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Genetics of dopamine and serotonin explain overlap in psychiatric disorders

Posted on January 20, 2022 by jcabanadominguez

Psychiatric disorders such as attention deficit / hyperactivity disorder (ADHD), autism, major depression or bipolar disorder, often overlap and occur together. For example, individuals with ADHD on average experience twice as many depressive symptoms as the general population without ADHD [1,2]. In addition to the distress and impairment that is brought on by a single psychiatric condition, having multiple conditions can hugely increase the severity of symptoms and hinder treatment. To better understand why these disorders overlap, we investigated the genetic risk factors that are shared among psychiatric disorders, and found several genes that play important roles in regulating two signaling-mechanisms of the brain: dopamine and serotonin [3].

Dopamine and serotonin are two important neurotransmitters (messengers molecules that transmit messages between brain cells) that control a wide range of essential functions in your brain (e.g. controlling your movements, cognition, motivation, regulation of emotions, and responding to reinforcement and reward). For that reason, alterations in these two systems have been related with the physiopathology of several psychiatric disorders, and also have been pointed as possible therapeutic targets for them.

We systematically explored the contribution of common variants in genes involved in dopaminergic and serotonergic neurotransmission in eight psychiatric disorders (ADHD, anorexia nervosa, autism spectrum disorder , bipolar disorder, depression, obsessive-compulsive disorder, schizophrenia and Tourette’s syndrome) studied individually and in combination. To do so, we used data from the Psychiatric Genomics Consortium (PGC, https://www.med.unc.edu/pgc/) to explore the entire genome in thousands of patients with different psychiatric conditions, which were compared with controls (individuals without any psychiatric condition).

In this way, we could identify variations in genes (and in groups of related genes) that confer susceptibility to a given disorder. For example, a gene named CACNA1C that is involved in the connectivity between brain cells, was found to contribute to both bipolar disorder and schizophrenia. Using this approach, we found 67 dopaminergic and/or serotonergic genes associated with at least one of the eight studied disorders, and twelve of them were associated with two conditions. Interestingly, five out of these twelve genes, including CACNA1C, belong to both the dopaminergic and serotonergic neurotransmitter systems, highlighting the importance of those genes that participate in both systems and their high interconnectivity. Next, we analyzed groups of genes that work together, and found that the dopaminergic genes have an important role in ADHD, autism, depression, and in the combination of all of the eight disorders that we studied. We also found that the group of serotonergic genes are relevant for the overlap between depression and bipolar disorder.

These results support the existence of a set of dopaminergic and serotonergic genes that increase the risk of having multiple psychiatric conditions. Having identified these genes, the next step is to investigate if any of these could be targeted by new drugs that directly influence specific parts of the dopaminergic or serotonergic system, compared to the more unspecific drugs that currently exist. That would be an important step for treating psychiatric comorbidity.

If you want to know more about this research, you can read our publication here.

This blog was written by dr. Judit Cabana-Domínguez. She is a postdoctoral researcher of psychiatric genomics at the Vall d’Hebron Research Institute (VHIR). The work described here is part of the CoCA project on comorbid conditions of ADHD.

References

McIntosch et al. (2009). Adult ADHD and comorbid depression: A consensus-derived diagnostic algorithm for ADHD (nih.gov) Neuropsychiatric Disease and Treatment, 5: 137-150. doi: 10.2147/ndt.s4720
Di Trani et al. (2014). Comorbid Depressive Disorders in ADHD: The Role of ADHD Severity, Subtypes and Familial Psychiatric Disorders (nih.gov) Psychiatry Investigation, 11(2): 137-142. doi: 10.4306/pi.2014.11.2.137
Cabana-Domínguez et al. (2022). Comprehensive exploration of the genetic contribution of the dopaminergic and serotonergic pathways to psychiatric disorders. Translational Psyciatry, 12(1): 11. doi: 10.1038/s41398-021-01771-3

What have we learned about ADHD comorbidities?

Posted on July 2, 2021July 2, 2021 by Jeanette Mostert

After 5.5 years, the CoCA project has come to an end. In this large-scale European research project, an interdisciplinary group of researchers investigated comorbid conditions of ADHD. They particularly focussed on depression, anxiety, substance use disorder and obesity, as these conditions frequently co-occur with ADHD in adulthood.

