 Thanks very much for that kind introduction. It's it's really a pleasure to be here right in the neighborhood I'm a neighbor in more ways than one. I am Of course right across the street at NIH Or my gadgets are on here. Okay. Thank you and Also live about three or four blocks from here So I pass by on all kinds of occasions have been in the ER with kids with broken arms and dog bites and The whole thing but so it's great to be here and talk with you about a subject that I have been immersed in over the past year in particular in the context of a Task force which was put together by the International Society of Psychiatric Genetics In order to put together some guidelines In a statement that would help guide clinicians and the public about the use of something that Maybe ten years ago seemed like a distant fiction, but which is with us today now. That is genetic testing In psychiatry, so I want to talk a little bit about the issues pertaining to genetic testing today I call the the talk uses and misuses of genetic testing in psychiatry Partly for dramatic effect, but also to to emphasize that this is still very much an evolving area where sometimes the practice has gotten way ahead of the data and Where we're scrambling to catch up in understanding how people think about these tests How they use the information that comes out of them and whether that information is actually going to improve patient care So here's an outline of my talk today I'll talk a little bit about the potential value of genetic information in psychiatry some of the key questions in evaluating genetic tests Review some of the currently available tests and also the the recent ISPG guidelines and Lay out some of the new challenges we face for clinical practice also for education and research so Genetic testing is important in psychiatry as it is in most fields of medicine because of what it might be able to tell us It might tell us about differential diagnosis an area where in psychiatry in particular We have grappled with the challenges of diagnoses that are based purely on clinical syndromes Without reliable biomarkers or other laboratory assays Genetic testing might also help us in prediction of treatment outcomes a recent article on on the series Nova Asserted that most psychiatric treatment is a trial and error basis I'm not sure that I would agree with that entirely But it does underscore the difficulties we have in deciding what is the best treatment for each individual patient and genetic information that might Indicate who's most likely to respond or even more importantly who's most likely to have an adverse event could obviously help a lot even if it only illuminates a proportion of cases Finally it would be helpful if we could identify individuals who are at high risk for serious psychiatric disorders This would allow us to carry out primary prevention research and actually measure the outcomes from various interventions and also might down the road enable psychiatrists to employ truly preventive strategies for example What we could do to prevent the the full onset of schizophrenia in an individual who's presenting with prodromal symptoms So these are just some of the potential uses for genetic testing and psychiatry for most cases We're not there yet, but in some cases we're beginning to Touch upon some of these areas Now whenever we talk about genetic testing like with most laboratory tests It's important to remember three key questions First of all, can that marker be genotyped reliably? This is what is called analytic validity and it's generally well established for single marker assays that are available through commercial or hospital-based or Cleabase laboratories, but actually it's much less certain for assays that are based on next generation sequencing generating the entire Nexomic or whole genome sequence on an individual which is a prospect that in the not too distant future Might be an option for many people who are coming to the hospital While these next generation sequencing technologies are very efficient and very inexpensive Compared to what it costs to sequence a genome just a few years ago There's still entire reasons for the genome. They're not well captured and there's also a significant problem of false positive findings Once we get past analytical validity the question comes up of how valid is the association between the genetic marker and the disease This is an area known as clinical validity and here the sample size of the tests That we use to establish the initial association and the replication of those findings in independent samples Are the key indicators of a valid association? But we also have to remember particularly for findings that might come out of genome-wide association studies Is the genetic markers that are identified might not actually be the underlying functional genetic variants? And actually for relatively few of the tests that are available based on genome-wide Association findings to date has the functional allele been identified so what you're looking at instead is a marker that reflects a nearby genetic variation and the degree to which those two Variations correlate might actually vary from person to person And finally and this is probably the most important question for a clinician is does the test result have any clinical? Utility is will it really change the way you diagnose or manage a patient? And here it's very difficult actually to predict upfront Which tests are going to have the greatest clinical utility even a test that have very large effect sizes And seem to provide unique information beyond what we could obtain through Physical exam and family history don't actually prove to have clinical utility when tested empirically in randomized trials Very few clinical tests Based on genetic findings have so far been through that sort of rigorous randomized clinical trial evaluation Another important question of course