 Good morning everybody. I hope you had all a good breakfast and I welcome you to this lecture series here Which I think is quite wonderful. I have been here regular. I've been here regular tender and today I wanted to tell you about attention deficit hyperactivity Just so that you know I have no conflict or at least as far as this lecture is concerned As Jean mentioned my lab studies various disorders One is actually holoprosencephaly as you see on your left It's a disorder of brain development and it's actually the most common Developmental disorder of the developing forebrain on your right You see a child that has what's now known as munkus syndrome It's the most common craniosynastosis syndrome and craniosynastosis syndromes are those that affect the skull of and really covering the brain so that was all Good and where people said oh max is working on everything above the neck Until we decided to work on something else and one is called fatty liver Which has to do with the developing brain believe it or not So genes that I expressed early during embryologic development in later life What they do is they have to do with Regenerating the liver there's a signaling pathway that my lab was involved and the gene that my lab was involved Identifying is called sonic hedgehog and we now know or Suspect that sonic hedgehog signaling has quite and has quite something to do with the developing liver So how did my lab get to come to study attention deficit hyperactivity? It's really I guess I felt mega-lomantic after we had identified four or five genes of Mendelian disorders where parent has a disorder it's passed on to the child And we thought let's work on something complex and what's there? What's complex and pediatrics for me? It had to be pediatrics with my background What's there complex and pediatrics that we would want to work on some people said you have to work on reading? disabilities you have to work on Autism and I decided I want to work on attention deficit hyperactivity It's a little bit of opposition defiant disorder in there in me And I felt that was something that might be a good a good work Where eventually I was hoping to work on really personalized medicine to see what can we do? How can we treat every individual who has attention deficit hyperactivity disorder? specifically for his or her underlying genetic basis, so let me give you a brief outline of what I'll talk about today I will give you an introduction to attention deficit hyperactivity Most people in the audience know what it is some of you may have it yourself Some of you may have neighbors other of you may have bosses who have ADHD I Tell you about the genetics of complex traits, and I want to be sure That when I talk about the genetics or the genomics of attention deficit hyperactivity Disorder and approaches that we have taken towards this disorder that you know You can replace this with any other complex disorder That is your favorite if you are as an internist work on hypertension if you work on MIs if you work on migraine headaches you just use that same Schema that I will tell you about and you will find genes that contribute to the disorder of your interests So I will tell you about the genetic approaches. I will tell you about ADHD susceptibility genes that we have identified I will briefly talk about Pharmacogenetic studies that really will I think are the first step towards Are you okay? All right good that are really the first step towards understanding how come Different people respond differently to different medications and Lastly, I will tell you about LPH and 3 in animal studies It's really it's a functional studies that tell us is the gene of interest that we found Is it really the gene that is helping? I've heard many colleagues critical of genomics and Genomic medicine I've heard them say How recently has a GWAS study cured my patient? And I want to make the point here that what we learn in genetics and genomics that what we learn Across the street at the National Human Genome Research Institute and in genomics and genomic medicine departments Across the country how that is actually helping everyday life in taking care of patients So of course all of you know that ADHD is described by Attention deficit and hyperactivity. So this is excessive in attention It's hyperactivity and impulsivity and the important part is for given developmental age So anyone in this audience would be expected to last through a 45-minute lecture with attention span Unless it is totally boring So I will I will watch for people who are looking at their blackberries after 10 minutes or so then I'm doing a bad Job if a child would would turn off his or her attention span after 10 minutes a five-year-old child that would be completely okay It's ADHD is the most common behavioral disorder of childhood prevalence numbers vary from person from from different groups But for minimum the prevalence of ADHD is 3% of school age children The probably the a better number is anywhere between 5 and 7 and a half percent of children ages 6 to 12 years old and What I find quite striking and I did not know that as a pediatrician that many individuals who have ADHD Grow up to either outgrow their ADHD or change the symptoms for ADHD and some of the symptoms or some of the Associated disorders can be oppositional defiant disorder can be conduct disorder or can be what is now called politically correctly substance use disorder and formerly known as addiction so that cigarette smoking alcohol dependence and so on so this is something that many Individuals who have as a child to have ADHD some of them anywhere between 30 and 50 percent Are adults who struggle with any of the comorbid disorders? So it's a very important a very important disorder to study and a very important disorder to take care of Individuals who have who are affected by this there is ample evidence for a genetic basis of ADHD And that comes really from familial attention deficit hyperactivity and from twin and adoption studies And that's really something that I will talk about a little bit more in detail So ADHD has really two main components one is in attention and the criteria And even when when the testing is done There's not a single blood test that can determine whether someone has ADHD But it's really based on behavior and based on questionnaires Ideally that comes at least from two different sources ideally at least from one parent mostly the mother in an ideal world It comes from another adult that might be a teacher a kindergarten teacher. So the there's seven Main findings there and that is makes careless errors in attentive to detail Sustains attention poorly appears not to be listening. That's