What has this extensive study brought us? Experts dr. Catharina Hartman (University Medical Center Groningen, The Netherlands) and prof. dr. Andreas Reif (University Hospital Frankfurt, Germany) were invited by Jonathan Marx for an interview on the online radio program Go To Health Media. In this program they talk about several aspects of the CoCA project: How often do comorbid conditions co-occur with ADHD? What do the genetics of ADHD comorbidities tell us? What should clinicians do to prevent or reduce these comorbidities in ADHD?

As professor Andreas Reif summarizes at the end of the interview, the main things that we learned from the CoCA project are:

Comorbidity in ADHD is a very big problem. Adults with ADHD frequently have co-occuring conditions such as depression, anxiety, obesity and to a bit lesser extent substance use disorder.
The type and prevalence of comorbidities differ between men and women.
There is considerable genetic overlap between ADHD and comorbid conditions. We think that at least part of the overlap between comorbidities is caused by genetic effects (next to environmental effects that also play a role).
The dopamine system plays an important role in comorbidity, through influencing brain processes.
Disturbances in the circadian system (i.e. sleep cycle) are unlikely to play a causal role in these comorbidities, but they might be a consequence.
Clinicans should look out for comorbidities when they treat ADHD patients, and inform their patients about their increased risk to develop comorbidities so that they can take preventive measures (i.e. be careful with alcohol to avoid substance use disorder). Secondly, clinicians should actively look out for ADHD symptoms when treating conditions such as depression, anxiety, substance use disorder or obesity.

Watch the full interview with both experts by clicking on the image below:

More information about the CoCA project: www.coca-project.eu

IS GENETICS BEHIND THE CO-OCCURRENCE OF ADHD AND OTHER DISORDERS?

Posted on May 10, 2021May 12, 2021 by Bru Cormand

A group of researchers from Spain, The Netherlands, Germany, Estonia, Denmark and USA have joined efforts to gain insight into the genetics of ADHD and its comorbidities. This ambitious objective was addressed by the Work Package 2 of a big project called CoCA: “Comorbid Conditions of Attention deficit/hyperactivity disorder (ADHD)”, funded by the European Union for the period 2016-2021.

In psychiatry, the co-occurrence of different conditions in the same individual (or comorbidity) is the rule rather than the exception. This is particularly true for ADHD, where conditions like major depressive disorder or substance use disorders frequently add to the primary diagnosis and lead to a worse trajectory across the lifespan.

There are different reasons that may explain the advent of the comorbidities: Sometimes the two conditions have independent origins but coincide in a single patient. Comorbidity can also appear as a consequence of a feature of a primary disorder that leads to a secondary disorder. For example, impulsivity, a trait that is common in ADHD, can be an entry point to substance use. Comorbidity can also be the result of shared genetic causes. The latter has been the focus of our investigations and it involves certain risk genes that act on different pathologies, a phenomenon called pleiotropy.

Our project started with an approach based on the exploration of candidate genes, particularly those involved in neurotransmission (i.e. the connectivity between neurons) and also in the regulation of the circadian rhythm. We used genetic data of more than 160,000 patients with any of eight psychiatric disorders, including ADHD, and identified a set of neurotransmission genes that are involved at the same time in ADHD and in autism spectrum disorder [1]. In another study we identified the same gene set as involved in obesity measures [2].

Then we opened our analyses to genome-wide approaches, i.e. to the interrogation of every single gene in the genome. To do that we used different statistical methods, including the estimation of the overall shared genetics between pairs of disorders (genetic correlation, r_g), the prediction of a condition based on the genetic risk factors for another condition (polygenic risk score analysis, PRS) and the establishment of the causal relationships between disorders (mendelian randomization). As a result, we encountered genetic connections between ADHD and several psychiatric disorders, like cannabis or cocaine use disorders [3, 4, 5], alcohol or smoking-related phenotypes [6, 7, 8], bipolar disorder [9], depression [6], disruptive behavior disorder [10], but also with personality or cognition traits, like neuroticism, risk taking, emotional lability, aggressive behavior or educational attainment [6 , 11, 12, 13], or with somatic conditions, such as obesity [11, 12].

All these results and others, reported in more than 40 (!) scientific publications, support our initial hypothesis that certain genetic factors cut across psychiatric disorders and explain, at least in part, the comorbidity that we observe between ADHD and many other conditions. This information can be very useful to anticipate possible clinical trajectories in ADHD patients, and hence prevent potential negative outcomes.