along the lines of clinical utility and one that's really relevant in psychiatry is do alternative treatments or Diagnoses exist. It doesn't do much good To have a genetic test that tells us a patient's less likely to respond to a particular treatment if there are no good alternative treatments available So when I gave a talk on psychiatric genetics ten years ago I might have had one slide on genetic testing as as a distant future prospect But actually here we are in 2014 and and actually genetic testing is already here in psychiatry in a variety of different forms Commercial panels are marketed to psychiatrists and psychologists to look for things like recurrent copy number variants that have been associated with developmental disorders such as autism Markers of the cytochrome p450 system, which I'll be talking some more about in a few moments that are presumed to give information about drug response and adverse events and the linked polymorphic region of the serotonin Transporter which has been variously marketed for a whole range of psychiatric and psychiatric treatment outcomes Like it or not. There's also direct marketing to patients and their relatives This is something that's gotten some news coverage in recent months when the Food and Drug Administration issued a warning to a company 23andMe that was providing genetic testing Directly marketed to individuals and making health claims associated with that These are generally based on snipper rays But actually we're also moving into the era or commercially available exome sequence is being provided now The most commonly used tests that are currently available through clinical laboratories are tests that you'll generally be familiar with There are the common risk alleles such as APOE4 Which is associated with the risk of late onset Alzheimer disease There are the copy number variants which can be ordered Usually on array tests as part of the workup of neural developmental disorders. It's possible to look for recurrent CNVs those that are known and are already Represented on existing panels as well as de novo CNVs Comparing the genome in the affected offspring to that of both parents We've also long had the ability to test for rare risk alleles such as those that caused phenylketonuria Expanded repeats that cause things like Huntington disease as well as traditional cytogenetics Which only occasionally comes up in routine psychiatric practice Although we nevertheless often do treat individuals who have Cytogenetically-based disorders such as a Down syndrome So these long established tests generally look at chromosomal and genetic lesions that can be considered causal I mentioned phenylketonuria Huntington disease fragile X syndrome Individuals who carry these well-defined genetic lesions can be thought of Having their disease as a result of that genetic change But we're now into a realm where more recently developed genetic tests are actually looking at Things that can be best characterized as genetic risk factors that are not causal. That is carrying the genetic marker is Neither necessary nor sufficient to develop the disease and a whole range of other factors often not fully understood Play a role in who will fall ill. This is certainly true of the APOE association with Alzheimer's disease Where for example individuals who carry the high-risk E4 allele have only a slightly increased risk of disease unless they have an affected first-degree relative Take a lifestyle factors also play a role in that Copy number variants that have been associated with autism and schizophrenia seem to show money of the same characteristics a Recent study out of Iceland which looked at a large population of Individuals who carried these variants found that in most cases they weren't identified as psychiatric patients although if they were carefully assessed they often had various kinds of cognitive impairments and Finally the the cytochrome P450 variations which are typically used To make predictions about drug metabolism, but again are not not determinative Either of that metabolism metabolism or more importantly of the treatment outcome at the same time Consumers can directly order off the internet a single nucleotide arrays that are Often presented along with health implications based on genome art association study findings Reporting that someone is at a one or two percent increased risk or three or four percent decreased risk of this or that common disease Some of these companies also offer results on Mendelian disorders including Rare mutations in the brachy gene, which is can cause early onset breast cancer APA we already mentioned and The marketing in the health claims is pretty tightly regulated or prohibited in some countries, but in others is still Pretty wide open in the case of 23 and me although they are now no longer able to directly market health claims To new customers health reports based on existing customers data are still provided We're also now into the realm where sequence either exome or whole genome is offered Obviously, this is to a very small portion of the population who were able to afford the Thousands of dollars this typically costs of this falls under a Roupic of personal genomes, which is actually gaining some popularity with certain segments of the of the younger population As well as other products that are based on one or a few individual assays So we're now already into a climate where there's a large variety of tests that are looking at different things Which have very different meanings? Depending on the context in which they are Provided and where clinicians no longer have a monopoly on that information so from a psychiatrist point of view, this is anxiety provoking and As a result, I think we need to really get up to steam on this and make sure that that we know what our patients Are thinking on when they come in to the office with a genetic question So these are some of the the Direct to consumer ads you can find on the internet. This is one that was meant to pick up Markers of suicidal ideation. This one I think has already gone under This is the website for 23 and me which modestly puts the company's history in the context of Gregor Mendel's discovery of the laws of inheritance And the completion of the human genome product project and this is one of the newer companies known as gentle and This actually offers a Whole exome sequencing the transcribe portion of the genome and is targeted particularly at expectant mothers Who might be worried about? 