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Traumas Epigenetic Impact on Mental Disorders

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In this week’s episode of Everything Epigenetics, I am joined by Dr. Janitza Montalvo-Ortiz, Assistant Professor of Psychiatry at Yale University, who shares her journey into the world of epigenetics and psychiatry. 

Dr. Montalvo-Ortiz explains the pivotal role of epigenetics in understanding the genetic and environmental factors contributing to psychiatric disorders and emphasizes the importance of trauma exposure in shaping mental health outcomes.

Our discussion covers her research into the epigenetic mechanisms behind psychiatric conditions, particularly in underserved populations like Latin Americans and military veterans.  She highlights the need for multi-omic approaches to fully unravel the complex interplay between genes, epigenetics, and the environment. Dr. Montalvo-Ortiz also discusses the development of epigenetic clocks like GrimAge, which assesses mortality risk and incorporates factors like DNA methylation changes due to smoking.

Furthermore, Dr. Montalvo-Ortiz shares insights from her studies on how lifestyle and psychosocial factors can influence aging at the cellular level, and dives into the specific epigenomic differences in individuals with nicotine dependence.

She concludes with her research on the epigenetic signatures of PTSD in US military veterans, spotlighting the potential for targeted treatments.

Join us as we explore these transformative insights, which not only deepen our understanding of mental health disorders but also open doors to innovative treatment strategies.

In this podcast you’ll learn about:

– What epigenetics means to Janitza
– Janitza’s journey
– Genetic and epigenetic mechanisms associated with psychiatry disorders
– How we can use epigenetics as a tool to learn more about psychiatric disorders
– Using multi-omics datasets (genomics, methylomics, transcriptomics, proteomics) to better understand the underlying mechanisms and identify predictors or biomarkers for these disorders
– Why it’s important to look at underserved populations and how we can extend these findings to the general population
– Psychosocial factors associated with GrimAge in Male US Military Veterans
– Epigenomic differences between smoking and nicotine dependence in a veterans
– Epigenetics in posttraumatic stress disorder in U.S. military veterans
– Current challenges in epigenetics
– What’s next for Janitza

Transcript:

welcome to the everything epigenetics podcast where we discuss DNA regulation in the insights it can tell you about

your health I’m Hannah wet and I’m the founder of

everything epigenetics today my guest is janitza Montalvo Ortiz

she is a professor at Yale and her research interests include the study of

the genetic and epigenetic mechanisms associated with Psychiatry disorders we

are going to be talking about epigenetics and mental health today and

how trauma exposure and Trauma type are related to mental health and what we can

understand with those outcomes through the lens of epigenetics

she really investigates how these trauma-related events increase the vulnerability to develop mental

disorders later in life her mission of her lab is to advance the

understanding of genetic and epigenetic architecture as a way to dissect the

underlying mechanisms of the complex interplay between genes and environment that contributes to an increased risk

for psychiatric disorders we’re going to talk about several of her studies really

looking at psychosocial factors associated with some of those biological age algorithms

in U.S military veterans and a lot of underserved underpopulation-based cohorts if you all

are wanting to learn how mental health can be studied through epigenetics this is the episode for you

and now for my guests Dr yanitza Montalvo Ortiz

welcome to the everything epigenetics podcast Dr Montalvo Ortiz I’m excited to

have you today yes I’m here thank you so much for the invitation of course and I

gave my listeners a little introduction to you before we started off here and I want to start this this show off a

little bit uh different and really start out with the question what has epigenetics done for you what is it it

mean to you it’s a really new field and I’d love to get your perspective there yeah so this is a very

um interesting question and it brings very happy memories from when I decided

to start getting into this field it was back when I was a grad student not a lot

of people were doing epigenetics in the context of Mental Health and I saw that as an opportunity to

develop myself as a researcher and as the field develops I have to say I

started to meet people in the field and even senior pis that has that

personality of like curiosity higher curiosity like being more you know

risk-taking people because it’s a field that you know it has so many unanswered questions

but still yet like promising in terms of addressing huge gaps in understanding

um the underlying biology of mental health which has a huge environmental component to it right so so yeah so I I

see epigenetics as an opportunity um to develop as a researcher and

um yeah it’s an exciting as you said New Field I would say relatively new

um but with a lot of promises and I’m so happy that I showed that as a career

um yeah moving forward yeah that’s a perfect answer I think that puts a lot into perspective too for maybe anyone

listening who’s very new to the field or again anyone who’s been in the field for for quite some time I think everyone in

this field of study has a lot of respect for each other because we’re taking a deep dive into the unknown but discovering

new things I I think you know I definitely learned something new multiple new things every single day and

um loved digging into to these uh items even further so that brings me more into

you know what are you you studying now I know that the mission of your lab is to advance the understanding of the genetic

