramatically reduces the false negative rate. Moreover, power is excellent to detect linkage for a broad range of single gene models with pleiotropic effects (selected on the basis of an unbiased search, not a priori plausibility) that fit the observed data on schizophrenia and thought disorder in siblings of schizophrenics and in the general population. Clearly, every endophenotype needs to be evaluated separately for its suitability using appropriate analytic methods, but these results provide a basis for optimism about the ideas that (a) a locus that is one of several for schizophrenia may also be a major locus for an endophenotype, and (b) incorporating endophenotypes into linkage studies may improve both efficiency (reduce sample size) and precision (reduce false negatives).

Two factors account for the power of the asymmetrical ascertainment design: (a) high recurrence of an endophenotype in relatives, and (b) ascertaining families conditioned on a disease in the probands. The asymmetrical ascertainment strategy capitalizes on the strong coupling between a disease, which has low penetrance, and an endophenotype, which has much higher penetrance. In other words, conditioning on schizophrenia in the proband maximizes selection for a gene that has a higher probability of being detected through its effect on an endophenotype than through its effect on schizophrenia. The presence of schizophrenia in the proband thus selects for genes for the endophenotype in relatives, and allele sharing for a closely linked marker would increase the rate of the endophenotype in first-degree relatives. The same principles provide a rationale for the success of linkage studies of nonpsychiatric complex disorders using endophenotypes (e.g., long QT cardiac syndrome, juvenile myoclonic epilepsy) (Greenberg et al., 2000; Keating et al., 1991) and for the promising findings of linkage studies of schizophrenia endophenotypes [e.g., Freedman et al., 1997 (P50); Arolt et al., 1996; Arolt et al., 1999; Holzman et al., 1988 (eye tracking dysfunction); Freedman et al., 1997; Matthysse et al., 2004].

Dr. Owen also wrote, "In my view, use of endophenotypes has much greater potential once risk genes, and preferably risk alleles, have been identified. This then allows the investigator to ask very specific questions about the functional consequences of a particular genetic risk factor in terms of altered brain function."

I agree that it is important to capitalize on the existence of positive findings by determining whether an endophenotype is linked to one or more of the genes and/or chromosomal regions that have been provisionally linked to schizophrenia. Such a demonstration would help to clarify the biological interpretations of linkages already reported in the literature, be strong confirmation of the linkage to schizophrenia, and support the interpretation that clinically unaffected family members with the endophenotype were nonpenetrant carriers of the same gene that contributed to risk for schizophrenia. Such an effort would have to be carried out selectively, however, because many of the reported linkages are likely to be false positives.

In 1988, Eric Lander pointed out: "Good genetics requires good phenotypes. Instead of concentrating solely on mapping schizophrenia per se, it may be fruitful to map the genetic basis for atypical biochemical or physiological responses found in some schizophrenics. Such traits ... may be more penetrant phenotypes of a schizophrenia susceptibility allele (that is, they may be present in relatives unaffected with schizophrenia); ... and, they should be easier to map ... one should search for traits that are enriched among schizophrenics and then test to see whether they also occur frequently in their relatives." It seems to me that it is also important to capitalize on the fact that a gene can have higher probability of being detected through its effect on an endophenotype than through its effect on schizophrenia (see above). The work of Freedman and colleagues on P50 is an excellent example. Strong linkage was detected for a locus on 15q14 and P50 inhibition, but the evidence for linkage to schizophrenia was much weaker (Freedman et al., 1997). The problem with conditioning linkage studies of endophenotypes on the results of linkage studies of schizophrenia is that the latter have a high false negative rate.

References:
Arolt V, Lencer R, Nolte A, Muller-Myhsok B, Purmann S, Schurmann M, Leutelt J, Pinnow M, Schwinger E. Eye tracking dysfunction is a putative phenotypic susceptibility marker of schizophrenia and maps to a locus on chromosome 6p in families with multiple occurrence of the disease. Am J Med Genet. 1996 Nov 22;67(6):564-79. Abstract

Arolt V, Lencer R, Purmann S, Schurmann M, Muller-Myhsok B, Krecker K, Schwinger E. Testing for linkage of eye tracking dysfunction and schizophrenia to markers on chromosomes 6, 8, 9, 20, and 22 in families multiply affected with schizophrenia. Am J Med Genet. 1999 Dec 15;88(6):603-6. No abstract available. 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

Greenberg DA, Durner M, Keddache M, Shinnar S, Resor SR, Moshe SL, Rosenbaum D, Cohen J, Harden C, Kang H, Wallace S, Luciano D, Ballaban-Gil K, Tomasini L, Zhou G, Klotz I, Dicker E. Reproducibility and complications in gene searches: linkage on chromosome 6, heterogeneity, association, and maternal inheritance in juvenile myoclonic epilepsy. Am J Hum Genet. 2000 Feb;66(2):508-16. Abstract

