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Live Discussion Transcript


Posted 12 March 2008

E-mail discussion
Printable version

Live Discussion: Gene Expression Profiling of Postmortem Human Brain

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Attendees/Participants

Tony Altar
Simge Aykan, Radboud University Netherlands
Jesper Brohede, Karolinska Intitutet, Sweden
Murray Cairns, Schizophrenia Research Institute, Sydney
Vibeke Catts, Brisbane, Australia
Doug Frost, University of Maryland
Carla Gallo, Universidad Cayetano Heredia, Lima, Peru
Sharon Graw, University of Colorado
Paul Harrison, University of Oxford
Vahram Haroutunian, Bronx VA Medical Center
Andreas Jeromin, Allen Institute for Brain Science, Seattle, WA
Tadafumi Kato, RIKEN Brain Science Institute
Joel E. Kleinman, NIMH
Tim Klempan, Douglas Hospital, Montreal
Barbara Lipska, NIMH
Christine Miller, Johns Hopkins University
Karoly Mirnics, Vanderbilt University
Paul Pavlidis, University of British Columbia in Vancouver
Silvana Sessarego, Universidad Peruana Cayetano Heredia, Lima, Peru
Akira Sawa, Johns Hopkins University
Cyndi Shannon Weickert, Schizophrenia Research Ins., University of New South Wales and POWMRI in Sydney Australia
Elaine Shen, Allen Institute for Brain Science
Sinthuja Sivagnanasundaram, Schizophrenia Research Laboratory, Australia
Beth Thomas, The Scripps Research Institute
Peter Thompson, University of Texas Health Science Center San Antonio
Hiroaki Tomita, Tohoku University
Mark Vawter, University of California, Irvine

Note: The transcript has been edited for clarity and accuracy.


Hakon Heimer
I'd like to introduce Akira Sawa of Johns Hopkins University and Mark Vawter of the University of California, Irvine, and I thank them for bringing us this idea and for their work to prepare the discussion.

Akira Sawa
Oh, so many people...wonderful! Hello and thanks for coming. We would like to structure this discussion into 20-minute segments. First, Mark will lead the session focusing on the importance of a gene expression profile database from control brains in which various confounding factors, such as PMI, and analytical methods will be discussed. In the second 20 minutes, I will lead the question of how neurodevelopmental disturbances underlying the pathology of schizophrenia can be studied in postmortem brains. We may need to discuss gene expression through development and aging. We may also need to discuss alternative approaches that can be combined with studies with postmortem brains. For the last 20 minutes, we wish to hear your opinions of which topics we need to discuss today. Do you have any ideas?

Mark Vawter
We can get started with ideas on controlling for gene expression confounds. We would like to discuss developing a database for postmortem gene expression using control subjects from different brain banks. (This addresses comments for ways to control artifacts and analysis; learn which genes are different due to confounds such as age, gender, PMI, pH, RNA quality. etc.) Our first question is, How does one evaluate gene expression confounds that occur in postmortem brain?

Karoly Mirnics
1) Clinical history, 2) pH, 3) 3'5' integrity, 4) yield/block would be pretty logical. Can we come up with something else that is reasonably objective?

Joel Kleinman/Barbara Lipska
Get large Ns and as much information as humanly possible!

Mark Vawter
Joel/Barbara, yes, “humanly” possible.

Paul Harrison
As always, Karoly's suggestions are spot on, as are Joel/Barbara's: we know basically which are the main factors (e.g., pH/RIN; see my comments on website), and now we have big enough brain series to finally nail the matter statistically. Of course, how we choose to interpret the results won't be so easy!

Elizabeth Thomas
Adding to Karoly's list: antipsychotic drug exposure.

Karoly Mirnics
Beth, do you mean tissue levels of antipsychotics or just history?

Elizabeth Thomas
Karoly, if tissue levels are available, that would be great. Questions: what do we think of recorded history? Do we believe them?

Vahram Haroutunian
Depends on the history. If history is derived from real medical or hospital records then okay; if it comes from self or informant reports, then not so good.

Christine Miller
Agreeing that pH can have (likely an indirect) effect on microarray output, and should be included in all analyses for confounding effect. What is your view about using results from low pH samples for transcripts that are resistant to pH, as long as the pHs are matched cases and controls?

Joel Kleinman/Barbara Lipska
No matching for pH is recommended for reasons that we have posted (see posted comments).