and epigenetic architecture as a way to dissect the underlying mechanisms of the

complex interplay between genes and environment that you know definition of epigenetics that contributes to an

increased risk for psychiatric Disorder so I pulled that right from your website I think it’s a great Mission uh tell us

more about what you’re studying yeah thank you so in my lab um we we have two

big um research areas one more devoted to understanding a better understanding of

human genetics in the context of mental health and Psychiatry traits and also

the study of epigenetics right and these two components do talk to each other

they are complementary um but I’m I’m curious about

understanding what’s the connection if they can indeed inform each other in a

better understanding of the pathophysiology of mental health disorders and you know what’s what makes

them unique as well um you know what’s the contribution of genetic variants to health risk and

what’s the contribution of epigenetic mechanisms in healthbreaks that are both

you know shared and unique yeah definitely well what about

um this just out of my curiosity as well what about your your upbringing and you know where did you first learn about

epigenetics or or hear of it um you know I wasn’t able to find much about your previous studies before you

really discovered this this epigenetic world so I’d love to even maybe know that and then secondarily what piqued

your interest in in mental health and in psychiatric disorders right so for the first question

um during grad school I um I was very into

um uh learning about uh the neural pharmacology overall

um you know but from a perspective of drug addiction since that was my

background when I did research uh University of Puerto Rico during college

but then at grad school at Northwestern University Chicago I was able to expand my horizons in the

research field um I remember that very first interaction with epigenetics

um again that was something new that my Pi said well you know there is something

emerging and interesting in this and I said okay I’ll take the risk I’ll learn

more about it and I attended a meeting in University of Chicago remember

that was uh um there was more in the biochemist area nothing at all mental health

and they were bringing to the table you know more knowledge about what

epigenetic is like I remember for example that was um the explanation of DNA methylation

which is one of the epigenetic mechanisms that one of the best understood in in humans so basically

please just methyl groups added to the DNA that can influence the way the chromatin the compartments of the DNA

are organized and subsequently influencing Gene transcriptional processes whether

the Gene gets on turn on or off basically right so this DNA methylation

I remember in this conference it was a huge deal that um biochemists were started to

synthesize the protein that were characterized to be involved in that what they call DNA demethylation pathway

so it was for this first time understandable that these epigenetic

mechanisms was was indeed plastic was Dynamic it could reverse itself with the

interactions with these enzymes um so and before that it was thought to

be you know just permanent you know game manipulation something gets methylated it will be like that uh you know all

your life but here you know it was the first characterization of that and I was

like okay so they are mechanisms that are explaining the plasticity of epigenetics and

um there’s also a crosstalk of how well if we understand how these enzymes

um play a role in these mechanisms we can then develop drugs that can Target

this and then you know modulate those uh changes

pharmacologically and could be you know eventually um be used for treatment so that was my

PhD Theses on basically so it was first understanding the

epigenetic mechanisms that happens through aging so understanding the changes in the brain

um at the epigenetic level were not the same when we are very old than when we

are young or adult right and those changes that happens with aging I was

trying to understand how that um diminished the efficacy of drugs for

example specifically antipsychotic drugs and how by complementing

antipsychotic drugs with epigenetic modulators like what’s called hdac

Inhibitors that could augment the efficacy of the um of the antipsychotic

treatment even in elderly people or in this case h mice which is the model that

I use to test this um so that was my main contribution of

my PhD thesis and um and then as a postdoc I wanted to take that into

humans like you know understand I guess studying the translational component of epigenetics

um and specifically in humans in the clinics how can that be transferable

um so in humans I felt that in order to better understand epigenetics I also

need to understand genetics right um because as I I said before they talk

to each other um and and play a combined role and unique role

both on increasing vulnerability of mental health outcomes but before going

to that I wanted to provide more insight or more feedback onto why I got

interested in mental health um so there are many neuroscientists

that shows the Neuroscience is a career um we if you we read our personal

statements they all start with well I have a grandma grandparent with Alzheimer’s diseases and that actually

has turned into a cliche but yeah unfortunately I had um well three of my grandpas had either

Alzheimer’s or dementia and that awakened a curiosity of understanding

what’s happening in the brain and you know what’s happening also in a way that

can makes the brain plastic and um and uh that you know even though we go

through different processes of the neuronal level they can be reversed by

treatment by eating better you know following all the doctors recommendations you have to eat well and

sleep well um you know exercise so how those things can help

um decrease the risk of suffering from neurodegenerative and Psychiatry disorders like Alzheimer’s and Dementia

and I found epigenetics as a way to better understand um those anecdotes that the doctors

represent and providing biological mechanisms and

hopefully also novel treatments on the road wow what a background I really

enjoyed that thank you for sharing that with us um no that’s that’s amazing and you know

as cliche like you mentioned it it sounds you know I think we all start with a story and then if we we have

family members especially when their health is being affected by some again field whether it be mental health