of course particularly difficult to assess in a teenager Follows through poorly on obligations disorganize avoids dislike sustains mental effort loses Needed needed objects easily distracted forgetful. So if anyone in this audience thinks boy, I forget things right and left I lose I lose my keys just about once a month. That would be two out of seven criteria You have to have more than two. So that doesn't make the diagnosis yet So then for the hyperactive impulsive type these are individuals These are children and the guys who fidget and squirm who can't stay seated is restless always on the go Talks excessively some people Martha Denkler at Kennedy Krieger in in Baltimore calls it motor mouse These are kids who can't stop talking. It's very hard for them to stop talking. There's like an urge there There's the impatient the intrusive and so Out of those criteria, I'm sorry. I said there were seven there nine criteria each They have to be six symptoms of each subtype So if you had anywhere between two four or five symptoms that would not make the diagnosis and most importantly For ADHD there has to be clear impairment and the impairment has to be there either in a social setting with friends In an academic setting at school or Occupational for all of us in the workforce here the symptoms have to be caused by the impairment has to be caused by age seven and then most importantly it has to be in more than one setting and Lastly, this is not something that's accounted by a four by Another condition like autism psychosis depression Let me tell you briefly about the history of ADHD and the history is really such that already in That dr. George still for the first time in 1900 in the medical literature Described symptoms of ADHD and these symptoms have been refined throughout the years most recently with a diagnostic standard manual number four in 1994 and the diagnostic standard standard manual the what I call the Bible for the psychiatrist will be there will be a fifth Edition either next year or the year thereafter and Javier Castellanos who is a friend and colleague who has worked with us on ADHD is working on the updated criteria as you can see already 1937 Dr. Bradley identified Benzedrine, which is one of the stimulants that helps individuals with ADHD and of course the best known is Ritalin and Methylphenidate and that is one of the medications that's taking being taken by many Individuals with ADHD and the pros and cons. I'm happy to talk about in the discussion afterwards However the discussion however the history of ADHD didn't really start in 1900 So there are some people who say when I was a kid 50 years ago There was no ADHD around and I wanted to convince you of the opposite. There was already in 493 before the current era Hippocrates described patients with quick responses to sensory experience But also less tenaciousness because the soul moves on quickly to the next impression And what he proposed to me it sounds a little bit like five element theory of Chinese traditional Chinese medicine He proposed an overbalance of fire over water and he already described the treatment as barley rather than wheat bread fish rather than meat water drinks and many natural and diverse physical activities and you will not be surprised that the physical Activities have come very much back into favor again because there are after all some side effects to medications and Lastly growing up in Germany. I cannot resist to tell you about a German. He's actually not a pediatrician He was a general physician. Dr. Heinrich Hoffmann who in 1845 described a book that describes all sorts of children's behavior So I knew this book by heart and my parents thought I was above average But they just had read it to me so many times. I couldn't read it I just knew it by heart and it's called a shovel Peter or slovenly Peter and this was drawn and Written by dr. Hoffman. He was a lousy poet But of course our own Mark Twain many of you will not know this our own Mark Twain spoke German fluently when he traveled through Germany around in the 1860s he saw this book translated it into English and it was really it was quite a hit in this country here So let me tell you two stories. There are many stories in the end I have to tell you this being a German story book it always ends bad bad So a child a child that sucks on the thumb you can tell what happens to that thumb a Child that plays with fire. There's just a heap of ashes left here So it's it's it's really deterrent. This was a way of educating Parents and children then just wanted to tell you about the story of fidgety Philip I just read you the beautiful version in English even though the version in German I could read to you without an accent here. Let me see if Philip can be a little gentleman Let me see if he is able to sit still for once at table Thus spoke in earnest tone the father to a son and the mother looked very grave to see Philip So misbehaved you can see what happens to him here in a moment here There's like family drama the dinner is gone Philip is under there and when you go through the lines line by line what you find is Philip fulfills eight out of nine criteria for the hyperactive type of ADHD The point as a geneticist that I'd like to make is when you look at the father I think the father has some problems and the problems of the father are twofold in Germany You of course children at the age of seven or eight I taught to eat with knife and fork but not this way if you look at the father how the way he holds his knife I would venture to say yes. He has anger management problems The other part even though in France you might drink red wine at dinner in Germany That's highly unusual So I would venture to say that the father might have some drinking problem as well So just want to point that out that dr. Hoffman you already about genetics here, so and then the next story is you can tell I won't read you this story here the story of Johnny had an ear and what happens to Johnny had an ear is Oh, let me just read it anyway because Mark Twain's English is just so beautiful as he trudged along to school It was always Johnny's rule to be looking at the sky and the clouds that floated by but were just before him lay in His way Johnny never thought about so that everyone cried out Look at little Johnny there little Johnny had an ear and you can see he falls over the the dog there The point that I want to make is that it isn't just a Johnny had an ear who fulfills seven out of the nine criteria for the inattentive type of ADHD I would venture to say which dog would bump into a person I would venture to say that the dog also has a touch of inattention and And Mauricio Arcos Burgos