Holzman PS, Kringlen E, Matthysse S, Flanagan SD, Lipton RB, Cramer G, Levin S, Lange K, Levy DL. A single dominant gene can account for eye tracking dysfunctions and schizophrenia in offspring of discordant twins. Arch Gen Psychiatry. 1988 Jul;45(7):641-7. Abstract

Keating M, Atkinson D, Dunn C, Timothy K, Vincent GM, Leppert M. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science. 1991 May 3;252(5006):704-6. Abstract

Lander ES. Splitting schizophrenia. Nature. 1988 Nov 10;336(6195):105-6. No abstract available. Abstract

Levy DL, Ji F, Krastoshevsky O, Harte CB, Holzman PS, Mendell NR, and Matthysse S. The power of asymmetric ascertainment in linkage analysis. Schiz Bull, 2005;31: 271. (Full report in preparation).

Matthysse S, Holzman PS, Gusella JF, Levy DL, Harte CB, Jorgensen A, Moller L, Parnas J. Linkage of eye movement dysfunction to chromosome 6p in schizophrenia: additional evidence. Am J Med Genet B Neuropsychiatr Genet. 2004 Jul 1;128(1):30-6. Abstract

Risch N. Linkage strategies for genetically complex traits. II. The power of affected relative pairs. Am J Hum Genet. 1990 Feb;46(2):229-41. Abstract

View all comments by Deborah LevyComment by:  Edward Scolnick
Submitted 8 January 2006
Posted 8 January 2006

I suggest anyone participating in this discussion read Chapter 12 of Genetics in Medicine by Nussbaum et al. I suggest they learn about Hutchinson Gilford progeria, San Fillippo syndrome, Hurler's and Scheie syndrome, and the work of Lifton in a metabolic syndrome in which all family memebrs have the identical mutation in a tranfer RNA with meager overlap in the members for the constellation of the symptoms and signs of the syndrome. Is the right strategy more detailed endophenotyping now? Or much larger samples with already available defintions and more detailed endophenotyping once real risk genes have been discovered?

References:
Nussbaum RL. McInnes RR, Willard HF. Thompson & Thompson Genetics in Medicine. 6th ed. Philadelphia: Saunders, 2004. ISBN: 0721602444

View all comments by Edward ScolnickComment by:  Daniel Weinberger, SRF Advisor
Submitted 9 January 2006
Posted 9 January 2006

If we accept that schizophrenia genes, or for that matter any genes for psychiatric disorders, do not encode for hallucination and delusions, or thought disorder, or panic attack, or the like, then it is hard to escape the conclusion that biologic traits related to the emergence of these behavioral phenomena will show greater penetrance of gene effects, that is, greater effect sizes, than will the behavioral phenomena. In my view, this is of even greater relevance when the genetic defects do not result in truncated or dysfunctional proteins, but likely in variation in gene regulation at critical times of development. Many individuals will harbor risk haplotypes in candidate genes and not show the behavioral associations. If we had the intermediate phenotypes related to the risk haplotypes robustly characterized, we would not need such huge samples to show clinical association to meaningful behavioral syndromes.

I think a clear example of this is the data that have emerged with the 5'HTTLPR variant and mood and temperament. Effects of this variant on function (and likely development) of a limbic circuit involved in regulation of negative affect have shown strong predictions of anxious temperament, much stronger than associations to genotype (Pezawas et al., 2005).

View all comments by Daniel WeinbergerComment by:  Margit Burmeister
Submitted 9 January 2006
Posted 9 January 2006

Regarding Mike Owen's point: "I think the crucial question is as follows: Is the genetic architecture of the relevant endophenotype simpler than that of the genetic architecture of schizophrenia, to a sufficient degree to offset the greater difficulty in collecting large samples?"

That isn't quite the point. There are two advantages with most endophenotypes:

1. They are usually quantitative, and if we believe that most of the genes change things quantitatively, incrementally, it is better to use a quantitative trait than a dichotomous diagnosis—there are quantitations of that advantage (e.g., Allison et al., 1998)—even if the heritability and complexity of the phenotype was the same as of the disorder.

2. For some endophenotypes (e.g., neuroticism), it is easier to collect samples, in part because one can measure them in a population sample—it is possible to measure N in 10,000 people, and some have done that; it is much easier than finding 5,000 depressed people and 5,000 ethnically, economically, etc., matched controls. This latter point may be the biggest issue with case-control studies.