Paul Harrison
Christine, absolutely. If pH (or any other factor) doesn't happen to affect the transcript (or other variable) concerned, it seems unnecessary to omit the data.

Karoly Mirnics
To Christine Miller, no matching can replace quality samples—GIGO (garbage in, garbage out).

Elizabeth Thomas
Is there any evidence that pH changes with aging? Joel's comment had suggested this....

Paul Harrison
Beth, some studies find weak inverse correlations of pH with age. I guess it's probably mainly because old people more often die prolonged (agonal, hypoxic/ischemic) deaths.

Joel Kleinman/Barbara Lipska
Yes, age matters for pH and for gene expression. By the way, we are about to make public expression data from >200 subjects across life span from DLPFC (normals), including cause of death, PMI, RIN, age, etc. You will be able to judge for yourself.

Sinthuja Sivagnanasundaram
Elizabeth, have a look at Rae et al., 2003—pH and aging.

Sherry Leonard
What about cause of death? Has anyone looked at correlation with pH or gene expression profiles?

Mark Vawter
Sherry, we have done that for rapid vs. non-rapid death, and it certainly gives different profiles. But we don't have sufficient N for each cause of death.

Joel Kleinman/Barbara Lipska
Sherry, you will be able to use our database to look at this.

Vahram Haroutunian
Sherry, cause of death vis-à-vis agonal state is clearly one of the most critical variables affecting RNA integrity. There are a bunch of data on this (Stan et al., 2006; Johnston et al., 1997; Harrison et al., 1995).

Paul Harrison
Sherry, we found weak effects of mode of death (rated on a four-point scale of suddenness) with pH, admittedly on a small sample by current standards, but not predictive enough in our view to be of great value. It needs looking at properly, though.

Cyndi Shannon Weickert
Mark, are you talking about evaluating confounds beyond the typical ways of "matching," statistical regression, covariance, etc.?

Mark Vawter
Cyndi, the statistical analysis methods of a large database is open for discussion, but first having critical information in a large database to analyze would be a great first step.

Joel Kleinman/Barbara Lipska
First, I (Joel) have big problems with "matching"! We really have too little information to be able to match. This is why it is important to get individual data and not "matched pair" data.

Vahram Haroutunian
I agree with Joel regarding matching as a general approach. I think it is too easy for us to think that we know all of the relevant variables for matching.

Mark Vawter
Barbara/Joel, okay, if not matching, then putting a large number of controls unmatched so we can evaluate the things Paul Harrison referred to that we agree matter.

Karoly Mirnics
Joel, no matching for pH may have a rationale, but there must be some limit to what we are willing to accept, especially if the other parameters start looking bad.

Cyndi Shannon Weickert
I agree with Joel and Barbara that there is no way to match people on every possible variable, but matching for things that we know impact RNA, like pH and age, does not seem like a bad place to start to me, especially if one does not solely depend on matched pair statistics to interpret the data. In other words, the reasoning that since we cannot match them on everything means that we should not attempt to match the groups on anything does not make that much sense to me.

Mark Vawter
Karoly, there were multiple questions regarding the variables you mentioned earlier, and some had suggested that controls could be put together into a large database to establish some ways to analyze for these variables.

Karoly Mirnics
All, I would like to discuss a creation of a standard series of some 50+50 male female control brains by decade of life, and we would distribute this to everyone as a reference?

Vahram Haroutunian
Mark, given the lack of consensus or practice in how "controlness" is defined, I don't think that this is a great idea, unless the database becomes so huge that differences are washed out.

Cyndi Shannon Weickert
Karoly, if the database of 50 males and 50 females across the decades of life is created, should it be created fresh? And if so, what platform should be used?

Karoly Mirnics
Cindi, yes, I would do it from scratch, with the Exon 1 Affymetrix arrays.

Paul Pavlidis
Hi, in response to the idea about building a database: my group does bioinformatics, and we're working on tools that are designed to facilitate coordinated analysis across labs. Our system is called Gemma. The way it would work is a data sharing consortium would be created in Gemma allowing secure access to consortium members. Participating groups would submit their data from control samples along with the various parameters (age, drug status, etc). The data can then be jointly analyzed in various ways. I would love to hear how people react to the idea.

Mark Vawter
Paul, okay, great news for topic 1, control database. Don't we have enough microarray chips done on control to send these to a central database?

Paul Pavlidis
Right, the idea is to use what people already have on hand.