in my lab could show that this trait is actually quite Ancestral so that we know this didn't just arise in people But it arose way back in our ancestors before we Emerged from the the animal kingdom so to speak Okay So I think by now I have everyone in the audience that I was told to just talk a little bit longer because people might come In a little later and now I wanted to tell you about the genetics of attention deficit hyperactivity And that is the question is always were you born that way? And is this really something where you don't have any choices about and the short answers of course to give you the answer Beforehand of course we have choices. There are susceptibility genes out there and when I talk about 88 when I talk about genes that contribute to ADHD You will hear me be very careful. There is not the ADHD gene But there are numerous genes that contribute to ADHD and I call these ADHD susceptibility genes ADHD is a complex genetic trait and any complex genetic trait is Of course caused by both the caused by genetics and the environment and I would even venture to say that it isn't just the Environment that has an effect on ADHD or the genetics that has an effect on ADHD I would even go as far that there is an interaction between the environment on the genes and on the gene from the genes to the environment I think the next slide points out really the complex genetics or for that matter actually Genomics it doesn't help if on your left you have all the genetic factors and on your right You have the environmental factors that there is one gene and if you only were to fix it you could cure the disease It's certainly not that easy so in order to better understand the genetics of Complex traits. I wanted to just a have a very very brief Discursion into something that I know you have heard all before in medical school and graduate school and that is that twins have been studied for centuries and Probably over the last 50 years more and more in genetics and of course as you know twins come in two They come in two kinds They come as monosygotic twins or MZ twins and disygotic twins on your right or DZ twins As you know in monosygotic twins, that's one fertilized egg that then splits up Completely and then there will be two individuals who have just about hundred percent of the genes in common It's not exactly hundred percent, but let's for the that's for the moment. Just leave it at that and they of course In the same at the same time in the in the in their pregnant mom And are born at the same time and then if they are raised in the same household Supposedly they have the same home environment Dizygotic twins are those that are no more similar than siblings Except for they were in the womb at the same time are born at the same time and their genetic material is that of siblings They're 50% of genes in common as you see in the twins on the right So twins monosygotic twins and dizygotic twins have been studied for ages And they have been particularly popular for To study the genetics of complex traits So what I'd like to do here is I would like to show you this slide And I think one more that I have requires just a little bit of attention So I'd ask you take a real deep breath and and nourish your your neurons and just stay with me for just two minutes What I wanted to and you can hear me when I walk away here Good what I wanted to show you is I wanted to show you a total of eight studies here And these are studies that were done between 1980 on your left and 1999 on your right so in essence in a almost 20-year period in different countries and these are all studies of ADHD What I wanted to show you is I wanted to show you on your left the blue bar is The value for monosygotic twins those are the ones who have identical genetic immaterial and the ones on your right and orange Are the ones with from dizygotic twins? So what this is these are twin Concordance studies these are studies that are very commonly done not just in attention deficit hyperactivity But in many other complex traits So if ADHD were 100% genetics what you would expect if one twin Has ADHD or if we have a total of 100 twin pairs then out of the twin pairs The other twins would have a hundred percent ADHD as well what we find in this study here It's about 70 percent if one twin has ADHD then out of the the other twins Only 0.7 or out of a hundred only 70 will have ADHD so that means that about 70% is genetics whereas 30% is environmental does that make any sense to you good I see nots wonderful if you look at this study Study done by complete by completely different group using different criteria, and they find about 80% is genetics and 20% is environmental 66% and so on you'd be surprised how actually Similar this is among the different studies when you then look at dizygotic twins the recurrence risk if one twin has ADHD Where the second twin has only 50% of the genetic material the recurrence risk is just about 25% and that makes perfect sense that is what we see in families if there's one child who has ADHD There's a 25% chance that the other twin has ADHD So this is a study that tells you about Heritability and I remember vividly when I came here to the National Institute of Health for an for an interview 1996 the first question that Francis Collins asked me when I told him I wanted to study attention deficit hyperactivity He said what's the heritability and I said 70% and he said oh that's higher than for diabetes Which he was studying and I had the job so So it's very important to know when you study complex traits that you know What is a heritability because if the heritability is zero you would be wasting your time? Even though I've heard many times from colleague It's a waste of time to study the genetics of ADHD, but I want to convince you otherwise I hope I could convince you based just on a total of eight studies done over a period of 20 years that about 70 to 80 percent of ADHD is genetics and 20% is environmental Just to give this to you in a different in a different study here Where the just the bars are in another way where here you see only mono zygotic twins listed and what you find Here is the heritability factor only of height is higher Schizophrenia is pretty high asthma is about 40 percent and breast cancer Which most people probably think has to be just a hundred percent of genetics and it's actually when you look at those numbers It's anywhere between 20 and 40 percent and the other part is environmental since I talk here about a behavioral Trade or behavioral most common behavioral disorder wanted to just show you those numbers for other Psychiatric disorder so for example the heritability for Alzheimer's is 58 