1,700 or more diseases that could be passed along to their children Interestingly this company Does claim that they provide genetic counseling as part of the product that they're offering Which is an interesting claim It's not not directly provided at least not professional counseling with any of the other companies as far as I'm aware I'll be talking about that issue more a few minutes so much of the direct to consumer genetic testing in particular occurs outside of the usual Context of informed consent, but we might also ask ourselves in psychiatry when we provide Genetic tests to patients. Are we thinking carefully about informed consent? This is of course the fundamental principle throughout medicine which respects an individual's autonomy and is Based on the assumption that there could be an objective presentation of risks and benefits Before an individual agrees to undergo a procedure, of course, this is routine for surgery would be unthinkable for us Take someone in for an appendectomy without Informed consent being executed, but actually it's quite rare for psychiatry. We do it Of course for things like electro convulsive therapy, but actually relatively few other circumstances This is important because it's now recommended that prior to clinical genetic testing recommend most professional societies that informed consent be provided And and yet I don't think we have good mechanisms for fulfilling this recommendation within most clinical psychiatric settings Now let me tell you a little bit about some of the the kinds of tests that are available and what you might want to be thinking about either Discussing with your patients or maybe even using in the near future. We know that psychiatric disorders are not monogenic so unlike Conditions like Huntington disease. We can't point to a single gene that can be considered causal They have very small impact on individual risk general in the order of one or two percent What's not clear yet is whether large sets of genes that could be tested together could have a larger impact When this has been done in research settings published studies find area under the curves on the order of 55 to 65 percent now when you order a prostate specific antigen or Cardiac enzymes for an individual presents to the emergency room with with chest pain the area under the curves So those kinds of tests are generally well over 80 percent So this is not within the realm that would be considered clinically useful But it's still an open question where their larger samples with better information might actually push this higher There's also the important issue of interaction with other factors such as family history Which is so far I've been relatively little scuddy than psychiatry. I mentioned the the one example of Family history of Alzheimer's disease in the first-degree relative and how important that was in the proper interpretation of the APOE result Similar examples may exist for these kinds of tests, but they haven't generally been investigated Now there's a different situation when we look at CNV testing These of course are the small chromosomal deletions and duplications which over the last five years have been found to be much more common in individuals of autism Schizophrenia and maybe bipolar disorder than they are in individuals who are healthy Now individually each one of these copy number variants is actually quite rare They may occur in one or two in a thousand of the population But there are so many of them that when they're taken together They may account for about five percent of autism cases Something on the order of three to five percent of schizophrenia and maybe about one to two percent of Bipolar disorder particularly bipolar disorder beginning early in life. So it's not Entirely insignificant proportion Carriers of some of these CNVs may also be at risk for other medical conditions when the CNV causes a what's called known as a contiguous Genes syndrome and the best example of that is the velocardiofacial Deletion on chromosome 22 which is associated both with schizophrenia and with cardiac and other health problems Now there are also a variety of pharmacogenetic tests that that are Available to clinicians Most of these have no evidence of clinical utility yet in psychiatry But yet you may see them often promoted within professional journals The cytochrome p450 tests which have been validly associated with metabolism of a variety of drugs including psychotropic drugs But where studies have not found evidence of clinical utility that is knowing the information has not been shown to alter decision-making or outcomes But more study is needed of this particularly in situations such as treatment resistant depression or an individual other atypical presentations or a typical reactions to antidepressants because generally the the clinical utility has been evaluated only in typical settings Another long marketed test is that of the serotonin transporter We've known for a long time that there is a Polymorphism in this gene that influences how efficiently serotonin is taken up from the synapse And you will call that it's direct blockade of the serotonin transporter That's thought to be an important part of the mechanism of the selective serotonin reuptake inhibitors So it seems stands to reason that that this Polymorphism could have an