Mark Vawter
Harry, Joel, Paul, Karoly, Sherry, and others, couldn't we pool data such as Paul Pavlidis suggests?

Joel Kleinman/Barbara Lipska
Mark, how do you pool data from different platforms??

Mark Vawter
Joel, good question; it is not a trivial exercise. Cross-platform data could agree on large effects with large N.

Karoly Mirnics
Mark, the problem of the data across sites is a huge issue; you have experienced this across the three Pritzker sites.

Mark Vawter
Karoly, yes, three sites is a huge variable. The Stanley dataset also had 9-11 sites. The meta-analysis showed greater strength than the individual studies.

Paul Pavlidis
Joel, we use the sequences of the probes to match them across data sets. It is true that when there is "disagreement," this can be a cause. But this can be addressed (in part) using the sequences. And I do not advocate actually combining the data sets, rather, comparing the results.

Elizabeth Thomas
Is the goal of these "control" database(s) to have a standard reference for comparing samples to those from schizophrenics?

Paul Pavlidis
Elizabeth, I think the idea we have right now is simply to address confounds. Is there a common "pH signature," for example?

Mark Vawter
Paul Pavlidis, I would suggest that to start the database, you could use the SMRI controls; there are 12 microarray experiments on about 50 controls. The Harvard brain bank also has public data, and GEO is a source of control brain expression. Our group put in 100 cel files awhile back. Pritzker consortium also dropped in 1,200 cel files to GEO.

Paul Pavlidis
Mark, yes, we have actually loaded all of the available Harvard and GEO data. And we will be downloading the SMRI data “any day now.” So we can indeed begin.

Vahram Haroutunian
Mark, my concern with pooling data from multiple sources is that although the groups all have good internally consistent criteria for cases and controls, I am not convinced that these criteria are externally consistent.

Paul Harrison
For pooling across sites, I think a key step would be QC to check comparability of measures between labs; e.g., send chunks of the same brain to different labs for assessment of yield/RIN/housekeeping genes, etc.

Sherry Leonard
For any pooled database, we could certainly provide information on smoking effects on gene expression. Data on effects of neuroleptics would also be needed.

Christine Miller
Another consideration in combining sites is the differences in SNP frequency (stratification), which obviously have gene expression implications that can be seen within the (admittedly small) Stanley collection based on geographic location of the samples collected.

Elaine Shen
Question regarding the databases and samples: how do you control for anatomic region across samples, experiments, laboratories?

Cyndi Shannon Weickert
Elaine, one way to begin to approach consistency in dissections across laboratories would be to provide a map and a photograph of the brain blocks before and after dissection.

Karoly Mirnics
Paul P, probe regions may mean different splice variants.

Joel Kleinman/Barbara Lipska
To all, it occurred to us during analyses of our expression data from microarrays that we also need to think about multiple transcript issue; one transcript may be affected in a very different way (by age, etc.) than other transcripts.

Paul Pavlidis
Karoly, we can track how each probe maps to known transcripts. This is indeed complicated by unknown transcript variety abundance, and also that there can be unknown transcripts.

Karoly Mirnics
Paul P, you may not have enough bioinformatics information to know the real alternate splicing that occurs in the tissue.

Paul Pavlidis
Karoly, yes, this is what I meant by “unknown transcripts”: there are unknowns. This means that disagreements among data sets could be difficult to address. But I think we can accomplish a good deal.

Karoly Mirnics
Paul, Mark, I am still worried about the patchwork of lumping all together. Previous experience shows that it does not work the best.

Paul Harrison
Karoly, I agree: unknown and uncharacterized splice variants (including multiple promoter usage and brain-specific isoforms) are a major issue.

Mark Vawter
Karoly, Paul H., with the sequence for each probe known on the commercial platforms, I think it would be possible to determine which part of the gene is interrogated. We won't know the splice variants unless we specifically try to measure each one. Is there an array that will do this?

Paul Pavlidis
Karoly, just one more comment. I don't advocate lumping the data together, but facilitating comparisons and meta-analyses can be done without that.

Karoly Mirnics
Paul P., you will still be limited with the small power of each data set (e.g., we are still screwed. ;-( )

Paul Pavlidis
Karoly, the reason to push for a meta-analysis is precisely to address the weakness of any individual data set.