I certainly would argue that we need to think of which endophenotype; if we look at imaging, Danny states that in some cases it may really be closer to the underlying cause, and thus effect sizes become larger. But we can't image 10,000 people. On the other hand, there are endophenotypes like neuroticism that can be administered large-scale. It seems that expensive endophenotypes like imaging have their place in determining how a genetic variant has its effect on behavior, but, due to the small numbers, are unlikely to be the mechanism to identify such genetic variants in the first place.

Cheap, larger-scale, quantitative traits like neuroticism are suitable to find new variants, but have to be tested against the disorder—not all variants associated with neuroticism will be relevant for anxiety disorders or depression, and not all executive function/cognitive associated variants will be relevant for schizophrenia.

Last, I want to comment on selection. Some groups (Flint and colleagues, mainly) have recently performed large studies with highly selected samples, picking the top 2 percent discordant or concordant siblings or the top 2-5 percent of extreme, and have not replicated any findings, not even those confirmed in many meta-analyses. Genes that act at the very extreme of a distribution are often different from those acting overall on the "garden variety" trait. For example, ApoE affects cardiovascular (CV) risk, but a very small group of subjects with early onset CV disorder has mutations in the LDL receptor—selecting for extremes may eliminate the ApoE effect on the bulk, and I think that is what happened in those studies.

References:
Allison DB, Heo M, Schork NJ, Wong SL, Elston RC (1998) Extreme selection strategies in gene mapping studies of oligogenic quantitative traits do not always increase power. Hum Hered 48:97-107. Abstract

View all comments by Margit BurmeisterComment 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 1 a.m. Wednesday morning our time. A few points from our discussions over the last few years in Steve Faraone's NIMH ADHD group and Joe Sergeant's European ADHD group which I think apply to all endophenotypes.

1. There have been very few studies of the heritabilities of endophenotypes, and those show less genetic variation than for the actual disorders. While it may seem these are closer to the genes, a key point in the Hsieh paper is that these methods are quite equipment-specific. In fact, when we met about a common set of endophenotype techniques for ADHD, we all felt our "own" set-up was the way to go, and even though there was some agreement on what to measure, there was much less on how to measure it.

2. Even less clear is the evidence on bivariate heritability of endophenotypes with the disorder. Certainly in ADHD, the one example we have is one of the measures used by Jonna Kuntsi and Jim Stevenson. This raises another question about whether these endophenotypes really are across the whole population (in which case twin studies as used by Jonna are appropriate) or are more specific to the disorder (in which case, affected families are the way to go).

3. Endophenotypes may not be specific to the disorder and are shared across many different conditions from ADHD to autism to schizophrenia. So it may be a vulnerability to a whole range of psychopathologies that is reflected in an endophenotype.

4. One ultimate aim of having endophenotypes may be to identify children at risk. A real problem is that we have very little normative data on what children are like at different ages on these measures—we simply do not know what is the "normal" range, and establishing that would take enormous effort. In addition, would anyone fund it?

Sorry to sound so negative, but I remain to be convinced that simply following endophenotypes is going to clarify rather than muddy the waters. That is not to say they may not be useful, but perhaps in more constructive ways. The paper three or so years ago by Assen Jablensky's group here in Western Australia (Hallmayer et al., 2002) that used fuzzy set analysis to distinguish groups of families with schizophrenia and showed linkage peaks specific to particular groups seems a much more useful path than simply to say, "Here is an endophenotype for schizophrenia." Recognizing endophenotypes for the schizophrenias may be the way to go.

Best wishes
David

References:
Stevenson J, Asherson P, Hay D, Levy F, Swanson J, Thapar A, Willcutt E. Characterizing the ADHD phenotype for genetic studies. Dev Sci. 2005 Mar;8(2):115-21. Review. Abstract

View all comments by David A. HayComment by:  Irwin Waldman
Submitted 10 January 2006
Posted 10 January 2006

It is worth noting that several researchers have systematized and extended the criteria enumerated by Gottesman and Gould and others (e.g., Almasy and Blangero, 2001; Castellanos and Tannock, 2002; Cornblatt and Malhotra, 2001; Doyle et al., 2005; Waldman, 2005; Waldman et al., in press) in such a way that they can be used to evaluate the validity and utility of putative endophenotypes for molecular genetic studies. Criteria for the validity of endophenotypes include its relation to the disorder in the population and within families, its expression in probands’ unaffected relatives, its heritability and common genetic influences with the disorder, and to a lesser extent, its psychometric properties. Criteria for the utility of endophenotypes in molecular genetic studies include its association with candidate genes that underlie the disorder, and its mediation and moderation of association between the candidate gene and the disorder (see Waldman, 2005 and Waldman et al., in press, for fuller descriptions and examples).