Alzheimer’s dementia Etc I think that makes us just more intuitively interested

um in that subject so yes unfortunately I’ve been affected um by Alzheimer’s too my grandmother had it and uh you know

it’s it’s yeah just very devastating to go through that process and see someone you know

who who you love go through that so um I’ve always been interested in that too I know I have an APO three four

variant so I’ve been more you know cognizant of of this field and what I

can do from a lifestyle perspective to mitigate some of those um you know effects that may happen with with age or

as I get older um you know the lifestyle factors no one really wants to hear it it’s very

repetitive but reducing the stress levels eating better exercising

um you know having quality and quantity sleep those those are all going to play in a role and epigenetics and genetics

is a great great way to tell us more about that um so it’s just uh you know fascinated by your background and then even the the

PHD thesis that you mentioned would you call that more of a pharmaco epigenetic

realm as well looking into you know how different drugs are affecting the epigenome yes if you can say yeah yeah

that will be a nice description yeah yeah I’ve spoken a little bit um about that field on on a couple of my podcasts

haven’t done a really great dive but I think it’s going to be really interesting um if you’re pairing you know how our

genes can be affected by different Pharmaceuticals and then and even our epigenetics as well because it’s just going to help more and more with that

preventative care and choosing the medication or therapy that is is right

for that person the more personalized we can get so um no thank you thank you for sharing that that background

um so what I’m getting from all of this in our conversation you know you’re using really cutting edge approaches to dissect this epigenomic landscape of

psychiatric disorders um in you know human peripheral and post-mortem brain tissue you’re focused

on studying substance use disorders um you know trauma childhood maltreatment post-traumatic stress

disorder major depression so a lot of interesting subjects here again people listening can can relate to this whether

through through themselves or maybe family members too so how can we use epigenetics as a tool to learn more

about these these diseases these disorders um what would you say the yeah the best

way we can do that is right so um as you mentioned before one

of the aims of my lab is to understanding the like between trauma exposure and the development of

neuropsychiatry traits um and you know what’s what’s the link there and um and we do know that a lot

of people are exposed to trauma across the lifespan but you see in fact the very minority that actually developed

mental health so I wanted to understand the recipients um you know in that Association

risk and both protective factors that can help us

um in designing preventive measures and also potential treatments that can help

prevent the development of mental health once we identify a person that is at

risk um so it’s understand sustainable mostly in

animal models that trauma do induce epigenetic changes that’s very well

characterized in the animal model literature and my mission is to characterize that further and more in

detail in humans but it’s so complicated because trauma exposure is very

heterogeneous you know it can manifest in many ways and at different times across

development um and as I said you know some people do

are like when exposed to the same level trauma some people end up with

um developing mental health outcomes or disorders and others don’t

so my mission is to understand epigenetic signatures at both peripheral

and brain tissue that Associates with those individuals that have a history of

trauma and try to also look at the specificity

of these signatures based on the trauma type trauma exposure and in the

developmental stage that it happens so it’s a very ambitious Mission but

um but you know essential to better understanding what’s the link between

trauma and mental health and we’re doing this as you said you

were doing this in peripheral tissue looking at the blood looking at saliva we’re doing this and the Brain

postmortem brain tissue as well in humans and also open to collaborate with

researchers working with animal models so if anyone hears this and it’s

interested in they’re interested in collaborating with someone doing this kind of work please reach out

um but yeah because I know their limitations on when working with humans there are a lot of environmental factors

there are a lot of um things that are not capturing the data um there are a lot of confounders

variations that we’re not able to then start the captures in our single regression analyzes and

um and also when we identify something ways to manipulate that and then identify

efficacy of treatment we do need partnership with people doing the animal model work

um so yeah so and also in humans one of the major limitations is to reach good

sample sizes big sample sizes because each individual has their own story and

these stories when putting together with other people is then hard to tease out

what what whatever we’re seeing in the data if it’s in fact what we’re

interested in studying or it’s not telling us something else right so that’s why having big sample

sizes in this studies that allow us to um correct or adjust or account for

confounders it’s important so that’s why I’m collaborating in consortia efforts

like the Psychiatry genomics Consortium post-traumatic stress disorder group where we collaborate with researchers

across the globe that has other cohorts that we can find a ways than to work

together combine cohorts and ask the same questions but then in better

powered sample sizes and the same with us the brain tissue so right now I’m

trying to put together a study looking at trauma exposure in the brain combining three different brain data

sets and reaching sample sizes of close to 400. so one of the biggest so far but

yeah you know um I get I guess you know sad the sample sizing in this cohorts do matter and we