impact on individual response to antidepressants, but in fact After more than 10 years of study the jury is still out on whether There's any consistent effect and if there is it's a small one There's also been weak associations with a broad range of other symptoms from anxiety to Personality traits which obviously complicates our ability to interpret results in an individual situation Others that are marketed by get have been little studied for their clinical utility Polymorphisms in this empty FHR. This was featured in the recent Nova presentation. I mentioned the serotonin two-way receptor. It's actually a Genetic marker that we were involved in initial discovery and BDNF which has been widely studied in a variety of situations and which is thought to play a role in The mechanism of antidepressant action Now there are some Pharmagogenetic tests that really are ready for primetime in psychiatry even though they they probably apply to drugs that we fairly infrequently use It's been discovered over the last couple of years that's particular genotypes in the Majors to compatibility locus the HLA locus are associated with severe adverse drug events Things like Steven Johnson syndrome, which can actually be life-threatening The initial discovery was that this particularly polymorphism Which is basically seen only in people of Asian ancestry was associated with Stevens Johnson Conferred a very high risk over tenfold and individuals who carried that the FDA altered their labeling for carbamazepine to reflect this finding and It's currently being evaluated whether use of this test prior to carbamazepine treatment in people of Asian ancestry Will actually reduce the incidence of Stevens Johnson syndrome More recently another polymorphism known as HLA A3101 has been shown to be associated with similar adverse Skin events in people of a variety of ancestries and so that might actually be more directly relevant In clinical settings with non-Asian patients So psychiatry should be aware of this It's still not crystal clear Whether testing will prevent these bad outcomes and we don't often prescribe carbamazepine anymore But it is occasionally used as an adjunct particularly for mood stabilizers other tests that have gotten a lot of press recently such as a big paper in the New England Journal Back in January claiming a strong association between genetic markers and lithium response in Asians Still await replication And you remember I was saying earlier that clinical validity Depends heavily on Replication first before we can really evaluate clinical utility genetic counseling This is also an area where in psychiatry We don't typically think of but where it might be actually increasingly important for us to have Relationships with genetic counselors if we're offering genetic tests to our patients Of course, we're all taught that genetic counseling is ideally used before genetic testing in order to evaluate its potential and Anticipate results to lay out potential scenarios for patients and make sure that they understand what the genetic test can and can't reveal Of course genetic counseling is also useful for understanding results and secondary findings But it's actually quite challenging when you consider most settings in which psychiatric care is provided To see how we're going to integrate traditional genetic counseling with psychiatric care Since there's really a need for both genetic and mental health expertise and doing that Many genetic counselors don't feel entirely comfortable with the kinds of counseling issues that are presented by people with major mental illnesses and many psychiatrists don't feel confident in Presenting many of the actuarial Risks associated with genetic testing results. So we need to figure out how to bring together These two areas if we're going to really providing responsible genetic testing to psychiatric patients Now another Thorny issue that can arise whenever More than a single genetic test is done is what's referred to as incidental or secondary findings This is particularly problematic for genome-wide tests such as exome sequencing studies and the idea here is that With any genome-wide test you might find Unanticipated genetic changes that have health significance You might find for example one of those highly penetrant breast cancer mutations. You might find a Polymorphism that substantially increases an individual's risk for other preventable disorders down the road In general then a plan is needed for identifying these incidental findings for reporting them back to the patient and for providing adequate counseling and Several organizations such as American College of Medical Genetics have provided some guidelines on this when they were issued last fall They're actually quite controversial because they seemed to create a new Duty of reporting and and I'm dealing with genetic information that many physicians are still uncomfortable with so this is an area that even in psychiatry we now are faced with and and We have to think about how we deal for example with a depressed patient Who's had an exome sequence study and on top of their depression has now learned that they carry a Mutation in the brick a gene that may require Prophylactic mastectomy and down the road. So these are really very thorny issues That that we in psychiatry are not used to dealing with this is a chart that I Found on the Children's Hospital, Philadelphia website that actually lays out some of the kinds of incidental findings that can come up Typically in the next home study. I talked about these high-risk medically actionable findings and these were the findings that the ACMG focused on These are conditions that could have a high impact on individuals health or on the health of their close relatives And where preventive strategies can be applied such as breast cancer Then they're also high-risk not medically actionable. These are even more problematic