percent attention deficit type activity in the second 75 percent alcohol dependence is as high as 60 percent or 55 percent and then you can go through the list and then you see at the bottom Schizophrenia is rather the genetics the heritability is rather high with over 80 percent So let me tell you what we did there are many approaches to study a complex trade and as a Geneticist I feel very strongly the most important part is really detailed clinical examination So this is what we did here. We looked at the severity of the phenotype We looked at the sub types. We looked at inattention hyper activity impulsivity We looked at co-morbidities oppositional defiant disorder conduct disorder alcohol dependence nicotine dependence and so on and then most importantly what we did as I mentioned for each of Those symptoms we looked at the individual severity. So how can this be done? Let me show this to you on the next slide here And I just have to this may be another one where you may have to take a deep breath and after that It's just smooth sailing. I think so what you see here on your left hand side you see the probability of a symptom occurrence or for let's make it a little bit easier for For a sake of understanding it a little bit better is if you are at zero You don't have the symptom if you are at one on on the left scale there You have it very severely so and then on here what you have is you have the individual Nine symptoms for inattention each tick mark here is a symptom for inattention hyperactivity impulsivity Oppositional defiant disorder and then these are the co-morbidities orders such as conduct disorder and oppositional defiant disorder and nicotine So when you look at individuals for example, it's hard for me to see. I think this is a brown line here So these are individuals who have very little symptoms of inattention very little symptoms of hyperactivity impulsivity Oppositional defiant disorder. They don't smoke. They don't drink in my lab They would call them the boringly normal so when you when you then look at individuals who are in blue For example, you see there's not much of an inattentive subtype But there's some subtype of both hyperactivity and impulsivity and you're not surprised that the impulsivity Goes together with oppositional defiant disorder and the part that I didn't mention is this is a scale This is not just for the others It's not just for the ones who have ADHD This is a scale where all of us would fit onto so some of us would be somewhere in the light blue line Some of us would be in this purple line Some of us would be in the blue in the brown line here and you can imagine there are other clusters there and The yellow line is a cluster of individuals who have more of the inattentive Instead of the hyperactive type and then as you can tell here These are individuals who are severely affected with both hyperactivity and and Inattention and some of them have with conduct disorders and some of them don't so Using those very detailed clinical findings allows us allows others to do human genomic studies and what they what they allow us to they first of all they allow us to really determine Heritability estimates and the heritability estimates are those that I showed you from twin studies There are other ways of doing this There's a factor called lambda s where you can do this in family studies and that's another measure for Contribution of genetics of environment you can do other Possible designs you can use candidate gene studies You can use genome white scents where you use Marcos where you use single nucleotide polymorphisms from around the genome and we have more of more and more of those Available now and you can do that in SIP pairs where all you have is you have two affected children with ADHD Or one child who has ADHD and another sibling that doesn't have ADHD You can use large family studies or you can do association studies The letter association studies or genome-wide association studies I'm sure something that you have heard many times now and there are many genome-wide association studies which show Beyond any doubt the involvement of a certain chromosomal region in a chromosome in a specific disorder For ADHD a large-scale study is ongoing It's a study that's happening at the Broad Institute I guess as we speak and includes numerous samples from from my group and from groups around the world So these are studies where you have over 10,000 individuals involved But let me show you how we use genetic approaches here We decided this was a number of years ago that we decided we wanted to use Small pedigrees on your left large pedigrees on your right where each individual who has A red dot in it has attention deficit type activity disorder the ones who don't have the red dot in it do not have ADHD and Doing this we find that there are disadvantages and advantages If you just have small pedigrees you need large samples if you have large pedigrees The disadvantages are they're hard to come by and I think then the other part that we wanted is Something that I'll tell you about in just a little moment and that is we wanted to have large families from genetic isolates and you all know their genetic isolates there where Individuals have been married always amongst one another like in Finland like in Iceland Like the Amish and we decided to study this the problem There's of course that many times their individuals were both Spouses where husband and wife both have the trade so it's very difficult to determine where does it come from and with ADHD? And that would be called genetically by linearity here So we would exclude those some time ago, and I can tell you in ADHD Our experience has been that when we looked at families that we had to exclude about 90% of the families and only 10% we could use for study because the 90% of the families we had by linearity That's a technical term here, and I think in plain English what it means is that people who have a high level of energy Like the company of other people with high level of energy and then they have children with high levels of energy Okay, so then the advantages Once you have a large sample then you really have a statistical power and by looking at large pedigrees You have patterns of segregation that you can study and eventually by combining both It is possible to identify genes that contribute to ADHD So let me tell you about the genetic isolate that we did study South America obviously and what you can see is there are the Andes Mountains and anyone who has seen Motorcycle diaries will know the Andes Mountain go all the way along the Along the Pacific coast of South America and then what I didn't know is in Columbia in South