want to have the biggest sample size possible and also the diversity of the

sample sizes is important because um although I haven’t talked yet about

that but um and that will come later down the road but it’s important to have

representation of different kind of populations in these um cohorts a study cohorts to make sure

that whatever we find in our studies is representative regardless of our

background yeah definitely there’s so many different factors to take into consideration when you’re measuring

epigenetics so you know what I’m hearing from you is we’re trying to link trauma

exposure trauma type and mental health and understand that that connection there and that’s that’s really hard to

do as you were alluding to because you know you may have trauma when you’re young but you don’t start to really go

through those processes until you become older there’s a lot of different exposures that could have happened across your time frame a lot of

different trauma types so there’s not really one great way to measure trauma so to speak right so I think what you’re

maybe trying to say and correct me if I’m wrong but you’re using epigenetics as a way to try and quantify that trauma

and see what it means see what genes are being affected in those mechanisms of actions yeah yeah I think that’s a huge

need in this space right mental health can can form um you know very large taboo people are

really nervous to talk about that sometimes times but I think the more we can talk about it and discuss it and have conversations like these where

we’re moving the field forward it makes for the best types of conversations right yep yep yeah

um something else that I I really like from your lab is you you also investigate multi-ohmic data sets so you

know your genomics your methylomics your transcriptomics proteomics Etc but to to get a better understanding of the

underlying mechanisms and identify predictors or biomarkers of these disorders you’re you’re looking at all

of these in in tandem um can you explain your your approach there a little bit and then maybe I’ll

back up a little bit um you know and maybe even defining to our audience what multi-ohmics is the

different omics and levels there right so um when we are studying epigenetics

um that doesn’t work in a vacuum right so epigenetic mechanisms also interplay

with genetic variants um also influence genetic Gene

transcription down the road we need to understand you know what’s the impact of changing

these epigenetic mechanisms on Gene regulation um do we have higher expression or lower

expression of of genes what happens at the isoform level what about alternative

slicing events um and then of course if we follow the central dogma of genetics

um over the DNA we have to understand at the gene level

what happens then at the protein level how that connects so changes that were

seen in gene transcription but that also have an impact on the protein levels

whatever is translated will that make a receptor be upregulated in the brain or

down regulated and why is this important like for example medications work on

receptors right so they interact with the receptors and go through a whole Downstream effects and we need to

understand if changes that were seen at the very end of the RNA or regulations

that the epigenetic structure or post-translational modifications how that all goes down into changes in

protein levels um so that’s why looking at most theomics is essential to get the big

picture um so Nala only looking at a single domain

um but also how that domain interests and um interfaces with other ones and

um how they also you know um complement each other in following

the same mechanisms and so oh and I want to limited that to

necessarily all the epigenetics like the epigenome the transcriptone the proteome

we also need to understand the Phenom which is essentially everything environmental that an individual is

exposed across their lifetime and The Chronic term which is all the brain

connectivity that happens in an individual understanding brain activity

and how brain regions connect to each other and talk to each other um and you know metabolism to other all

these other things that also are part of the individual biology and that could

also have an impact on health risk yeah wait did you say the connect Dome

yes I’ve never heard of that omic before so I’m gonna I’m gonna add that to my

list and do a little research on those so yeah you know when you’re incorporating these these multi-ohmic

factions if you will it’s it’s more of that big picture how do they interplay how do they affect one another where do

you see that effect um and I think it becomes really interesting then when you talk about a single omic how do you measure that

ohmic and then you know how do you go from there so these are you know subjects in in their their own realm in

its entirety so um being able to connect with people kind of like you were talking about earlier and putting all

this data together can can help us make more conclusions on a larger scale

um one thing you you brought up was um talking about a lot of the research you’re doing isn’t is performed in an

underserved populations and that it’s important to make sure we have representation and and diversity

um specifically you look at a lot of Latin American populations and military veterans which will be one of our main

focuses today as we talk through some of your Publications um and it may be rather obvious but I I

love just asking you as the expert here with with your background in your work why is it important to look at these

populations and how can we extend these findings to the general population which again as you hinted to is our

overarching goal right so um my my lab on one of the main goals of

my lab it’s um making sure that our findings are transferable across populations and we I

notice a huge gap and um better understanding of it the human genetics and populations like at mixed

populations like Latin American I’m a little bit biased because I’m Puerto Rican but

um but yeah and also the complexity of analyzing um data from people that has admix

backgrounds so admix being a mix of different ancestry groups

um and what we notice is uh um human genetics feel was rapidly

advancing uh we had from we started identifying genetic variants associated

with multiple disorders started off with schizophrenia in better power samples

but um there were still underrepresented populations that were being left behind

um and I wanted to address that cap and also a better understanding what you

know ad mixture face a role in also health risk

um and why that this is important also in epigenetics is because many of these

start genetic studies um when they do what it’s called genome-wide Association studies they