things like being homozygous for the APOE4 allele and Knowing then that an individuals that substantially increase risk of Alzheimer's disease but without any preventive treatment that can be applied Incidental findings can also apply to drug response Carrier status for conditions that may only be penetrant in homozygous individuals and then that there's this Broad range of these low or medium risk common disease variants Which in general people have not considered within the realm of incidental finding reporting duties But which will over time I think complicate the edges of what's a medically actionable result So I think you've probably got a sense from what I've said so far that we we're Getting to the point where the technology has perhaps outpaced The education both of clinicians and patients. I know when I was in medical school about 25 years ago We thought we were getting a cutting-edge Genetic education, but we were taught very little about actually how to to explain a genetic test to a patient and how to use those Results in in in planning treatment Probably because very little was known then and we're still in a situation where what we know about these tests and And how to use them is very limited This might be especially true for psychiatrists who often Are working in a specialty where? Genetics seems like a relatively peripheral concern even though we recognize that most major psychiatric disorders are highly familial I Mentioned already that genetic counseling is not the same as mental health counseling and that in order to provide competent genetic counseling Psychiatrists will may need to know a lot more about genetics than we typically do Of course the other important thing is that the indications for genetic testing are often not clear some of the the widely marketed tests for for example antidepressant response often Talk about situations where patients have failed to respond to typical antidepressant treatment Who have so-called treatment-resistant depression or who have suffered adverse events on usual doses of Medications, but it's really actually not very clear Whether genetic information in those kinds of patients can actually be used to more intelligently pick The next treatment for that kind of patient, and that's a real problem because we don't really know when we should use a test on the other hand patients often have very little understanding of genetics and Surveys have consistently found that The public overestimates the importance of genetic findings Equating a genetics with destiny or thinking in terms of the the one-to-one causal Relationships from indelian diseases that are actually quite different than what we're generally talking about when we consider clinical genetic testing and psychiatry It can be very difficult to explain to individuals particularly in the context of a mental health crisis how The the much more nuanced information that comes from a genetic test might be useful in Evaluating their condition or planning their care There's also the concept of the genetic risk factor Can be easily misunderstood? Because people don't think generally in terms of statistical risk or actual risk In terms of their health or their long-term well-being And it's actually actually very rather difficult to explain to an individual That that a particular test result increases their their risk for a future outcome by five ten or fifteen percent Surveys have consistently found that people actually have a very poor Intuitive feel for what that means of course we need a lot more research to answer a lot of these questions and It's worth noting that this important clinical validity that is how Reliably a genetic marker is associated with a disorder is still uncertain for most genetic tests that are used in psychiatry We still need replication and large samples for most of these findings and Also, we need to know the universe over which these findings are valid And remember a clinically valid gene tests may still lack clinical utility They may not really have an impact on the way you can manage a patient and on the outcomes of your treatment Effect sizes may be too small to have much of an impact and the gene test may provide little unique information For example, someone presents to the clinic with a psychotic episode and they have a strong family history of schizophrenia That probably is much more informative in your differential diagnosis than any of the genetic tests that you could do now That would implicate a specific genetic lesion in that individual so It's not clear yet whether we have any genetic tests particularly in psychiatry that do better than in good family history Finally, there's a question about whether genetic testing might actually do harm to patients. We're all taught first to do no harm And little is known about how psychiatric patients deal with genetic test results particularly those that might have Potentially serious health implications. There have actually been a few studies of Genetic test results information being given back to patients in a variety of settings not psychiatric patients And it seems reassuringly that it doesn't seem to do much harm There was one study that was published last fall in the murder of psychiatry Which suggested interestingly that when people were told that they carried the APOE for allele that allele that's associated with Alzheimer's disease They tended to underestimate their their memory performance Even though objectively their memory was no worse than matched Peers who did not carry that that allele So I guess that's a harm in some ways that it's shaken on individuals confidence in their memory abilities But I think more importantly what that study raises is the question about whether particularly in the realm of Behavioral and mental health whether there may be subtle harms from Genetic testing that will be actually very difficult to carefully evaluate except in the