Schizophrenia Research Forum - A Catalyst for Creative Thinking
Home Profile Membership/Get Newsletter Log In Contact Us
 For Patients & Families
What's New
Recent Updates
SRF Papers
Current Papers
Search All Papers
Search Comments
News
Research News
Conference News
Plain English
Forums
Current Hypotheses
Idea Lab
Online Discussions
Virtual Conferences
Interviews
Resources
What We Know
SchizophreniaGene
Animal Models
Drugs in Trials
Research Tools
Grants
Jobs
Conferences
Journals
Community Calendar
General Information
Community
Member Directory
Researcher Profiles
Institutes and Labs
About the Site
Mission
History
SRF Team
Advisory Board
Support Us
How to Cite
Fan (E)Mail
The Schizophrenia Research Forum web site is sponsored by the Brain and Behavior Research Foundation and was created with funding from the U.S. National Institute of Mental Health.
Live Discussion Transcript


Posted 23 February 2006

E-mail discussion
Printable version

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

Return to Discussion Text

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!

SRF News
SRF Comments
Text Size
Reset Text Size
Share/Bookmark
New Schizophrenia Fact Sheet for Patients and Families

Latest BBRF Research Breakthroughs

Visit our Facebook page and our Blog.

Support the Brain & Behavior Research Foundation Today.

Research Participants
Collaborators
Copyright © 2005- 2014 Schizophrenia Research Forum Privacy Policy Disclaimer Disclosure Copyright