look at the whole genome um our genome-wide level uh Associated

genetic variants and um they identify sometimes genetic variants

or we identify genetic variants that map into places in our genome that there are

like multiple genes in that area right so it’s not really well understood is

this Gene is this genetic variant mapping to this gene or is it like all these different genes also play in a

role in the risk or instead of Gene that is like nearby and not even in that region so how do we address that

question we do use for example epigenetic data to get a better

understanding of you know whatever findings we get from chiwas and then

identify the functional but it’s called functional genetic variants

um so we look at a text sequencing data we look at um to look at the chromatin landscape

um going to the notion that where we have open chromating we have like more

like a lot more going on in terms of Gene regulation we look at here’s some

modification landscape we look at DNA methylation um and you know all these layers of Gene

regulation we use that information to better inform the functionality of the

genetic variants that we see um so I know in the news people say oh they found a gene for this disease it’s

not actually the gene it’s a genetic variance and these genetic variants could be higher prevalent in one

population but absent or non-existent in other populations so that’s why it’s

important to do these studies in different ancestral populations to make sure that the genetic variants that were

identifying they’re also prevalent in their population and whatever

benefits could arise from applying this to clinical settings could also benefit

populations that are not as well represented and also incorporating diversity in

epigenetic work or related functional work is essential because the epigenetic patterns could also vary across

populations so we want to make sure that the um when assessing functionality of

genetic variants we’re using the right tools and the most informative tools also for

underrepresented populations yeah I think getting that nomenclature

right is huge I’m sure that that drives you Bonkers as you know a scientist you know hey the genes and then the genetic

variance and understanding what that means um but but you’re you’re exactly right that the more diverse of a background we

can get from a genetics and epigenetic standpoint because we’re all going to be exposed uh to different things even if

we’re in a different location so you know even people in in neighboring States neighboring cities you know I can

um I’ve seen Data before that uh by having a raw idat file or looking at someone’s raw methylation values you can

even tell where they live down to the ZIP code based on what they’ve been exposed to so really having a diverse

group um and again different ancestral populations um I think is is something hopefully

this this community and people in this field are you know gathering around and putting more effort into

um I’m going to switch kind of uh um you know from talking about your research in a general way to

getting more in into your your papers so um I remember seeing your name first on

this paper here uh you were looking at the psychosocial factors associated with grimage and male U.S military veteran

veterans um yeah can you describe this paper to us tell us tell us what you found

um you know I think our listeners are probably familiar with grimage as well but I don’t think we’ve ever talked about grimage too much in depth so even

if you want to you know explain the death predictor a little bit further too that’d be great yeah sure I mean I’ve

heard I I did listen to previous podcasts and then I did my homework um and I I I’ve noticed that there has

been conversations on um the first generation and second generation epigenetic looks but yeah

you’re right like the definition itself of pre-mage which is the um the

epigenetic clock that uh we have evaluated more recently

is basically an epigenetic clocks that is meant to be a predictor of mortality per se because it includes for example a

DNA methylation surrogates of plasma proteins that are associated with mortality

um a risk and also incorporates DNA methylation based estimators of smoking

um specifically smoking packed for years um so it can be it combines

um in addition to cpgs it combines that perspective uh or

cpgs Associated specifically more with mortality sort of like to come up with a

predictor of mortality risk but also incorporate that um aspect of smoking which has you know

it’s a has a huge effect in DNA methylation patterns

um and something that has been widely consistent across the literature and

also something that has been closely linked to aging and to immortality risk as well so

it’s sort of a unique and sort of different from other epigenetic clouds and the fact that they you know it’s a

combination of these two components that’s why I I really like it and we have to set other multiple fa genetic

class which I’m sure like um other researchers have done the same and so far green age has been constantly

the one that you know has a better correlation with chronological age and

has performed better in our analyzes so in the psycho psychosocial

um study we have published two recent studies in the same cohort but looking

at different um aspects and this is in collaboration with Rob petersack and uh one paper the

first author um it’s uh Amanda who has done an amazing work on putting all the data

together and Peter na um and I obviously was happy to

collaborate with them um so what we do is what we did is that in a thousand hundred thirty five U.S

male veterans we look at the associations of green age

with different psychosocial and lifetime factors so

and what we found is that when we look at health and lifestyle when uh what came up as explaining the

most variants of accelerated um remage was the number of days engaged

in physical exercise and I have this down sorry I don’t forget the details because I I feel like

you know the mag the magic is in the details of what we found in this paper so each additional day was associated

with 19 decreased odds of having accelerated Greenwich

so the more you exercise the less accelerated readmage so the less your

um biological aging basically right so and then this was also we saw also

associations with um uh higher accelerated um remage with lifetime history of SUV