America There are a total of three parts to it There are the Western Andes the Eastern Andes and the Central Andes here and then in the middle of it There is a an area called Antiochia Which is nestled in between the Andes Mountains on either side and the the main city There's called Medellin that name may be familiar to some of you for a different reason here and This is where a group lives that call themselves a Pisces these are highly educated people Their origin he came from Spain came 400 years ago from Spain immigrated there and stayed there amongst themselves and did very little mixing with The natives for a number of reasons and one was because they're so highly educated Many of them are MD PhDs some individuals in my lab are Pisces very highly educated people Okay, so this is a pedigree from the Pisces where at least the generation that would be my generation Whether our individuals anywhere between 8 and 16 siblings and I can tell you for a geneticist That is truly a dream come true to have a family that has 16 siblings that can't get any better than that It's just fantastic Okay, so this is a real-life pedigree. I had to you you'd be thinking what what what do these symbols mean? Why doesn't he make just a square and to circle for males and females my IRB told me if I do that Someone in the audience could recognize the family. So I refrained from that. So what you have here is What you have here is you have Individuals who have ADHD or possibly ADHD and in the same real pedigree This is not compute just computer generated, but this is a real-life example There are some individuals who have conduct this order or positionally fine disorder and the point that I wanted to make that some Of those disorders conduct this order can go Individually separately as you see here and then in some ADHD and conduct this order So it's it's a study that requires lots of Computational support and what you see here is many times and of course that's not in the children's generation But only in the adult generation you find alcohol and nicotine dependence So I will jump from this slide to the next slide Which were which I would have given a 45 minute talk about just from one slide it what this requires about a million dollars five postdocs work and do the linkage studies in a total of 400 people coming up with regions in the genome that have Significant regions of linkage telling us in these regions on chromosome 4 chromosome 5 chromosome 17 chromosome 8 and chromosome 11 we can expect genes to find genes that contribute to ADHD and To again fast-forward by a year or two I will go directly to the gene that was identified by Mauricio's Mauricio Arcos Burgos in my lab now at the University at the National University of Australia Where he identified a gene called? Lutrophilin 3 and Lutrophilin 3 is a member of the LPH and Family subfamily and it's something that's called G protein coupled receptor These are quite common genes and quite important genes and I wanted to just point out they are Important as you can tell here these are lipid moieties here, and this is a cell membrane This is outside the cell this is inside the cell these are the transmembrane domain regions And so what this G protein coupled receptor Lutrophilin 3 does is it transfers a signal from outside of the cell to inside of the cell and When we looked at Marcus within this gene we found that there are some genes actually sorry I promised you there would not be any complicated slight more. This is definitely the last complicated slide here So where we find that if you have a certain Haplotype that is certain base pairs at specific places in this gene We can tell based on these Based on these this haplotype we can tell that this is what we would call the protective haplotype if the child inherits the gene with this haplotype the child most likely will not be affected whereas if the child inherits this haplotype with specific base pairs in it what that is telling us the child has a four times higher chance of having ADHD and we named that the susceptibility haplotype versus the protective haplotype in green We went on to study We did a number of studies. We used LP agent 3 looked at expression in the brain and we find that it is expressed exactly at those parts in the brain that actually have to do with ADHD certain parts of the Anterior cortex certain parts of the cerebellum, but we wanted to do something else and we looked at the Pisces They were willing to participate in a brain imaging study a metabolic brain analysis using what's called proton magnetic resonance spectroscopy and what we did is we looked at the one age MRS Index and that is an index of neuronal number metabolism or viability and There is a specific ratio there after having given this talk many times. I can even pronounce it I will I will spare you the details here and what we did is we looked at Individuals from the Pisces who have at least one copy of the susceptibility gene or even two copies And then we looked at the Pisces who have at least one copy of the protective haplotype And then we looked at individuals who have different variants and let me show you what we find What I realized the arrow bars have disappeared on the slides here But what we find is if you either have two susceptibility haplotypes that means on both chromosomes you have a susceptibility haplotype When you have that or you have one susceptibility haplotype you have a different ratio of the n-acetyl aspartate to creatinine ratio Compared to if you have one or two protective haplotypes So what that is telling us that based on a difference in underlying genetics Genetic haplotype if you have either the susceptibility haplotype or the protective haplotype You have a different ratio of brain metabolism Happening and this happens to be the the right medial and blood right lateral Thalamus we picked specific regions here known to be involved in ADHD and Now I wanted to switch from are we convinced this is a gene that causes ADHD to actually does it help us so if we are convinced this gene has to do with ADHD Which everything is speaking for it including including the the the brain met metabolic studies We wanted to see so if that is correct Does it help us with treatment and just to give you a just very very brief overview And there are a few slides and this is one of them courtesy of dr. Nora Volkov from the National Institute of Drug on drug abuse Where this this where she gave me this slide where the diagnosis of children with ADHD is reported in the 4 to 10 year old range as 5 and a half percent in the 11 to 14 year old range as 8.6 percent and 15 to 17 as 9.3 percent what I find striking is and I trained in pediatrics