Vahram Haroutunian
Agree with Karoly and Paul P. on both sets of last comments. Comparison of different control groups, especially with known demographics such as race, sex, and age would be very informative. Yes, I think the ideas here need to be flushed out much more.

Paul Pavlidis
Karoly, I agree that it would be ideal to have a single gigantic control data set, but even then “independent” confirmation by smaller studies would be beneficial. Anyway, I agree we need to discuss this more elsewhere.

Akira Sawa
Dear all, it sounds like we have substantial consensus in the need to build a control brain database in which many confounding factors are addressed. Regarding each factor, it seems we still have debates (it would be exciting to spend another 2-3 hours, but we have only 35 minutes left). Mark, how about summarizing the discussion of these topics into what kind of common control database may be possibly built?

Joel Kleinman/Barbara Lipska
I am not sure that we really have any consensus on building the control database. Before anyone can reach any consensus there has to be a well-defined question.

Mark Vawter
Joel, yes, it may need some time to develop, given the feedback here today.

Karoly Mirnics
Organizers, this is a good first meeting, but we will need more time on each of these topics if we are to arrive somewhere. Would it make sense to have a follow-up, with a bunch of concrete suggestions on how to do it, and then move toward specifics?

Sherry Leonard
Could we have a meeting at Biological Psychiatry?

Joel Kleinman/Barbara Lipska
Sherry, yes, we should.

Mark Vawter
Sherry, yes a meeting in person at SOBP.

Cyndi Shannon Weickert
I would like to meet face-to-face at SOBP; it beats getting up at 4 a.m.!

Mark Vawter
Paul Pavlidis, thanks for the suggestion. I hope you can join us at SOBP.

Paul Pavlidis
Just checked my calendar: looks good. :)

Joel Kleinman/Barbara Lipska
Barbara and I are going to release our database in a user-friendly format. I don't know what else you want us to say or do.

Karoly Mirnics
Joel, we are salivating.

Joel Kleinman/Barbara Lipska
Karoly, hungry?

Karoly Mirnics
YUUUUUUUUPPPPP. Yummmy data!

Akira Sawa
Joel and Barbara, great! Thank you!

Mark Vawter
Joel/Barbara, thanks much.

Akira Sawa
Dear all, the first half has been very productive in exchanging our ideas on this important topic openly. This is just an important start, not to get a superficial conclusion now. How about moving to the next topic? In the second 20 minutes, I will lead the discussion of how neurodevelopmental disturbances underlying the pathology of schizophrenia can be studied in postmortem brains. We may need to discuss gene expression through development and aging. We may also need to discuss alternative approaches that can be combined with studies with postmortem brains.

Mark Vawter
Paul P., when Joel/Barbara’s data are available, that will be a tremendous resource, but Joel, please tell us more.

Akira Sawa
Joel and Barbara, as far as I know, your group has obtained very interesting expression data on genetic susceptibility factors for schizophrenia during development and aging?

Joel Kleinman/Barbara Lipska
Akira, developmental expression data are important and they will be accompanied by extensive genotyping data.

Mark Vawter
Joel, what data would you make available?

Joel Kleinman/Barbara Lipska
Barbara won't let me type anymore today. From Barbara now: just wait a few more weeks/months.

Sherry Leonard
Joel/Barbara, will you have cause of death expression data, not just agonal state rank?

Joel Kleinman/Barbara Lipska
Sherry, yes, all detailed information.

Tadafumi Kato
Akira, we don't know the exact brain region causative for schizophrenia and bipolar. How can we identify the region to examine? Most of the data in the Stanley database deal with frontal cortex. However, is it the crucial region? I think it is impossible to find the region by postmortem brain studies only.

Karoly Mirnics
Akira, Kato, I strongly believe that SCH and BP are systemic brain disorders, and we will find some different and some similar disturbances across virtually all brain regions in schizophrenia.

Joel Kleinman/Barbara Lipska
Our focus has been DLPFC. We will do hippocampus next for all of our normals and 200 patients with schizophrenia, bipolar disorder, and MDD.

Cyndi Shannon Weickert
I think that there is now ample evidence to suggest that the molecular pathology in schizophrenia may be cortex-wide; that gives us many regions of the brain to examine. Should there be a focus beyond DLPFC?

Sherry Leonard
Cyndi, I feel that the hippocampus needs more study in schizophrenia, perhaps as subregions.