Dr. Bru Cormand is full professor of genetics and head of the department of Genetics, Microbiology & Statistics at the University of Barcelona. He leads workpackage 2 of the CoCA project (www.coca-project.eu) on the genetics of ADHD comorbidity.

References

Connection between sleep and mental health – a special case for ADHD

Posted on April 22, 2021April 22, 2021 by Dina Sarsembayeva

Bad sleep is… well, bad for you

Ever seen that meme with Homer Simpson lying awake in bed until 4 am and then falling asleep 8 minutes before the alarm rings? If it felt relatable, then you definitely know how relevant sleep problems can be! That situation shows problems with falling asleep (insomnia) as well as very late sleep timing (read more about this in my previous blog about circadian delay). Both are linked to an infinite number of health problems, especially mental illness. In fact, a typical teenager on TV can demonstrate how bad sleep affects you. Remember how moody, bad-tempered, inattentive at school they usually are or how much they drink and smoke? Well, bad sleep relates to very similar mental health problems: mood disorders, anxiety, aggression, attention deficit hyperactivity disorder (ADHD) and bad habits like smoking, drinking alcohol and taking drugs. The connection between bad sleep and ADHD, however, is one of the most studied.

What about sleep in people with ADHD?

We know that up to 80% of ADHD patients suffer from insomnia^1,2 and most of them have a circadian delay³. Researchers commonly find that if a person has insomnia symptoms and later bed times, then this person also suffers from more severe ADHD⁴. Although it’s not clear why exactly this happens, some think that a natural circadian delay doesn’t let you fall asleep at socially acceptable times, so you regularly get insufficient sleep^5,6. Interestingly, people without ADHD who sleep poorly also develop the same symptoms – inattention and hyperactivity⁷. You might even say that insomniacs develop temporary ADHD! This makes the connection between ADHD and sleep even more curious and important.

What did our research find?

My colleagues and I wanted to know if the same association with sleep happens in other mental illness and if it is different from the connection to ADHD. For this, we examined information from around 38,000 persons in The Netherlands with ages from 4 to 91. Each of them filled in a long online survey with questions about their sleep habits and mental health.

Later, we divided all these people into three groups based on their sleep behaviour. The first groups were people who prefer earlier sleep times and reported no insomnia symptoms. The other two groups comprised persons who preferred later sleep times (a sign of circadian delay). These groups differed in one thing: one group had very few symptoms of insomnia and the other a lot.

After that, we measured if some of these groups had more severe symptoms of mental illness, including ADHD. And yes, the groups with circadian delay – even the ones without insomnia – really did have significantly higher severity of all mental illness compared to early sleepers! Moreover, the individuals in the circadian delay group with insomnia had more mental health problems than those who slept well. In ADHD specifically, this link between circadian delay and insomnia was as large for symptoms of inattention as for hyperactivity/impulsivity. Children and adolescents had even stronger relation between poor sleep and mental health problems, just like that moody teenagers I mentioned before.

Why this matters

Insomnia and circadian delay, as we see from these results, is a common problem for different types of mental illness. Good sleep usually means better mental health, so people diagnosed with a mental illness might want to improve their sleep behaviour. The good news is that reducing mild insomnia might be easy: anyone can get blinders to keep their bedroom dark and drink less coffee. Circadian delay, though, is harder to change, because it is mainly ruled by your genes. This means that those born as late-night birds need to adapt their life to a more nocturnal rhythm to avoid worse mental state. Sadly, we all know it is often impossible. Younger people, for whom sleep is so important, still need to wake up unnaturally early for school. Adults go to sleep only late at night, even if they’d happily nap at 9 pm, because they were working all day and need to finish their house chores. Current expectations of a good worker and student fit morning people but fail to help and only cause more insomnia for those with a circadian delay. Unless we want to feed all adolescents melatonin tablets every day, our society needs to be more tolerant to our individual circadian preferences.

Dina Sarsembayeva is a neurologist and a research master’s student at the University of Groningen. She is using the data from the CoCa project to learn if the circadian preferences and sleep problems can be turned into profiles to predict specific psychiatric conditions.

