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

Posted on 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, rg), 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

  1. Comprehensive exploration of the genetic contribution of the dopaminergic and serotonergic pathways to psychiatric disorders | medRxiv
  2. Cross-disorder genetic analyses implicate dopaminergic signaling as a biological link between Attention-Deficit/Hyperactivity Disorder and obesity measures – PubMed (nih.gov)
  3. Attention-deficit/hyperactivity disorder and lifetime cannabis use: genetic overlap and causality – PubMed (nih.gov)
  4. Genome-wide association study implicates CHRNA2 in cannabis use disorder – PubMed (nih.gov)
  5. Genome-wide association meta-analysis of cocaine dependence: Shared genetics with comorbid conditions – PubMed (nih.gov)
  6. Association of Polygenic Risk for Attention-Deficit/Hyperactivity Disorder With Co-occurring Traits and Disorders – PubMed (nih.gov)
  7. Investigating causality between liability to ADHD and substance use, and liability to substance use and ADHD risk, using Mendelian randomization – PubMed (nih.gov)
  8. Genetic liability to ADHD and substance use disorders in individuals with ADHD – PubMed (nih.gov)
  9. Genetic Overlap Between Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder: Evidence From Genome-wide Association Study Meta-analysis – PubMed (nih.gov)
  10. Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder – PubMed (nih.gov)
  11. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder – PubMed (nih.gov)
  12. Shared genetic background between children and adults with attention deficit/hyperactivity disorder – PubMed (nih.gov)
  13. RBFOX1, encoding a splicing regulator, is a candidate gene for aggressive behavior – PubMed (nih.gov)

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

Posted on 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 insomnia1,2 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 sleep5,6. 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 by Dener Cardoso Melo
Photo by Jacqueline Munguía

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

  1. Schultz, W. (2015). Neuronal reward and decision signals: From theories to data. Physiological Reviews, 95(3), 853-951. doi:10.1152/physrev.00023.2014
  2. Wise, R. A. (2002). Brain reward circuitry: Insights from unsensed incentives. United States: Elsevier Inc. doi:10.1016/S0896-6273(02)00965-0
  3. 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
  4. 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
  5. 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

The genetic architecture of the brain

Posted on 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:

 

 

 

Food & mental health: the Eat2beNICE project

Posted on by Jeanette Mostert

We all know that a healthy lifestyle is beneficial for our health. But many of us forget that eating healthy, exercising regularly and getting enough sleep is also important for good mental health. In the Eat2beNICE research project a large team of researchers is investigating the link between food and mental health, specifically impulsivity, compulsivity and aggression. To share this knowledge with the rest of the world, they work together with food consultant Sebastian Lege.

The Eat2beNICE project just released a video to explain what the research is about and why it’s important. In this video Sebastian Lege visits the project coordinator Alejandro Arias-Vasquez, en several other researchers in the consortium.

More information about the Eat2beNICE project can be found at http://www.newbrainnutrition.com