substances disorders and alcohol use poor sleep um also not being married or cohabiting

with someone with a partner um with a greater accumulative trauma

exposure and this is also something that we found using the horopath

um epigenetic block uh on a previous published paper and also in terms of psychological factors

we found an associations with lower disposion dispositional gratitude and

openness so people that are more gratitude has less biological aging

basically so and I think that’s why understanding social determinants of health is

important to know you know what aspects of our environment what aspects of our

social life of our nutrition of our exercise our associated with these

parameters are biological aging which are you know also associated with health

risk so that’s what’s one of the papers we found

that was like a close to 20 percent of our cohort had

Accelerated Green age and um again this was linked to uh being

less likely to be married being obese um being current smoker

um suffering from alcohol use disorder or PTSD and PTSD showing greater

severity of symptoms of PTSD and Reporting more cumulative traumas so yes yeah

very interesting no and I I think I appreciate you going into the details I think we need those details right

um and I’ll link that paper in in the show notes so if anyone wants to give it a read I definitely recommend it but um

yes understanding I think how those social determinants of Health actually affect our mortality our morbidity our

grimage these biological age predictors so um I think you hinted at it already through noting that but what else do

these results suggest um you know what are the applications here is it really people saying okay

here’s my lifestyle here’s where I can improve I really thought the Gratitude part was interesting too and the

openness I keep seeing articles like that in my um you know Google Alerts that you know that the more you Express

gratitude the better your aging is so I thought that was um a good snippet as well yeah

um so uh like for example one of our like Rob Peterson the collaborator

um he looks at this from lens from the clinical perspective right he because he wants to look at interventions that we

could do in veterans that can help their quality of life and subsequently their

health outcomes and he said well these gratitude findings so interesting

because we could just use gratitude inform interventions and and hopefully

see how that impacts the health outcomes in in in in our veteran population

so there certainly you know um therapeutical Integrations that could be

informed based on our findings and it will be very interesting to see how that

you know um certainly if that indeed can have an

effect yeah yeah I agree are you looking to do an Interventional trial in the

future or you know maybe your colleagues because that’s what everyone wants to know I think the better question I should have

asked there um instead of what do these results suggest you know what’s the the clinical use or how can we use this yeah and and

you know our daily life yeah so before going into a full clinical trial um what we are intending to do is to try

to replicate this in independent cohorts right to make sure that what we’re

seeing is not you know some experience finding but in fact it’s a real finding right so and yeah next step is to

replicative finding and then I I would say definitely

um we have clinicians uh you know that are at The Cutting Edge of um of

Designing treatments for trauma population so I’m sure will be easy to

find collaborators that will be interested in assessing this in in this

population definitely and I think the the replication part of the study you know that’s just as an important part as as

any any of this entire process so I’ll be excited to follow along with your work and hopefully get to that

Interventional level too um all right the next study here so you

you’ve also had a paper looking at the epigenomic differences between smoking and nicotine dependence in a veteran

cohort um so you did mention this earlier too you know the epigenomic literature on

smoking is a very well established um but studies evaluating the world epigenetics and nicotine dependence are

limited I actually you know prior to looking at your work didn’t know anything about um nicotine dependence with the the

epigenetics so yeah let’s let’s talk a little bit about this study can you describe that there and walk us through

yeah of course um yeah so one of the main questions that I had um and it’s because the

cohorts that we study another quality School yield pen led by Joel galenter

and um Presley um they uh it’s a cohort that we have a

lot of people with substance use disorders because it’s meant to study the genetic substance use disorders and

the same cohort I use for the first ewas that I publish in the literature that is

published in the literature um of opu’s dependence um and and it was in a woman population

and I wanted to make better use of that cohort and I saw the opportunity that

maybe we can use this cohort to disentangle the question of you know uh

smoking signatures from nicotine Independence in a way to

um not only uh differentiated smoking from nicotine Independence but also potentially finding biomarkers of

nicotine dependence which are greatly needed in the field um but we have the major limitations

that smoking is so um that the effect of smoking is so substantial in in methylation that um

studying this will be very hard um if it’s not enough in a cohort that

we have high prevalence of substantive disorders so I saw this an opportunity to study

this and this is the core that we’re expanding the initial findings from the veteran cohort uh no it’s called the

nhrbs um and we’re looking now at sex differences but

yeah telling this long story short um we use the veteran cohort to look at

the differences between smoking and nicot Independence which we are now expanding in the open court and what we

found is that um the genes that were associated with nicotine dependence and not

um the and we didn’t found in the smoking ewas were related to neuronal differentiation

so we have for example the neurology one gene it’s a finding that we didn’t see

in the it was smoking but we only see it when evaluating nicot Independence we

also see two other genes one of them we see a high replica a higher correlation

with between blood tissue and brain tissue so potentially relevant in the

brain as well and then by doing commentilation analysis which is you know different