in the early 80s I We didn't have that many children on medication when you look at this now, and this is a study from 2007 you find in the 4 to 10 year old range about almost 4 percent or 3.7 percent are on medication 6.3 percent are on medication 5.2 percent are on medication and these are is not a percentage of individuals with ADHD But this is a percentage of school-age children who is on ADHD medication So we felt it was particularly important to see how our children responding to medication and what we did is we looked at interviews that we performed with parents while children were of medication on your left symptoms of medication or symptoms on medication and Many of you may know that parents or at least some parents take their children off medication During the summer break. They do not take them off while they're in school as you know ADHD medication is the second most common medication used in college-age Adults, but just in the time of of exams here So when when we look at those what we find here this zero mark would be the in un in quote-unquote would be the The ideal world here and here the symptoms for 1 through 9 for inattention and 10 through 18 for inattention So here are the again the different what I call latent classes or what our Psychiatry colleagues call latent classes where everyone in this room will fall into any of those categories What you find the same individuals were tested of Medication and on medication and what is striking you find even though that Medication has a appears to have a beneficial effect for most of those classes So you see that the black line that's very severe there gets a little bit better But not really much you see that some children respond quite well to medication So for example those in the red line who have quite severe symptoms in the 2 to 3 range and whereas here They are just about in the normal range So for those individuals for those children Stimulant medication seems to be quite the thing to do with limited side effects But then as you see there's some individuals and that's about up to one third of children who are on stimulant medication They do not respond very well at all when we now look at our snips our Helplotypes ADHD susceptibility Helplotypes versus the protective appetite we find there's a different response to medication And we were very pleased when we saw this because based on this study it will give us With doing some more work on this it will give us some idea Will a child respond to medication or not as a first step towards? Towards thoughts personalized medicine So let me summarize this part here. We One of the genes for ADHD Lutrophilin 3 confers susceptibility to ADHD This was replicated in many many studies around the world We had in the end up to 6,000 or even a little bit more than 6,000 individuals Participating we find that LPH in 3 is expressed in all the right areas that are related to brain We find that LPH in 3 susceptibility Altos changes the circuits the metabolic circuits in the brain that are implicated in ADHD and Lastly we find that variants are associated with response to stimulant medication So let me just show you the papers here and the person that I've talked many times About is the first author on this paper Mauricio Arcos Burgos many of the people who are on this paper I see in this audience here, of course many people are from abroad Javier Castellanos Joan Bailey Wilson from from our own Institute Here's a replication study from Spain that shows in an adult Sample that this is that this is identical and then I wanted to show you what we have done what what my lab has done We have done behavioral genetics in the zebrafish and I just wanted to show you There's something what you can do what you see on your left here You see this is a fertilized zebrafish egg and Zebrafish are these tiny little critters They are called zebrafish because they have stripes on their back looks just like zebras except for in fish and very small And this is the first fertilized egg and there is a technique called Morpholino knockdown where you can use specific a specific genetic tool where you can down Regulate the gene expression in this developing zebrafish Nowadays they are much better methods out there Like a one method is called tailing where you Continuously take down regulate the gene expression, but this was the best that we could do a number of years ago and So you let the fish develop and after five days the fish five days after post fertilization this fish can Can swim freely and can you can do all the testing in the world? So we did all the testing in the world. It's a little hard to test a tension span in the zebrafish Didn't quite know how to do that But you can test activity in the zebrafish and to my dismay last night the fish still Swem on this slide and when I looked at it this morning my fish start a strike here So you just have to believe me when when you do these these little critters This is a petri dish just about this big on a on a microscope And this is done with taking a picture every millisecond So if with a thousand pictures in one second you can see where each fish is going and you can study each fish Individually when we do this and we compare the behavior of zebrafish that are altered that have a down Regulated lateral fill in three gene what they do they go to the light source much faster. They're adventurous They are thrilled thinking they're just going there real quickly when you compare fish by fish And when we do this with thousands of fish compare them with normal control We find if we downregulate the protein or the gene and then the protein of lateral fill in three We find that there is a significant difference and we can tell the ADHD zebrafish from the non ADHD zebrafish So what we would feel us that this and other assays in the animal model might be a wonderful way of Finding additional treatments that are very specific for children with ADHD where indeed currently One size doesn't really fit all where we want to based on those studies where we want to see what can be done With regards to specific treatments for a specific person this work has been confirmed by other groups by Laura Bailey quiff and very much to my delight a former graduate student in the lab Dian Wallace has now Has now studied mice where she downregulated lateral fill in three and she finds there There is addictive tendencies and mice just imagine drunk mice and hyperactive mice That have problems when lateral fill in three is downregulated So let me close by telling you where is this all going and and let me just sum it up here I think I could convince you that number one ADHD is a complex genetic trait It's the most common