right populations and with the right sample sizes and We still don't know much about the long-term effects of this kind of genetic knowledge 10 or 20 years Out and what kinds of changes in behavior this kind of information has So to try to address these things and not get too far behind the curve the International Society of Psychiatric Genetics Which is the the major research organization for psychiatric genetics put together some guidelines in 2008 and 2009 through a task force and at the time there was a broad Recommendation against all genetic testing with the exception of these very well established tests such as PKU fragile X and Huntington disease Which in reality rarely used by psychiatrists It became clear to us though particularly with the advent of direct-to-consumer genetic testing that we needed a more comprehensive statement on the issue so in 2012 and 13 we put together a second task force to update the recommendations in light of recent research interestingly we couldn't come to consensus on it however and The draft recommendations from the task force were actually not adopted by the board of the society So they never made it to the light of day So we went back to the drawing board in the fall of 2013 And decided to crowdsource the work to a large group of members in in the Society we have about 40 or 50 people on the task force now from all over the world It's very challenging to do a conference call when you have someone in Sydney, Australia and Vancouver, British Columbia There's no time that you can do it where someone doesn't have to get up very early or stay up very late But it's a representation. I think of a of how much interest there is in this issue around the world So we did a series of conference calls aiming at a broad consensus and we came up with final recommendations that were actually adopted by the board just recently and what you're now posted on our website if you Want to look at these in detail? That's the the web address We're also planning to publish a peer-reviewed scholarly review in one of the psychiatric journals in the coming year But let me give you a quick rundown of the recommendations just to get a feel for where we stand right now in terms of expert opinion on this subject First of all the task force recommended that genetic tests should only be carried out if patients have given informed consent and That's problematic for many of the direct consumer tests and also is not necessarily routinely done in psychiatric settings The task force felt that from major adult psychiatric disorders such as schizophrenia Bipolar disorder etc Single genetic variants are not sufficient and there are no genetic tests that can establish a diagnosis or predict individual risk And this is actually quite a strong consensus among the members of the task force even given the large literature on genetic risk factors for these disorders The task force felt differently about copy number variants Which as I mentioned have been identified at people the autism spectrum disorders of schizophrenia Since these may help diagnose rare conditions with important medical and psychiatric implications and could also have implications for for families Many times when individuals present with the onset of schizophrenia It's it's it's puzzling and frightening to the family without any explanation why this occurred Identification of a causative CNV therefore might actually help explain an individual case and also as implications for the genetic risk in siblings and offspring if that's a An inherited or a de novo event in that family The task force also felt that clinicians should consider evolving pharmacogenetic testing recommendations and treatment decisions The idea here was this is really fast-moving Psychiatrists need to know about The association with HLA and carbamazepine, but there may be others that very very soon down the line will come out and there's actually a nice Registry of these kinds of tests that's available on the FDA website And also the FDA labeling can be helpful guidance but the the group felt that Evidence remained quite inconclusive as to the possible clinical utility of this cytochrome p450 testing But that more research is needed particularly in those specialized situations. I mentioned earlier. There were four more recommendations One that all genetic tests with health implications should be accompanied by professional genetic counseling This was meant to address the issue of direct-to-consumer testing But also to alert clinicians to the need for having genetic counseling resources available when they use genetic tests The task force also felt that patients who have psychiatric illness or for tests that relate to psychiatric conditions Counselors should possess clinical expertise in mental health or at least work in a context where that expertise is immediately available the task force whoops the task force talked about genome-wide testing and the possibility of incidental or secondary findings and Recommended that this possibility should be clearly communicated prior to the testing and that procedure should be in place for dealing with such findings And should be made explicit with patients beforehand Warning people gee we might find something you don't expect and his is how we'll deal with it The task force advocated better education of mental health professionals and genetic medicine And also a need to safeguard privacy of individuals genetic testing results and reduce stigma in the community We have legislation in place in the US that protects individuals from their genetic testing results being used against them for example in provision of health insurance But that information can still be requested prior to a life insurance policy for example or in Evaluation of premiums for long-term care insurance, and that's still a concern when genetic testing is done and Finally the task force called for expanded research