Cyndi Shannon Weickert
One thing that is important to understanding how schizophrenia develops—beyond just looking at how individual SNPs or haplotypes impact brain development—is to build a mechanistic understanding of the risk genes so that genetic polymorphisms that may impact development of the normal human brain can be grouped more conceptually. Also, I would like to point out that other groups have microarray gene expression across human brain development and that Maree Webster and I had a poster at Davos in 2006 on the gene expression changes in the lead genetic candidates. Of the 13 genes examined, only dysbindin and RGS4 show a protracted increase in expression during development and take a decade to reach adult levels. The majority of schizophrenia susceptibility genes show a decrease in expression with increasing age. The high expression of these genes in the first postnatal year suggests that they may be playing a prominent role in brain development. We hope to make this data public as well.

Mark Vawter
Joel/Barbara, aren't you working on SNPs vs. gene expression vs. development?

Joel Kleinman/Barbara Lipska
Mark, yes.

Vahram Haroutunian
I have not been able to clearly identify for myself how gene expression data during development should/can be interpreted in the context of changing numbers, sizes, and types of neurons, glia, etc. Do we know what the relevant expression denominators are? Are conventional denominators used in arrays applicable to brains that are undergoing such huge changes, especially during the first couple of decades, let alone fetal tissue?

Mark Vawter
Harry, what about looking for genes that are turned on or off during development?

Joel Kleinman/Barbara Lipska
Harry, We agree that relative to what age group or standard is an issue. We have created a standard reference with multiple brain regions and ages to compare and contrast any individual sample.

Akira Sawa
Harry, if we are interested in information on cell types, laser-captured microdissection (LCM) may be useful, which we frequently use to address this question. Do you agree with me?

Vahram Haroutunian
Akira, yes, I agree about LCM, but it is still a question for me whether "housekeeping" genes in an adult neuron are "housekeeping" in the same way in fetal. We know that this is not the case for many genes.

Joel Kleinman/Barbara Lipska
Harry, we do not use housekeeping genes for comparing in our developmental array studies.

Paul Harrison
Having Joel/Barbara's goldmine of developmental data will be great; it will no doubt show lots of interesting genes with interesting ontogenic trajectories of various kinds, but to interpret clearly (and to prove or disprove anything vis-à-vis schizophrenia), we will need complementary approaches (as well as the SNP data).

Tadafumi Kato
Mark, to know the consequences of development, study of DNA methylation will provide useful information in addition to gene expression.

Mark Vawter
Tadafumi, yes, the same DNA provides different messages in different brain regions, so studying methylation by region by gene will be informative, yet challenging. Are there any high-throughput methods for DNA methylation assays?

Tadafumi Kato
Mark, we are developing and other groups have already published microarray-based methylation analysis.

Cyndi Shannon Weickert
Tadafumi, I agree, and people are starting to look at this (Akbarian and others), so finding a way to add other types of biological information on a large data set would be good (as a second step), like uploading DNA methylation or proteomics data, but how would all this be managed? It seems to me that something like this (back to the database idea) would have important implications for many aspects of medicine beyond schizophrenia.

Tadafumi Kato
Cyndi, the only way to have meaningful information is to integrate everything: expression, SNP, CNV, and methylation.

Mark Vawter
Tadafumi, yes, systems biology (integrating everything in a large comprehensive view)!

Paul Harrison
Tadafumi and others, as methylation is both temporally and regionally (if not cell-type) specific in human brain (e.g., Ladd-Acosta et al., 2007), it won't be trivial to do this.

Akira Sawa
Integrating everything...important. Please do include time course in these parameters.

James Chao
Perhaps network analysis, too, with gene coexpression.

Tadafumi Kato
Akira, and tissue heterogeneity should also be included, using dissection or other methods.

Elizabeth Thomas
Regarding developmental changes, if we consider that development (i.e., myelination) continues into the late twenties, looking at subjects early in illness would be important. Our microarray findings (not yet published) suggest that the most dramatic changes in gene expression occur early in illness (less than 5 years from diagnosis, subjects all 18-25 years old).

Cyndi Shannon Weickert
Elizabeth, looking at changes in gene expression proximal to the onset will be very valuable! Good work.

Elizabeth Thomas
Cyndi, thanks.

Mark Vawter
Joel/Barbara, are there any young schizophrenia subjects or high-risk brains that could be studied?