Disorder behavioral disorder in childhood that goes on into adulthood has different forms addiction smoking alcohol Conductors order and others are part of it So our studies really are very were very interested My lab and others are very interested in predictors of treatment response Why expose a child to methylphenidate with a best-known one is Ritalin if the child doesn't respond if we know this in advance Why not use different treatment modalities for children who do not Respond then of course we would want to have predictors of long-term Outcome and those are studies we have done we have completed, but I didn't include them here We wanted to have severity of core symptoms and I can tell you we have looked at different genes If you have susceptibility on two different loci Let's say lph in three susceptibility loci and another gene that's called n-chem one Neural cell adhesion molecule number one if you have both of those genes that predicts a more severe outcome And we want to know about Association with comorbid disorders such as oppositional defined disorder Conduct disorder substance use disorder and the goal of all of this is really that we have personalized diagnosis and treatment for children in the future that it isn't like that's as some people proposed Let's just put Ritalin into into the drinking water or have Ritalin O's and as you can see kids go crazy for Ritalin O And I hope that we don't go there, but that we really go towards personalized medicine This work couldn't have been done without the help of many many people this photo is slightly too old But the ones who are in the in the photo have done the work is Mauricio Arcos Burgos Siggy Baylock Maria Acosta isn't here Jorge Ivan Villes over there Many others have contributed and some of the slides that I showed today are from Nora Volkov Thank you very much for your attention Thank you The way I understand it is there are different Inherited different factors that contribute to bipolar disorder then contribute to attention deficit type activity as you can imagine, of course In common disorders and ADHD is as common as some people say 5% or up to 10% It's not so uncommon to have both to have attention deficit and attention deficit type activity and By polar disorder at this at current point at this point in time I don't know whether there's a common etiology or just true true and unrelated The question the question was is there a common etiology are there same genes that cause By polar disorder and attention deficit type activity. Is that about correct? Okay, and the short answer is that at this point I don't think genetically there's evidence there for a common threat in Bipolar disorder and ADHD Is there less ADHD in Europe than in the US and does early discipline has any preventive effect? That is a wonderful question and you heard all the question I mean when I talked in Germany some 10 years ago when I talked about ADHD and the study that we do in the US They said the ones that had ADHD. They're all immigrated to the US. We don't have it here Of course, we know that's not true We know that is not true and ADHD exists as much in Japan in cultures where there's lots of structure there However, the environment has quite an impact on behavior Okay, let me give you an example of a colleague of mine from Japan whose two boys were born in Japan He did a two-year postdoc in Seattle and the kids were in an in a kindergarten And they loved it the kids came back to Japan and after two days both parents were called into the school And this is highly unusual that parents get called in and they were told their child Their children climb on the table. They don't listen to the teacher and the parents were slightly embarrassed But then they thought that was what happened in Seattle They could they could climb on the table in their kindergarten. So structure does help and home environment does help It doesn't change the genetics, but it changes the output. It changes the behavior there. So Yes So the question was of course what what I had here is or I said that about two-thirds of children respond to ADHD and one-third don't and that was of course an exaggeration and what as you could see on the study that we did almost Every child responds in some way, but the question is is it good enough or is it not good enough and whether it's then Two-thirds respond or eighty percent respond. I think it's probably more a question of semantics Different studies in monogynetic twins who were separated Have there been studies in monozygotic twins that were separated there only case reports there But not large-scale studies in those case reports the The studies come out just about the same as as was here. So yes I have a two-part question. The first is with the environmental component. Is that reversible or non reversible? In terms of ADHD and the second part is that I see a dose with chronic pain sleep Disturbances which are poor coping that have higher levels of ADHD than maybe they're Siblet there are the people of the environment. Is that considered? Environmental or just poor coping skills that then just brings out something that was there The last part I find both of your parts are fascinating. Let me address the first part first Can you just remind me Okay, is it we environmental component reversible so the genetics is what we have of course But it's what we do with it is I guess is what we care for so some people with ADHD Seek out certain Professions I could give you many examples where when you go to YouTube you see people do things yet You wouldn't want to do in a lifetime that I find dangerous Bikers yes, you see high jumpers with these little flapping wings. They're like oh it makes me shut up But there there are people in the medical field who are very successful at this And I know one colleague at an Ivy League University He was he was the most gifted emergency room physician because he was so good He was promoted to division chief and he failed miserably Because that was not it didn't suit his his his genetic makeup So I think you can choose what you do but at the same time you can You can as a parent you can provide an environment that helps Children to grow and to learn structure where they do better than non-structure Children who have lots of exercise do better than children who don't have exercise Interestingly, there are studies out there. I Hate to say this thinking my boss will see this this video here. There are studies out there where Individuals with ADHD have been taught meditation Meditation seems to have an effect. I'm not sure there's a significant p-value there so that various non medication Modalities appear to have an effect whether