from ewas analysis the epigenous white analysis where you just do a linear regression and look at the association

between each cpg side with the phenotype of Interest commonthylation analysis looks at

correlation between cpg sites are nearby and how the group of correlated cpg

sites are associated with that is called modules are associated with the phenotype of Interest

and we identify that one of the main modules associated with um nicot

Independence was enriched for nicotine addiction which was you know

um very reassuring that what we’re seeing in the analysis with nicot Independence specifically were informing

in fact that trade and not smoking and what we see in that module are genius in

the Gaba family that are very well known and um in the STD in the substances

disorders field that’s associated with addiction including nicotine addiction and also shown in animal models to be

involved in in nicotine addiction so um I think we did a really good job at

disentangling um the smoking from nicotine Independence in our methylation data and

identifying potential specific signatures for each trade but

you know essentially more for nicotine Independence which is the work we have in the cap in the literature and now

what we’re intending the yellow pen cohort is to expand that to a larger cohort and also incorporate women to see

if there are sex differences as well gotcha very interesting super cool I

thank you for explaining that I have a lot of follow-up questions um can you just describe the difference

between smoking and nicotine dependence as it relates to to this study I think that’s important yes yes so um so

smoking are just what how we treated smoking is current smokers so people

that just use smokers however not everyone that smokes suffers from liquid

Independence not everyone develops addiction um you know they could be Korean smokers

now and then stop uh the week later and then never smoke again whereas there are

other people that there will be smoking now and then they will just keep smoking and smoking more and then developing a

tolerance so they need more packs per day and then they will develop

withdrawal syndromes symptoms so when they stop smoking they will start having

physical reactions in their body um and having that urge to to smoke

again have it that craving so when they started developing these symptoms then they you know they have developed

nicotine dependence so that’s why it’s essential and it’s very important to

differentiate between the two because we want to understand you know what’s related to ex just exposure to smoke

just exposure to um to the nicotine whereas what’s more

related to the addiction surrounding the chronic use of nicotine yeah I think

that’s important and and nicotine dependence as well you know I know they have like those patches or you know the

pouches does would that fall under the nicotine dependence category too right so people that are using patches

most likely is because they have developed nicotine dependence and are using the patches as a way to eventually

stop smoking um yeah yeah that makes sense no thanks for for differentiating that and then so

you’re really looking at the neurodevelopment impacts of addiction um by you know you said the Gaba family

is being affected and then you also did you say um you were doing the e-walls

but then you also did the co-methylation is that what you said it was called so you’re looking at a group of methylation

markers little clusters that are next to each other to see if they’re being affected in maybe the same way or different yes okay perfect yeah

um new definition there as well I’ll outline that for people just so they can understand the difference but um I think

it’s important to differentiate because even with those smoking signatures I know DNA methylation you’re not going to find

a stronger signal between anything else and uh smoking with that you know a lot of the

um DNA methylation signatures are going to be more accurate than your self-reported smoking habits

um so it’s it’s you know you can count that the second hand smoke into that and it’s it’s hard to differentiate so I

think we we need to have that nicotine dependence arm of this study as well and appreciate the work that you’re doing

there yeah thank you um I can give some uh

advancements on some research that we’ve been doing yeah linking epigenetic aging

through Suds I have a very talented postback that is running analysis looking at at the Yelp and cohort that I

mentioned looking at epigenetic aging including remage and we’re looking at

across the board comparing different substance use disorders so of course nicotip dependence was the one that I

was more prominent as the impact of accelerated epigenetic aging and something very interesting is that when

we look at using cell reported data when we look at current smokers never smokers

and former smokers epigenetic Aging for never smokers it’s very similar to

former smokers but when we see um current smokers The Accelerated

roommates is like huge so it’s very interesting to see and it is consistent

with the literature that once you stop smoking you know you have to chances to go to

um yeah where we were when you were at the very beginning yeah again reversible so former and you know never smokers

look basically the same but current we can see a very large difference so it can help you know maybe people

um try and decrease that that habit that use of smoking yes yeah

um okay I know we’re we’re getting short on time here I have one other study I want to talk about

um the last paper uh is gonna be the ewas where you’re actually looking at post-traumatic stress disorder in U.S

military veterans so here I know you identified six genome-wide significant

cpg sites associated with past month PTSD so maybe more current and I’m sure

you’ll get into that and then three cpg methylation sites with lifetime PTSD so

yeah curious to to hear a little bit about what you found what these genes um do in the cpg sites they they’re you

know related to and map with what are they involved with those those mechanisms of action yeah sure yes

um so we evaluated PTSD two different ways looking at paths um month so people

that have reported symptoms of PTSD within the past month and their lifetime

um people that have just history of PTSD die diagnosis across you know their lives