Joel Kleinman/Barbara Lipska
It is unclear to me why we would have young patients with schizophrenia in a postmortem study. Given the importance of genotype, there is no substitute for having numbers as large as possible for the index and control groups—this is far more important.

Mark Vawter
Joel/Barbara, hmmm, since genetics is only one part, it seems that the early brain changes could be seen independent of genetic risk.

Joel Kleinman/Barbara Lipska
What early brain changes are you referring to?

Mark Vawter
Joel/Barbara, it is an open hypothesis: are there brain changes in young subjects at risk for schizophrenia? Some early imaging data suggest brain region size differences. (Early unpublished differences in cases vs. controls presented at the 2007 ICOSR meeting in Colorado Springs by John Gilmore from UNC.)

Akira Sawa
I believe that data of gene expression from young people (0-20 years old) should be an important reference in comparison with that from adults. We do not have to get data from young-onset schizophrenia patients, but it may be important to know age-dependent gene expression change in order to properly interpret data from aged schizophrenia patients and controls. Don't you think so?

Joel Kleinman/Barbara Lipska
Akira, yes, we agree completely!

Paul Harrison
Joel/Barbara are right about sample size being crucial; once we get into the hundreds of subjects, it becomes realistic to examine contributions of genotype, stress, age, etc.

Cyndi Shannon Weickert
I think one thing that having young patients with schizophrenia helps with is sorting out what David Lewis et al. referred to in their latest review paper as the four "C’s" (Lewis and González-Burgos, 2008). If you can look at gene expression early enough in the disease, you may be able to start to better order the events of the pathology and to understand what the consequences may be in molecular terms as they "unfold." Studying genotype is one way to go, but we all know that many "risk" genes are found in people that never go on to develop schizophrenia, so there is no better substitute for studying schizophrenia than the schizophrenia brain itself.

Karoly Mirnics
Paul, in this climate of competition (and not collaboration, regardless what NIH is trying to sell), will we ever arrive at hundreds of samples?

Paul Harrison
Karoly, not in the U.K.; that's for sure!

Mark Vawter
Karoly to Paul, I think meeting at SOBP to discuss putting together hundreds of samples could also be helpful.

Karoly Mirnics
Mark, that would be the Holly Grail of this research.

Joel Kleinman/Barbara Lipska
Collaboration only occurs when it is in the interest of both or all the collaborators.

Akira Sawa
By the way, we have only 3 more minutes. We now have 47 colleagues in this roundtable!! We still have a lot to talk about. Maybe different occasions at SOBP over wine/beer. Today's chat should be an important template for future scientific discussions. Dear all, do you have something to add in the last 2-3 minutes?

Hakon Heimer
The room will stay open as long as you like if you want to "rush the speaker" or gather in small groups, but as Akira said, now is that time for final statements, since some people have to leave for lunch, dinner, or go back to bed in the other hemisphere.

Cyndi Shannon Weickert
Hakon, how can anyone sleep with all this excitement!

Tadafumi Kato
Genetic studies are going from common SNPs to multiple rare variant studies. The postmortem brain studies may also go to the same direction. The cause may differ patient to patient.

Joel Kleinman/Barbara Lipska
Okay, my last comment of the day. Toxicology on brains of patients with schizophrenia has cost us $590/case. WGA chips cost about the same.

Karoly Mirnics
A new wrench: my biggest issue still remains disease homogeneity. Two schizophrenics may be very different from each other, and we have no power to uncover the substratifications. Yet, virtually all statistics we use assume that all schizophrenics are suffering from a similar disturbance (I am guilty of this as charged, too).

Joel Kleinman/Barbara Lipska
Karoly, absolutely correct. This is part of the reason that genotypes are crucial.

Christine Miller
Karoly, although two schizophrenics are very different from each other, they also can be very different within the same family. Presumably, the genetic component within the same family is quite similar....

Karoly Mirnics
Christine, in postmortem you will have no family members, but unrelated subjects.

Christine Miller
Karoly, yes, but my point was that disease heterogeneity can exist even within a largely similar genetic (and similar gene expression) background. Timing of gene expression may be key.

Vahram Haroutunian
Christine, agree. I was struck by a comment that Joe Coyle made to me yesterday. Schizophrenia does not breed true. The offspring of two phenotypically similar schizophrenics may have/often have a very different syndromic or symptomatic profile.