efforts to clarify the role of genetic testing in psychiatry I should say this initially said to clarify the utility if any of genetic testing in psychiatry But we were able to reach a broader consensus by by writing this a little bit more generally So that's the the current state of expert opinion on this matter and so you can find this on our website I may agree or disagree with it, but it represented a broad consensus of the field at the moment so in conclusion genetic testing is becoming a reality in psychiatry like it or not and Clinicians and patients are going to need to deal with an increasing onslaught of genetic data and genetic claims in the near future Despite that the clinical utility of psychiatric genetic tests is generally limited or unknown The use of certain genetic tests in specific situations may be warranted such as C and V testing in the first onset of a schizophrenia or autism But there's a need for more genetic education both of clinicians and patients so that we know when to order tests and how to Interpret the results properly for patients and we need additional research to better understand the landscape That that we're working in especially in psychiatry genetics and how we can use genetic tests to alter treatment in positive ways and That's all I have for the moment. I'd be happy to take questions HTTP Okay, so two questions. How does the serotonin transport or link polymorphic region the LPR relate to the risk of depression? And that's been very widely studied With a collectively thousands of patients around the world and I think the answer is still ambiguous There seems to be a ancestry based difference So that one allele seems to slightly increase risk of depression in people of European ancestry but the work in the opposite direction in individuals of Asian ancestry and I think most people feel that probably what this is telling us is that the genetic context matters a lot and Probably matters more than the variation of that individual marker That doesn't mean that's not a great thing to study in the laboratory because it really does get very close to The mechanism of a lot of antidepressants, but as a clinical test, it's it's just not there and probably never will be the other question is What is the recent research tell us about the genetic differences between the major mental illnesses? And what I can say about that is it's so far From the genome art association studies which look at common genetic variants that have a small impact on risk That there's a lot of overlap Substantial overlap between bipolar disorder and schizophrenia and some overlap as well between major depression and those two conditions And even some overlap with things we wouldn't think of as really being in the same spectrum such as autism and ADHD I Don't know exactly what that means But I think for the prevailing opinion is that probably at this point. We're picking up genes that have very general impact on brain development and morphology and that deviations from the ideal Along those lines may actually put individual risk for a range of conditions depending on their individual life circumstances and other risk factors The story could change a lot though as we as we start to look at these less common markers That that play a larger impact in these such as these CNVs because they seem to be more narrowly defined in in their diagnostic range although there is substantial Overlap there between CNVs that confer risk for autism and schizophrenia a lot of the same And with bipolar disorder seems that they're there they tend to be smaller, but that they involve many of the same genes Calcium channel gene you mean yes Yeah So one of the these overlapping genes and one of the first that was identified by the genome my association studies is this gene CAC na1c That encodes a voltage gated calcium channel That is clearly important in membrane potential in the brain It common variations in that gene have been associated with both bipolar disorder and schizophrenia pretty robustly and But with an odds ratio on the order of 1.1 So I think this gives us perhaps more insight into Mechanism than it does in diagnosis But it does seem to Fit with a growing story That that calcium signaling in the brain is probably important particularly in bipolar disorder Yes, so can we use genetic testing to sort of sort out underlying bipolar illness and prevent a bad outcome When we use antidepressants the answer right now is no, but we would we would dearly love to have that kind of test one experiment that hasn't been done, however is to use these aggregate of Tests of common variation across the genome and see how well that differentiates individuals With depression and bipolar disorder one study did suggest that that individuals who have first degree relatives with bipolar disorder tend to have higher scores genetically for bipolar disorder And people with whose relatives only have depression have lower scores But of course you could learn that by just doing a good family history Yes, so that these these conditions the aspirin particularly falls into this range of the autism spectrum disorders and That's not routinely genetically tested in most in most university medical centers probably less so in the community And there is a strong association with the same Rare copy number variants that are seen in autism Yes It's a thorny issue and it's actually an area where we had Some of the greatest difficulty in reaching consensus on the task force Most of the task force members felt fairly strongly against direct-to-consumer testing, but there was a Important subset who thought that we shouldn't be too paternalistic and we ought to respect Individuals rights to learn their genetic information themselves and and to be empowered To to discuss that information with their their clinicians on an equal basis and It's it's hard to to argue that that shouldn't happen So it really