um so in a way to understand you know since we’re looking at epigenetics can we identify signatures that are you know

um associated with currently like having or expressing symptoms of PTSD whereas

can we still have those epigenetic signatures from PTSD that happen you

know um a long time ago or uh longer than

um current symptoms so um we did this and we identified as you

said sex uh different cpg sites with the um Uh current or past month PTSD ewas

and three with um the lifetime PTSD he was and

um I wouldn’t go too much into this because again I do value

replication in a way to understand if whatever we’re seeing is you know

actually real um so I would talk about what we replicated so we were able in the paper

we were able to replicate one of these findings in the radio trauma project

cohort um and uh you know with the same direction effect

um this is what’s with the c and p7 um finding and from the those nine you

know we were more confident of Designing because we were able to replicate it and it was like in a very mixed also

um cohort I think it was African-Americans and um the main finding was in European

America so the fact that we replicated and we replicated in a different ancestry cohort you know it it provided

us confidence and also reassuring that maybe the findings are indeed transferable across ancestries which is

an important thing to consider and then we said okay so we’re seeing

um this uh replication um the lifetime PTSD we’re seeing this

in the blood um we wonder what about in the brain are we seeing changes in the gene expression

of this Gene associated with PTSD in the brain so we look at data from the VA brim bank

and I said the national Center of PTSD brain Bank and um in a cohort where we

have um PTSD cases and healthy controls we evaluated tissue from the orbital

frontal cortex one of the cortical regions also associated with um PTSD in

the literature we found that we see differential

expression of this Gene in the brain associated with PTSD so not only we were

able to replicate this finding in an independent cohort and in the in the different ancestry but we’re also look

like validating this finding and changes in the brain and at the gene expression

level so I think it was a very neat story a follow-up on that will be to do

it in a larger and more diverse cohort and see if it replicates and potentially

identifying novel hits associated with PTSD and not only in saliva’s the

samples but also we’re looking at in the evaluating human postmortem brain as

well yeah that’s great that you had access to that that brain tissue and you’re able to you know look at that even further

um I may have missed it you said it was the cmp7 is that correct e and p7 and

and what is that exactly known for semp7 sorry s yeah s um so it’s a gene

involved in transcriptional regulation but what’s very intriguing is that it

has come up uh genetic variants of this Gene has come up and G was associated

with uh risk-taking Behavior yes okay I remember reading about that

now the the light bulb just came out of my head so yes oh very very cool stuff you have going

on here Dr Montalvo Ortiz I’m super excited about all of the work that’s coming out in the replication studies

and just digging more about the connection between mental health and Trauma and what epigenetics can tell us

about that so we’re we’re almost done with this podcast I do have um a curveball question I always ask

everyone at the end um that wasn’t on the agenda um but if you could be any animal in the

world what would you be and why I did tell you I did my homework so I was expecting already oh darn yeah

yeah um so I came to think about but actually when I heard it

um the very first time the first postca podcast sorry I instantly thought about

a bird actually any kind of bird not like specifically I’m not in uh very nerdy on

birds but I think it’s sad that they can just fly whenever they want like get to

a different town country and yeah a lot of different things I I you know I love

travel so I guess I see myself as a bird there you go well yeah you were the I forgot

that you’ve listened to some so maybe I should start asking people like a random question and you know I’ll make

something I think yeah you could tell about the personality of the person yeah

yeah but you had an answer you thought about it I love it a bird is great well

um you know I just I appreciate your time more more than anything I know you’re super busy with with um

everything you’re doing in this research and you know everything you’re giving to this field um for any listeners who want to connect

with you where can where can they find you right so I can certainly share my email on the website that you can

disseminate if that will be good and yeah I’ll be more than happy you know

people that are interested in collaborating with us uh please reach out and I wanted to thank you Hannah I I

think this podcast is an amazing idea I think it’s a very good platform to bring

researchers and experts in in epigenetics together and you know I I I

had a like really fun time to hear your previous podcast so you know

congratulations on this work as well yeah well thank you for for those kind words that that means a lot so you know

this is is definitely a new area for for me in terms of like the production the marketing you know I’m not very creative

so it’s really fun to have this outlet and really talk to experts like you so um no I really appreciate that and um

you know for everyone listening again thank you for joining the everything epigenetics podcast remember you have control over your epigenetics so tune in

next time to learn more thank you so much thank you bye bye

About this Guest Expert

Dr. Janitza Montalvo-Ortiz
Janitza’s research interests include the study of the genetic and epigenetic mechanisms associated with psychiatric disorders. She investigates how trauma-related events increase the vulnerability to develop mental disorders later in life.

More About me

Everything epigenetic
Everything epigenetic
Traumas Epigenetic Impact on Mental Disorders
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