1. Kessler, R. C. et al. Lifetime prevalence and age-of-onset distributions of mental disorders in the World Health Organization’ s. World Psychiatry 2007;6:168-176) 6, 168–176 (2007).

2. Lugo, J. et al. Sleep in adults with autism spectrum disorder and attention deficit/hyperactivity disorder: A systematic review and meta-analysis. Eur. Neuropsychopharmacol. 1–24 (2020) doi:10.1016/j.euroneuro.2020.07.004.

3. Coogan, A. N. & McGowan, N. M. A systematic review of circadian function, chronotype and chronotherapy in attention deficit hyperactivity disorder. Atten. Defic. Hyperact. Disord. 9, 129–147 (2017).

4. Lugo, J. et al. Sleep in adults with autism spectrum disorder and attention deficit/hyperactivity disorder: A systematic review and meta-analysis. Eur. Neuropsychopharmacol. 38, 1–24 (2020).

5. Çetin, F. H. et al. Chronotypes and trauma reactions in children with ADHD in home confinement of COVID-19: full mediation effect of sleep problems. Chronobiol. Int. 37, 1214–1222 (2020).

6. Eng, D. et al. Sleep problems mediate the relationship between chronotype and socioemotional problems during early development. Sleep Med. 64, S104 (2019).

7. Lunsford-Avery, J. R., Krystal, A. D. & Kollins, S. H. Sleep disturbances in adolescents with ADHD: A systematic review and framework for future research. Clin. Psychol. Rev. 50, 159–174 (2016).

What do rewards have to do with mental health problems?

Posted on September 28, 2020 by Dener Cardoso Melo

What do you think of when I say “rewards”? Perhaps you think of the points you collect every time you shop or the badges you get when playing a videogame. Well, then you’re right! A reward can be anything. A good grade, going on a trip with friends, a smile, and even that dessert you crave in the middle of the night. Rewards are any stimuli with the potential to make us seek and consume them, and if we like, we will probably want to get them again [1].

Actually, you crave that dessert because you ate it once, and you liked it so much that your brain learned that eating that dessert again will make you feel good. This happens because of a neurotransmitter called “dopamine” released when you eat the dessert, giving you that little rush of pleasure. Now your brain knows what you like and will want more of that.

By now, you probably have realized that rewards are present in virtually everything we do in our daily lives. That is why seeking and consuming rewards are considered to be a fundamental characteristic of human behavior. These rewards that we keep consuming guarantee that we stay alive by eating and drinking water, for example. Rewards also have a huge influence on how we experience positive emotions, motivate ourselves to perform tasks, and learn new things [2].

What about the relationship between rewards and mental health problems?

Although rewards are natural stimuli that make us keep doing healthy and nurturing things, it can also become a problem. Rewards are not the problem itself, but some people can have an unhealthy behavior towards rewards. That’s where mental health problems come in. Did you know that most mental health conditions have alterations in how rewards are processed in the brain? It’s so common that these so-called reward processing alterations are now considered a “transdiagnostic feature,” meaning we can find them across different mental health conditions [3].

Reward processing is a term to refer to all aspects related to how we approach and consume rewards. For instance, how you respond after getting a reward (responsiveness), how motivated you are to go after a reward (drive/motivation), how impulsive you are when trying to get new and intense rewards (fun-seeking/impulsivity). So, as you can see, it’s not only about getting the rewards, but many different things play a role in a simple action we do.

Let’s think of an example: You are going to a party with your best friends. You are motivated to go out with your friends because you’re always happy when you are around them [this is the drive/motivation]. Once you are at the party, you meet your friends, talk, laugh and are happy you decided to join because you’re feeling that rush of pleasure [this is the responsiveness aspect]. At some parties, things can get a bit out of control, and some people might do risky things on the spur of the moment, like binge drinking. You refuse to binge drink because you thought of the risks, and you don’t want to be in trouble later [that’s the third aspect, the fun-seeking/impulsivity].

Now, let’s think of how that party would be for people with reward processing alterations. In the case of a very high drive, they would be super motivated to hang out with friends. On the other hand, if they have low responsiveness, they wouldn’t be able to have fun at the party even though all of their friends are there and the party is super fun. Lastly, in the case of high fun-seeking/impulsivity, they wouldn’t think of the risks and consequences and engage in binge drinking anyways.