that is good in the long run. I don't know your second question was quite Provocative and intriguing. It's something. I don't know you if I if I get it correctly you said that Individuals who have pain syndromes some seem to have better coping skills than others. Is that correct? They might have worse coping skills and that group that have worse coping skills might then have Seemingly a higher level of ADHD than other patients I see in the practice, and I don't know if that's just bringing out something. That's there I don't know the answer to that. I find it quite intriguing I'd love to talk some more about it to you what I find quite striking is so ADHD The other the susceptibility to it is they are almost from birth and at different stages in life They're different challenges to master So some people some people would say that how come my child had never ADHD out of a sudden He's in college and now he starts smoking pot drinking doing this this and this and this and there may be some in the room Who have children who do that and what it means is you have different challenges to cope with It's not that out of the sudden the child has ADHD, but out of a sudden there's a different structure There's there's a different environment there like the coping with pain that out of the sudden the resources that were learned and successful Over lifetime may not be sufficient anymore Can you just clarify the association with the landfill and three and this susceptibility to medication Secondly I mean could this Both questions are great and for the second one I almost feel as if I paid you to to ask that question So I did not for full disclosure here. So I think to answer your first question and that is What is Which which of the ones which of the susceptibility of the protective one go together with with response to stimulant Medication so the one the susceptible susceptibility haplotype goes together with response to stimulant medication So the answer is yes, your second question was so good that I forgot it and say it again one more time Yes, okay Yes, we thought exactly the same thing because we thought obviously you know all of you in the audience You pay my salary. I'm a federal employee This is your tax dollars at work and we were wondering how does something from a remote Culture, how does it affect the rest of the world and in the beginning? We didn't know of course and we were hoping that we would learn something about ADHD That would lead us to pathways that we might that might be useful for studying ADHD in the US And of course all of our SIPA studies. They are done within the US We were very pleased very very pleased once we had identified That were fit in three in this rather specialized population to confirm it in our US ADHD study We could confirm it in not just a sample that we had collected here, but in a sample That dr. Josephine a liar at Children's Hospital of Philadelphia had collected We could confirm it there that there's a significant p-value for an association to ADHD We could confirm it in Norwegians We could confirm it in in a group of Spain never mind that's kind of confirming the ones that had left to to South America we could confirm it in Germans could show yep You have had it all along anyway So we didn't have samples from Asia, but we have samples we have had samples from most European Ancestry cultures and of course in the US our sample is very heterogeneous very etiologically diverse including Hispanics African people of African-American descent as well as an expert in neurology Can you comment on the palmist as a place that you would choose where you designing a central nervous system as a place Yeah, I appreciate the promotion to the neurologist which I'm not But let me give it a try so there are certain areas in the brain the thalamus being one of them that has specifically to do with Excitability there are the nuclei the putamen other nuclear in the brain where More or less stimulation will have an effect on behavior and that's probably as far as I could go Yes So this is something that interests me a lot Especially it interests me a lot since there are side effects, and I I do not think that Every child responds well to methylphenidate at this point There are numerous studies out there that are mostly Underpowered so the short answer is I don't think the answer is in yet Yes What about and how does it have to do with ADHD Yes, yes, so as you know, there are numerous Books out there popularized books have been at many ADHD support groups And that is quite a lively undertaking their physicians out there who have ADHD themselves who write books about this Who write books about the hunter and gather our genes and all of that? And so what what we did find was we looked at the genes we looked at the susceptibility haplotype so these are unpublished data and we find that the susceptibility haplotype is the actually the Ancestral gene that's the gene that has been there earlier So all of you in the in the audience who who do have the susceptibility for ADHD Who have this gene? They're the ones who came first the ones that don't have the that have the protective gene There would be the quote-unquote mutants. However nowadays Being that that we don't have a hunter society anymore But children will have to sit still in class and that has only happened over the last 150 years or so at least for the general Population there are there's certain behavior that Either favors or is favored by the susceptibility gene versus the the protective haplotype. Does that make sense? Yes I say it again in the image In the imaging To show those areas What what the area was all what did this was not a non-invasive so this was not with this was not with with Any any contrast is that your question? Yeah, but I think they have labelled amphetamines that could be used in Imaging now to show exactly where where they go. Okay, so those are studies I don't think those are studies that could be used in children. I don't I'm not aware of those studies I understand your question, but I don't think that study Can can you do you do the answer to that study? Okay, sorry. I'm unable to answer that question It's one last question here Yeah So so the question is The Neanderthal genome do they have the susceptibility or the do or do they have the protective haplotype? We haven't checked yet. As you know, there were colleagues from our Institute Who have who have participated in that we have not checked what what my lab has done is We have looked at our closest relatives and our closest relatives the various Non-human primates. They all have the susceptibility haplotype. So Okay, I think Thank you very much That was fun great audience