Karoly Mirnics
C. Miller, you may be right, but there is so much we cannot control—age of death, medication, lifestyle, genetic makeup—and this makes two schizophrenic brains so different that they may show very few commonalities in a gene expression pattern. This is a question that plagues us all. Joel's genotyping may get around the genetic issue, but what to do with the rest?

Sherry Leonard
Chris Miller and Karoly, there are huge effects of stress on gene expression, and stress could be very different for each subject. Also agree that methylation is an important parameter to think about, as is miRNA.

Cyndi Shannon Weickert
Does anyone know how many postmortem brains are even available around the world, if the brain banks were to cooperate with this notion?

Karoly Mirnics
Cindy, good ones or bad ones:)))

Vahram Haroutunian
Cyndi, an update of Paul Harrison's paper a few years ago: doing a meta-analysis on brain weight in schizophrenia (Harrison et al., 2003) could help identify the numbers of cases.

Cyndi Shannon Weickert
Thanks, Vahram, I will have a look. G'day everyone and I vote for having the meeting in Sydney! Cheers!

Helga Smith
Karoly, maybe if you ask the families that have multiple members with schizophrenia via places like schizophrenia.com you could get better/younger samples after suicides?

Karoly Mirnics
Helga, we tried many things, but the reality is that most of the banks grow by four to five good schizophrenic brains a year.

Hakon Heimer
Karoly, that's a disappointing statistic. Perhaps SRF can get NARSAD/NAMI more involved.

Helga Smith
Karoly, I have read all parent message boards for 10 years and this problem of getting brains has never been discussed. The parents would love to help.

Karoly Mirnics
Helga, believe it or not, the availability of the high-quality brains is the most limiting factor in our research. Thank you all; I am looking forward to a great meeting at SOBP.

Joel Kleinman/Barbara Lipska
Who will organize something for SOBP?

Sherry Leonard
Can Akira and Mark organize something for SOBP?

Mark Vawter
Joel, I would offer to do that with Akira and others. As a reminder, please e-mail nico@schizophreniaforum.org for an interest in meeting/discussing topics 1, 2 further.

Paul Harrison
Good session! Here's to a meeting at SOBP. Bye.

Akira Sawa
Mark and Joel, great!

Vahram Haroutunian
Joel, I think that an NIMH-organized meeting/working group around this topic would be better than a few minutes at SOBP.

Tadafumi Kato
Thank you, everyone; very hot session!

Christine Miller
Thanks to everyone!

Joel Kleinman/Barbara Lipska
Okay. If the group wants NIMH, I will try to set it up. Otherwise, we can try for SOBP or a small meeting at my home.

Sherry Leonard
Joel, I hope you have a big house!

Joel Kleinman/Barbara Lipska
Yes, I have a big house. Barbara and I are signing off for now.

Mark Vawter
All, I see names on the right of many others who didn't get a word in. Thanks for coming today. We will send out a transcript...and Akira and I will arrange a follow-up.

Cyndi Shannon Weickert
Just kidding, of course. I prefer SOBP, not NIMH! Should we meet a day early to have more time?

Akira Sawa
Dear all, thank you very much for coming!

Hakon Heimer
A big round of applause for Akira and Mark.

Joel Kleinman/Barbara Lipska
Hands clapping.

Sherry Leonard
Many thanks.

Karoly Mirnics
Organizers, great job.

Elaine Shen
Thanks to the organizers. I've found this to be very interesting and hope to get involved more in future discussions.

Mark Vawter
Elaine, I think we will need to try this again.

Tony Altar
Mark, thanks for the offer to send out the transcripts for this meeting, and keep me in mind for the next one.

Mark Vawter
Tony, sure, we didn't really even address medications. I think that will be important as part of understanding the pathology.

Andreas Jeromin
Great forum. I would like to see some other issues discussed as well.

Tony Altar
Andreas, what other issues did you have in mind?

Andreas Jeromin
Inter-laboratory comparison of RNA and tissue QC, for example, need for imaging. Histology as part of the acquisition.

Hakon Heimer
Tony, Andreas, please write a comment at the discussion page on any other issues.

Mark Vawter
All, thanks again for your comments, and please post more at the Forum. Hakon, I will be logging off. Great job hosting this forum.

Hakon Heimer
Well, I think we're done, Mark. A good day's work and it's only morning in California.

Akira Sawa
Hakon, Nico, Mark, and friends, I will be logging off. Thank you very much!

Hakon Heimer
Akira, thank you for bringing this lively crowd to SRF.

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