As I mentioned before, these alterations play a role in different mental health conditions. They can affect one or more aspects of reward processing, and they can be either lower or higher than average. For example, people with ADHD can show higher risk-taking, meaning that they are more susceptible to take big risks without thinking about the consequences [4]. This impulsive behavior might be a reflection of the altered fun-seeking aspect of reward processing. Another example is the lack of interest in social interactions in people with autism spectrum disorders [5]. This lack of interest might reflect a reduced drive/motivation to go after social rewards.

These are just some examples of what reward processing alterations might look like in the context of mental health problems. There are still a lot of open questions. As part of my PhD research, I am trying to answer some of them. For example, which came first? Are reward processing alterations causing mental health problems, or are they just mere symptoms of these conditions? If you want to learn more about this topic, stay tuned as more blog posts will come!

Dener Cardoso Melo is a PhD candidate at the University Medical Center Groningen (UMCG). He is using data from the CoCA project together with other datasets to investigate the potential causal role of reward processing alterations in different mental health conditions.

References

Schultz, W. (2015). Neuronal reward and decision signals: From theories to data. Physiological Reviews, 95(3), 853-951. doi:10.1152/physrev.00023.2014
Wise, R. A. (2002). Brain reward circuitry: Insights from unsensed incentives. United States: Elsevier Inc. doi:10.1016/S0896-6273(02)00965-0
Zald, D. H., & Treadway, M. T. (2017). Reward processing, neuroeconomics, and psychopathology. Annual Review of Clinical Psychology, 13(1), 471-495. doi:10.1146/annurev-clinpsy-032816-044957
Luman, M., Tripp, G., & Scheres, A. (2010). Identifying the neurobiology of altered reinforcement sensitivity in ADHD: A review and research agenda. Neuroscience and Biobehavioral Reviews, 34(5), 744-754. doi:10.1016/j.neubiorev.2009.11.021
Stavropoulos, K. K., & Carver, L. J. (2018). Oscillatory rhythm of reward: Anticipation and processing of rewards in children with and without autism. Molecular Autism, 9(1), 4. doi:10.1186/s13229-018-0189-5

Common mental health symptoms in ADHD

Posted on August 13, 2020August 13, 2020 by Jeanette Mostert

Image by Anastasia Gepp from Pixabay — Excessive, uncontrolled mind-wandering is common to ADHD, but also to other mental health conditions. Mobile apps that prompt questions during the day can give more insight into the nature of these symptoms and how they differ between (often comorbid) conditions.

The majority of individuals with ADHD have one or more comorbid disorders. Comorbidity is a technical (and admittedly, not very cheerful) word for ‘co-occuring’, meaning that multiple disorders or conditions are present at the same time. Anxiety and depression are the most prevalent conditions that co-occur with ADHD.

Researchers and clinicians want to better understand this comorbidity in ADHD. Does having ADHD increase your risk of developing other conditions? Is there a biolgical mechanism that underlies both ADHD and other conditions? Or are symptoms of ADHD actually broader than the attentional, hyperactivity and impulsivity problems defined by the DSM/ICD, and therefore also linked to other conditions? Or all of the above?

Going with the third option (which by no means excludes the alternatives), clinicians have noticed that many individuals with ADHD experience symptoms that are not specific to ADHD, but are also often seen in other psychiatric conditions. You could call these symptoms ‘mainstream’, or ‘common’ mental health problems. Some examples that are often experienced by those with ADHD are emotional instability, sleep problems, low self-esteem, distractibility and concentration problems, and mental restlesnesss or excessive mind wandering.

Understanding these comorbidities better is important, because often one condition can hide the ‘true’ underlying condition. For instance, a person with ADHD who experiences many symptoms that are also characteristic of anxiety (i.e. low self-esteem, excessive mind-wandering, sleep problems, avoiding difficult situations). In such a case, the person could receive treatment for anxiety problems, while he or she is actually needing treatment for ADHD.

To distinguish between these conditions better, we need to find out more about these common symptoms. Being distracted can have many different causes and can happen in many different situations. For instance: are you distracted due to pervasive negative thoughts, because the task you’re doing is boring, or because you’re thinking of many related things and drift off to new ideas?