is I think comes down to Trying if we're going to let the information out Let's give all the information and make sure people really understand the complexities involved the very very small risks and That that that these markers confer or the very small effect sizes they have in terms of treatment outcomes and Try to have the conversation So personally, I think you're right to put these tests on your website In the context of the information that's there and to highlight in particular when we don't have clinical validity Much less clinical utility Many of these tests exist just as an individual reports in a journal Now, but it's a it's a tough area Somebody has a Yeah, so Yeah, so if I if I understand what you're saying is this idea of people ought to know What risk they they might post to subsequent generations and and can genetic information be used for that and In I'd say the in most cases for psychiatric disorders We can't do that unfortunately But there are some rare instances where someone carries a well-established pathogenic copy number variant And that if they reproduce they will have a 50% chance of passing that under their offspring And then their offspring when herit's it will be at a 10 to 20 fold increased risk of illness we can talk about that and And I think would be helpful to know that but that's about one in a thousand patients So what we really need is is is be able to have that kind of conversation with the majority of patients And that the way that's based now You probably have these conversations yourselves as we say well if we look at the family study data We can say that if you have schizophrenia your offspring I have about 10% risk of the illness the same as about true for bipolar disorder And so most of your kids will be fine, but that's often not very satisfying the individual patients Absolutely, if we could if we could say who's at the greatest risk you know and what about situations where you have a family where where maybe a parent has say bipolar disorder and Among the kids one of them is starting to have behavioral issues in their their teens it would be great to know whether that's the bipolar illness presenting early and Should be treated as such or whether it's something else and if we had a highly specific genetic tests We could do that. I just don't see that on the horizon Yes, so the idea is the other than the importance of family history in psychiatry and other fields and Let me tell you this is I have a whole talk on this issue Where I try to impress on residents that they need to learn how to do family histories and make it part of their routine practice And that if it's done, right, it actually doesn't need to be that time-consuming But that the the information they obtain is so valuable I think it's very striking how often people don't know about a family history Particularly of psychiatric disorders Suicide in the family is Yeah, so suicide is often not talked about People have had accidental or unexplained deaths for example They might know they had an uncle or aunt who was institutionalized, but they don't know the details so I think that's also part of our Education and de-stigmatization process is to teach young people Ask your relatives about their health understand what they've got Because it could be relevant for your own health down the road and and the enormous interest in things like direct-to-consumer genetic testing and Genealogy etc shows that people really are interested in this. We just need to help them channel it One specific Yes, it does family history help us with treatment decisions. Yeah, I think common sense tells us it must The empirical data on this and psychiatry is limited, but there've been a couple of papers suggesting that that SSRI response might be familial and that lithium response is probably pretty strongly familiar but Everything that's familial is not genetic But but the familiarity might be might be helpful when you're choosing from a variety of equally effective drugs In choosing one for a particular patient It's also helpful I as you I'm sure know that if somebody's brother or sister has had a drug and it responded well to it That that creates positive expectations That that can be useful in and motivating a patient to take that drug and stay on it until it works In the treatment so does genetic testing have any bearing in the treatment of Asperger's as far as I'm aware It does not however It may very well Be known in the near future that individuals who have autism spectrum disorders that are associated with particular CNV's Will have a particular course of their illness and might respond uniquely to certain drugs That's certainly being evaluated right now in a couple of ongoing studies. There's a large study at CHOP That's looking at this and another in Iceland run by decode But the the data is not in yet Yes, well, thanks for the opportunity to say that Um We in in in my group we study two things in particular We're interested in large families with bipolar disorder for sequencing studies that that are ongoing We particularly like families where we can compare first or second cousins because that tends to be genetically very powerful Another area that might be particularly relevant to your own clinical practices was they were quite interested in looking for the Genetic risk factors for treatment resistant depression and we're putting together Panels of individuals who have failed to antidepressants trials often. These are people who present for electroconvulsive therapy Doing exome sequencing on them and looking for unique or rare variants that might explain The failure of existing treatments to work for their depression these kinds of studies need fairly large samples So I'm always delighted to talk with you if you have a patient who might fall into one of those categories And what we could do to enroll them in the research project Certainly, how was it? Oh good