Such criteria have recently seen application beyond the domain of adult schizophrenia and affective disorders to include childhood ADHD and executive function measures as putative endophenotypes (Doyle et al., 2005; Waldman, 2005; Waldman et al., in press). In brief, this work may represent an encouraging first step in the use of putative endophenotypes in molecular genetic research on childhood ADHD and other psychiatric disorders, given findings that suggest several executive function measures as valid and useful endophenotypes for ADHD.

References:
Almasy L, Blangero J. Endophenotypes as quantitative risk factors for psychiatric disease: rationale and study design. Am J Med Genet. 2001 Jan 8;105(1):42-4. Abstract

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

Cornblatt BA, Malhotra AK. Impaired attention as an endophenotype for molecular genetic studies of schizophrenia. Am J Med Genet. 2001 Jan 8;105(1):11-5. Abstract

Doyle AE, Faraone SV, Seidman LJ, Willcutt EG, Nigg JT, Waldman ID, Pennington BF, Peart J, Biederman J. Are endophenotypes based on measures of executive functions useful for molecular genetic studies of ADHD? J Child Psychol Psychiatry. 2005 Jul;46(7):774-803. Review. 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

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

Waldman, I.D., Nigg, J.T., Gizer, I.R., Park, L., Rappley, M., and Friderici, K. (in press). The Adrenergic Receptor 2alpha Gene (ADRA2alpha) and Neuropsychological Executive Functions as Putative Endophenotypes for Childhood ADHD. Cognitive, Affective, and Behavioral Neuroscience.

View all comments by Irwin WaldmanComment by:  Kurt Salzinger
Submitted 13 January 2006
Posted 14 January 2006

I was delighted to read the two Gottesman and Gould articles on endophenotypes because of the behavioral mechanism that I have posited for a number of years (Salzinger and Feldman, 1966; Salzinger, 1984; Salzinger and Serper, 2004). The behavioral mechanism is the Immediacy Mechanism. It states basically that the behavior of schizophrenia patients is largely controlled by stimuli immediate in the patient's environment. In the reviews cited above, many areas of schizophrenic functioning lent themselves to such an interpretation. Thus, a deficit in working memory could be explained in terms of the patient's inability to respond to stimuli (old words or numbers) not in their immediate environment. The Continuous Performance Test has shown that when schizophrenia patients are given the task of responding to stimulus X only when preceded by the stimulus A, as the interval between A and X increases, the performance deteriorates precipitously for schizophrenia patients, compared to normal or other psychotic patients. We have also been able to show that their tangential speech could be explained in their inability to respond to remote response-produced stimuli of thoughts they had expressed earlier in their preceding utterances. Many other examples of preponderant responding to immediate stimuli are to be found in the cited papers.

Finally, I would like to mention that the posited mechanism in referring to the temporal position of stimuli in the environment makes it relatively easy to test in animals and therefore exactly of a form desirable for an endophenotype.

References:
Salzinger, K., Portnoy, S., Feldman, R.S. (1966). Verbal behavior in schizophrenics and some comments toward a theory of schizophrenia. In P. Hoch & J. Zubin (Eds.) Psychopathology of schizophrenia. New York: Grune & Stratton.

Salzinger, K. (1984). The immediacy hypothesis in a theory of schizophrenia. In W.D. Spaulding, & J. K. Cole (Eds.) Nebraska Symposium on motivation: Theories of schizophrenia and psychosis. Lincoln, Nebraska: University of Nebraska Press.

Salzinger, K. and Serper, M. (2004). Schizophrenia: The Immediacy Mechanism. International Journal of Psychology and Psychological Therapy, 4, 397–409.

View all comments by Kurt SalzingerComment by:  Ritushree Kukreti
Submitted 30 January 2006
Posted 30 January 2006

The multifactorial etiology of schizophrenia makes it a complex interaction of symptoms. A network model of the interaction/crosstalk between the neurotransmitter signaling systems is presented in our recent paper (Gupta et al., 2006) to emphasize the importance of the genes in the molecular mechanisms of the disease and drug response. These genes may serve as potential susceptibility genes and drug targets for schizophrenia. The crucial point for the identification of a significant biological marker(s) includes the experimental validation of the genes involved in the neurotransmitter signaling systems, and coupling of our knowledge of genetic polymorphisms with clinical response data (endophenotypes) promises a bright future for rapid advances in personalized medicine.

References:
Gupta S, Jain S, Brahmachari SK, Kukreti R. Pharmacogenomics: a path to predictive medicine for schizophrenia. Pharmacogenomics. 2006 Jan ; 7(1):31-47. Abstract

View all comments by Ritushree Kukreti