To learn more about the nature of these symptoms, researchers have given mobile apps or smartwatches to participants with ADHD. Several times a day, the watch buzzes and the app prompts a question that the person has to give answer to immediately. Questions can for instance be: How are you feeling right now? Have good/bad things happend to you in the last hour? How much has this affectd you? Were you concentrating on a task or where you distracted? Where you tinking about something (un)pleasant? etc. This method called ‘experience sampling’ can give very valuable information about someone’s symptoms. When combining the information from a lot of individuals, this can also identify differences between different disorders, that were not really known before.

If you want to learn more about this topic, you can watch this webinar by professor Philip Asherson from King’s College London. He explains the common mental health symptoms of ADHD in more detail, and gives examples from his research, also using experience sampling.

This blog is based on the webinar by Philip Asherson “ADHD in the mainstream” that was created as part of the CoCA project. The CoCA project investigates comorbid conditons of ADHD: .

How psychiatric genetics can help to guide diagnostic practice and therapy

Posted on June 4, 2020 by Jeanette Mostert

Recently, professor Stephen Faraone from SUNY Upstate University in the USA gave a webinar about genetic research in psychiatry (especially ADHD) and how this can help to better understand diagnosis and provide better treatment. In this blog I will share with you some highlights from this webinar.

ADHD is a continuous trait in the population

ADHD is not something that you either have or don’t have. Rather, symptoms or characteristics of ADHD are present in the entire population, in varying severity. The system for psychiatric diagnoses is however based on categorical definitions that determine when a certain combination of symptoms and severity can be classified as a particular disorder. Although these categories can be of great help to provide public health data or determine insurance coverage, they often don’t really match individual cases. Hence there arise problems with heterogeneity, subtypes, subthreshold cases and comorbidity.

Genetic research has shown that psychiatric conditions such as ADHD are not caused by a few single genes, but rather by thousands or tens of thousands genetic variants that each contribute slightly to the ADHD risk. These so-called polygenic risk scores form a normal distribution across the entire population, with the majority of people having low polygenic risk scores (so a low to average risk of ADHD), while a small portion of individuals have a very low or very high risk. This adds to our understanding that ADHD is a continuous trait in the population.

*Image from the webinar by prof. Stephen Faraone*. *The higher the number on the x-axis, the higher the genetic risk of having ADHD. Negative numbers mean reduced genetic risk of ADHD.*

2. Comorbidity in psychiatry is the norm, rather than the exception

In the webinar, Stephen Faraone explains that in 90’s it was thought impossible that an individual can have both ADHD and depression. Now, we know better than that. There are substantial genetic correlations between different psychiatric disorders, meaning that the genes that increase the risk of for instance ADHD, also increase the risk of schizophrenia, depression, bipolar disorder, autism and tic disorder. This is further evidence that psychiatric conditions are not separate, categorial entities but rather arise from similar biological mechanisms.

3. Personalised medicine and pharmacogenetics are not yet sufficiently established to adopt widely and replace current medication on a broad scale

The second part of the webinar was about pharmacogenetic testing. This means that an individual’s genetic profile is used to determine whether a drug will be effective, and in what dose. Although this sounds promising, there is still a lot of discussion about the validity of such tests. This is due to varying results, differing protocols and large heterogeneity between studies. In some cases, pharmacogenetic testing can help to find the right treatment for an individual, for instance when this person is not responding well to regular treatment, but it is definitely not a fool-proof method yet. Better randomized controlled clinical trials are needed to improve reliability of these tests.

You can watch the full webinar here: https://www.youtube.com/watch?v=DLgqdJWZKIo

The genetics of having multiple mental health conditions

Posted on May 26, 2020May 26, 2020 by Jeanette Mostert

We know that psychiatric conditions have a strong genetic component. This means that genes play an important role in determining an individual’s risk or vulnerability to develop a psychiatric condition. However, there is evidence that there are genetic variants that increase the risk for multiple psychiatric disorders. This is called pleiotropy. Researchers of the “Cross-Disorder Group of the Psychiatric Genomics Consortium” have searched the entire genome of 727,000 individuals (of whom 233,000 were diagnosed with a psychiatric disorder) to identify genetic variants with such pleiotropy.

The researchers found one particular gene – called DCC – that increases vulnerability for all eight disorders that were investigated: ADHD, autism spectrum disorder, anorexia nervosa, bipolar disorder, major depression, obsessive compulsive disorder, schizophrenia and Tourette syndrome.

They also found more than 100 genetic variants that predispose to at least two psychiatric disorders, and around 20 variants that are associated with four or more. This means that the genes that contain these variants can be interesting to further understand why certain individuals are more vulnerable to develop psychiatric illnesses than others.

One of the researchers, professor Bru Cormand, explains more about this research in this blog.

Further reading: Cross-Disorder Group of the Psychiatric Genomics Consortium (2019): Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders. Cell, 179(7): 1469-1482.e11.

Professor Cormand is involved in the CoCA research consortium where he investigates the genetic overlap between ADHD, major depression, anxiety disorder, substance use disorder and obesity. To read more about this, see for instance this other blog by him and dr. Judit Cabana Dominguez.

The notorious evening chronotype and my master’s thesis

Posted on May 8, 2020May 11, 2020 by Dina Sarsembayeva

Almost every person, healthy or not, suffers from occasional problems with sleep and circadian rhythm. In the modern days of 24/7 smartphone use and transcontinental flights, our internal body clock is having a hard time adjusting to the external cues. For the persons suffering from mental health issues, their impaired sleep cycle can be one of the cornerstone problems of daily living. Sleep problems have been confirmed to be a first symptom, consequence, or even a cause of such psychiatric conditions as major depression, bipolar disorder, ADHD, autism, substance abuse, and even aggressive behaviour. Their strong relations, however, have not been studied systematically and broadly just yet.

Why study the circadian rhythm?

Circadian rhythm is our inner clock that regulates a lot of important processes in the human body, including the sleep/wake cycle, the release of hormones and even the way we process medicines. This clock is run by the brain region called the hypothalamus, which piles up a protein called CLK (referring to “clock”), during the daytime. CLK, in turn, activates the genes which make us stay awake, but also gradually increases the creation of another protein called PER. When we have a lot PER, it turns off CLK production and makes us ready to sleep. As CLK is getting lower, this causes a decrease in PER, so that the process starts again with elevating CLK waking us up. This cycle happens at around 24-hour intervals and is greatly influenced by so-called zeitgebers, or time-givers, like light, food, noise and temperature. When our retina neurons catch light waves, the suprachiasmatic nucleus in our brain stops the production of the hormone called melatonin that induces sleep and starts producing noradrenaline and vasopressin instead to wake us. This is the exact reason why you cannot fall asleep after watching a movie at night.

*Figure 1. The smart protein CLK wakes us up and its friend PER gets us to sleep.*

Sometimes our body clock fails to function, as in the case of jetlag when we feel bad after changing a time zone or social jetlag when we have to start work early at 8 am. It can go as far as a circadian rhythm disorder meaning you have either a delay or advancement of sleep phases or an irregular or even non-24-hour daily activities preference. However, in the general population, a small variation in the rhythm is quite normal and is usually referred to as a chronotype. It defines your preference of when to go to sleep and do your daily activities and is divided into 3 distinct versions. The radical points of these variations include a morning chronotype, or “larks”, who go somewhat 2-3 hours ahead of the balanced rhythm, and an evening chronotype, or “owls”, who are a little delayed. The larks feel and function better during the first half of the day and go to bed rather early, while the owls prefer to work in the evenings and go to bed and wake up naturally late. The third chronotype is the in-between, balanced version of these two.

arjan-stalpers-itBTNoD1PpA-unsplash — *Figure 2. The ‘owls’ seem to have questionable personalities and suffer from psychiatric conditions more often!*

What’s my study about?

Previous research has shown that many psychopathologies are linked to an evening circadian preference. For my master thesis research, I am investigating whether we can identify specific profiles in sleep and circadian rhythm problems that are linked to specific mental health problems. There was even a curious study where researchers linked the Dark Triad personalities, which include people with tendencies for manipulation, lack of empathy, and narcissism, to the evening chronotype. Maybe this leaves some evidence for the famous quote that “evil does not rest”. However, there’s a great variation in sleep duration and perceived quality of sleep in patients with various diseases. We hope to divide such persons into more or less accurate groups with a sleep profile that would predict and aid the correct diagnosis of one or the other mental health condition.

The psychopathologies are included in our study as so-called dimensions, which look at each psychiatric syndrome not as with a norm/pathology cut-off but rather as a continuum of symptoms severity. This approach allows us to see if the sleep/circadian profile we identify refers to mental health in general or can be a distinguished part of a certain psychiatric condition. It might be that all dimensions, like depression and autistic spectrum disorders, have an evening chronotype and some non-specific sleep problems. Alternatively, we might find out that a person with symptoms of depression would sleep more or less than average and go to bed later, whereas a person with anxiety would go to sleep later as well but wake up at night very often despite an average summed up sleep duration.

The circadian rhythm changes throughout a lifetime from an early to an evening chronotype towards adolescence and then gradually shift back to the earlier preference with older age. Across the whole lifespan people constantly face varying quality of night sleep. Moreover, each psychiatric condition has a particular age of onset and sometimes changes its character with time. These are the reasons why our study will also look at how the sleep/circadian profiles change within the development phases from children (4-12 years) to adolescents (13-18) to adults (19-64) to the elderly (≥65) and if they affect males and females differently.

Why would it matter?

Should we discover distinct links between the profiles of sleep/circadian problems and certain conditions, other studies can then look into whether these profiles could be the reasons behind developing a mental health condition. It’d be interesting to finally learn what is a chicken and an egg in each profile-disease relation. For instance, should we really treat ADHD patients with melatonin and bright-light lamps instead of stimulants?

sabri-tuzcu-KHBvwAnWFmc-unsplash — *Figure 3. Maybe if we adopt a typical cat’s lifestyle, we get less mental health problems. 🙂*

Dina Sarsembayeva is a neurologist and a research master’s student at the University of Groningen. She is using the data from the CoCa project to learn if the chronotypes and sleep problems can be turned into profiles to predict specific psychiatric conditions.

Further reading

Walker, W. H., Walton, J. C., DeVries, A. C. & Nelson, R. J. Circadian rhythm disruption and mental health. Transl. Psychiatry 10, (2020).
Logan, R. W. & McClung, C. A. Rhythms of life: circadian disruption and brain disorders across the lifespan. Nature Reviews Neuroscience vol. 20 49–65 (2019).
Jones, S. G. & Benca, R. M. Circadian disruption in psychiatric disorders. Sleep Med. Clin. 10, 481–493 (2015).
Taylor, B. J. & Hasler, B. P. Chronotype and Mental Health: Recent Advances. Curr. Psychiatry Rep. 20, (2018).

The genetic architecture of the brain

Posted on April 17, 2020 by Jeanette Mostert

Genes play a big role in determining the architecture of our brain: the way it’s folded, the thickness of the outer layer, and the way different brain areas are connected. By combining data from all over the world, a large collaboration of researchers from the ENIGMA consortium has now identified almost 200 genetic variants that are involved in this brain architecture. These findings can help us to further understand the genetics of brain disorders.

Our genes contain the blueprint of our bodies. They contain information about how our cells function, and they determine for instance the colour of our eyes and hair, or whether we like cilantro (coriander) and bitter tastes. For some traits we know very well how they are influenced by genes. Eye color for instance is coded by only a few genes. But for many other traits such as height and personality, many different genes are involved. In addition, other (non-genetic) factors also influence these traits, such as malnutrition that can cause stunted growth.

The architecture of the brain is influenced by a large numer of genes, of which we still know very little. To investigate this, researchers combined genetic data of over 50.000 individuals with MRI-data. MRI-scans can show in detail the thickness of the outer layer of the brain, where all the brain cells are (also called the grey matter). They can also be used to measure how much this layer is folded, which gives information about the total surface of this outerlayer. This brain architecture is unique to every individual. The extent of the folds and the thickness of the outer layer have previously (in other research studies) been linked to cognitive abilities and various neurological and psychiatric disorders, such as Alzheimer’s disease, schizophrenia, depression, autism, and ADHD. It is therefore helpful to understand the genetics of this architecture, because it will help us to better understand the genetic mechanisms of these conditions.

The findings from this research study are also explained in this video:

This important research can only be done by combining a lot of data and collaborating with a large number of scientists and institutes. The ENIGMA consortium has been set upt to facilitate this kind of world-wide collaboration. The research that has now been published is the combined effort of more than 360 scientists from 296 departments across 184 different institutions and universities. They also made their results downloadable so that everyone who is interested can have a closer look.

The full publication can be found here: https://science.sciencemag.org/content/367/6484/eaay6690

See also our previous blogposts about these topics: