It is not uncommon for individuals to suffer
from two or more psychiatric disorders at the same time. The appearance of
these disorders frequently follows a specific order, and one disorder may
predispose to others, all of which in combination contribute to the worsening
of the quality of life of the individuals who suffer them. This is usually
associated with more severe symptoms and worse prognosis. In addition, making a
diagnosis and applying personalized treatments becomes more challenging in this
context. By investigating the genetic overlap between disorders, we gain better
understanding of why the disorders frequently co-occur.
In mental health, substance use disorders often
appear when there is another mental condition. This is the case for attention-deficit/hyperactivity
disorder (ADHD) and substance use disorder, where individuals with ADHD are
more likely to use drugs during their lifetime than individuals who do not have
ADHD. In particular, cannabis is the most commonly used substance among
individuals with ADHD, which can also lead to the use of other drugs and to the
worsening of their symptoms. ADHD is one of the most common neurodevelopmental disorders, affecting around 5% of
children and 2.5% of adults, and is characterized by attention deficit,
hyperactivity and impulsivity. Both ADHD and cannabis use are conditions
determined partly by environmental factors but where genetic factors also play
an important role.
We recently investigated the genetic overlap
between ADHD and cannabis use, and found that the increased probability of
using cannabis in individuals with ADHD, can be, in part, due to a common
genetic background between the two conditions. We identified four genetic regions
involved in increasing the risk of both ADHD and cannabis use, which could
point to potential druggable targets and help to develop new treatments. In addition,
we confirmed a causal link between ADHD and cannabis use, and estimated that
individuals with ADHD are almost 8 times more likely to consume cannabis than
those who do not have ADHD. This evidence goes in line with a temporal
relationship, where the ADHD appears in childhood and the use of cannabis
during adolescent or adulthood. This suggests that having ADHD increases the
risk of using cannabis, and not vice versa.
This research has only been possible thanks to
large international collaborations by the Psychiatric Genomics Consortium (PGC),
iPSYCH, and the International Cannabis Consortium (ICC), where the genomes of
around 85 000 individuals were analysed.
Overall, these results support the idea that
psychiatric disorders are not independent, but have a common genetic
background, and share biological pathways, which put some individuals at higher
risk than others. This will help to overcome the stigma of addiction and mental
disorders. In addition, the potential of using genetic information to identify
individuals at higher risk will have a strong impact on prevention, early
detection and treatment.
María Soler Artigas is postdoctoral researcher
at the Psychiatry, Mental Health and Addictions group at Vall d’Hebron Institut
de Recerca (VHIR), also part of the Biomedical Research Networking Center in
Mental Health (CIBERSAM). Her research is part of the CoCA consortium that
investigates comorbid conditions of ADHD.
From road rage and bar fights to terror attacks and global confrontations, humans tend to be an aggressive species. On the average, members of the same species cause only 0.3 percent of deaths among mammals . Astoundingly, in Homo sapiens the rate is around 2% (1 in 50), nearly 7 times higher! There are two crucial aspects that favor this kind of behavior: dwelling in social groups and being ferociously territorial. The chances are that struggle for various resources like suitable habitat, mates and food played a key role in shaping aggression in humans, favoring genetic variants that promote aggression and therefore increase changes of survival. Indeed, anthropologists who lived with exceptionally violent hunter-gatherers found that men who committed acts of homicide had more children, as they were more likely to survive and have more offspring . This lethal legacy may be the reason we are here today.
You probably know some people that could be characterized as “having a short fuse”. Perhaps you have even pondered why they seem to have such a hard time to keep their temper in check? Indeed – while scientists have known for decades that aggression is hereditary, there is another crucial component to those angry flare-ups: self-control. In humans, the impulses to react violently stem from the ancient structures located deep within the brain. The part capable of controlling those impulses is evolutionally much younger and located just behind the forehead – the frontal lobes. Unfortunately, this “top-down” conscious control of aggressive impulses is slower to act compared to the circuits of eruptive violence deep in the brain.
People who are genetically predisposed toward aggression actually usually behave more violently than the average only when provoked. People not genetically susceptible to violent outbursts seem to be better able to remain calm and “brush it off”. The ones who are predisposed in fact try hard to control their anger, but have inefficient functioning in brain regions that control emotions – in the frontal lobes . Several studies have found that men genetically susceptible to act aggressively are especially likely to engage in violence and other antisocial behavior if they were exposed to childhood abuse . Again, we see that although genes may carry certain predispositions, there are essential environmental aspects that determine the final outcome.
Early physical aggression needs to be dealt with care. Long-term studies of physical aggression clearly indicate that most children, adolescent and even adults eventually learn to use alternatives to physical aggression . Still, the importance of proper guidance and favorable environment cannot be understated. As mentioned before, Homo sapiens have been found to cause 2 percent of deaths among their fellows. However, this has fluctuated substantially throughout the history and in different cultures. During the medieval period, human-on-human violence was responsible for stunning 12 percent of recorded deaths. For the last century, people have been relatively peaceable compared to the Middle Ages, violence being the cause of death in just 1.33 percent of fatalities worldwide. In the least violent parts of the world today, the homicide rates are as low as 0.01 percent .
Our brains have evolved to monitor for danger and spark aggression in response to any perceived hazard as a defense mechanism. Aggression is part of the normal behavioral repertoire of most, if not all, species; however, when expressed in humans in the wrong context, aggression leads to social maladjustment and crime . By identifying genes and brain mechanisms that predispose people to the risk of being violent – even if the risk is small – we may eventually be able to tailor prevention programs to those who need them most.
 Gómez, J. M., Verdú, M., González-Megías,
A., Méndez, M. (2016). The phylogenetic roots of human lethal violence. Nature 538(7624), 233–237.
 Denson, T. F., Dobson-Stone, C., Ronay, R., von
Hippel, W., Schira, M. M. (2014). A functional polymorphism of the MAOA gene is
associated with neural responses to induced anger control. J Cogn
 Cicchetti, D.,
Rogosch, F. A., Thibodeau, E. L. (2014). The effects of child maltreatment on early signs of antisocial
behavior: Genetic moderation by Tryptophan Hydroxylase, Serotonin Transporter,
and Monoamine Oxidase-A-Genes. Dev Psychopathol 24(3), 907–928.
 Lacourse, E., Boivin, M., Brendgen, M., Petitclerc,
A., Girard, A., Vitaro, F., Paquin, S., Ouellet-Morin, I., Dionne, G.,
Tremblay, R. E. (2014). A
longitudinal twin study of physical aggression during early childhood: Evidence
for a developmentally dynamic genome. Psychol Med 44(12):2617–2627.
Asherson, P., Cormand, B. (2016). The genetics of aggression: Where are we now?
Am J Med
Genet B Neuropsychiatr Genet 171(5),
There are stories how people with ADHD, like Richard Branson, achieve amazing success in entrepreneurship or in other fields as they have managed to leverage their strengths in the right way and in the right career. Might some of the ADHD-related genes also link with working in an enterprising positions like sales, management, journalism?
Indeed, we found that one potential ADHD gene, encoding the enzyme catechol-O-methyltransferase (COMT) that has two different variant forms (Val variant and Met variant) is associated with working in an enterprising position among the parents of the ECPBHS sample . Men, who inherited the Val variant of that gene from both parents, were more often in professions considered enterprising and were more satisfied with their job than other men. In addition, individuals, who inherited the Val variant from at least one of their parents, reported themselves more frequently as in a managerial position.
However, this single gene effect on our career choice should not be considered big and there are other factors that associate with our career choices. For example, it is conceivable that people select jobs appropriate for their personalities , and entrepreneurship is a more convenient occupation for some personalities than for others [3; 4]. We found subjects working in an enterprising position having higher scores of extraversion although there were no associations between observed gene and extraversion, indicating that extraversion and the observed gene independently contributed to entrepreneurship.
Individuals, who worked in an enterprising position or as a manager also perceived that they had more supportive relations with parents in their childhood. Interestingly, while perceived supportive relations with their mother were more important for men, support from the father in their childhood was more crucial for women. More support from family also helps to obtain higher education that was associated with working in an enterprising position or being a manager, as education increases entrepreneurship because of the higher self-confidence, lower perceived risk and enhanced human capital .
However, it is also the context that regulates who decides to start a new company, what kind of company they will start and how aggressively they will pursue growth and with what outcomes . Therefore, our results might not be easily repeatable in all other samples as subjects of our sample of middle-aged men and women who live in Estonia mostly built their careers after the collapse of the Soviet Union and following systematic transition to an entrepreneurial economy. In such new market economies, market entry barriers and competition were low, therefore it was easier to establish and run imitative (as opposed to innovative) businesses .
To sum it up, although we found that working in an enterprising position or as a manager is associated with Val-variant of COMT gene, it is good to remember that beside genes we are also influenced by environment.
Triin Kurrikoff, Health Sociology Analyst in the University of Tartu, Estonia, member of CoCA project.
Katre Sakala, ECPBHS project manager in the University of Tartu, Estonia, member of CoCA project.
 ECPBHS – The Estonian Children Personality Behavior and Health Study started already in 1998 and is a longitudinal multidisciplinary study. The participants of the study were 9 and 15 years old at that time and by now they have participated in four study waves. The sample of parents of ECPBHS included more than 1000 middle-aged individuals, both men and women. The main focus of ECPBHS is health and lifestyle.
 Kristof, A. L. Person–organization fit: An integrative review of it conceptualizations, measurement, and implications. Pers Psychol,49, 1–49 (1996).
 Baron, R., & Markman, G. (2004). Toward a process view of entrepreneurship: The changing impact of individual level variables across phases of new venture development. In M. Rahim, R. Colembiewski, & K. Mackenzie (Eds.), Current topics in management. Vol. 9. (pp. 45–64). New Brunswick, NJ: Transaction.
 Zhao, H., Seibert, S. E., & Lumpkin, G. T. The relationship of personality to entrepreneurial intentions and performance: A meta-analytic review. J Manage,36, 381–404 (2010).
 Jiménez, A., Palmero-Cámara, C., González-Santos, M.J., González-Bernal, J., Jiménez-Eguizábal, J.A. The impact of education levels on formal and informal entrepreneurship. BRQ-Bus Res Q, 18, 204-212 (2015).
 Acs, Z.J., Audretsch, D.B., Lehmann E.E. & Licht G. National Systems of Entrepreneurship. Small Bus Econ:16, 527–535 (2016).
 Earle, J. & Sakova, Z. Business start-ups or disguised unemployment? Evidence on the character of self employment from transition economies. Labour Econ,7, 575–601 (2000).
Have you ever heard of that people with ADHD are more likely to be obese than those without? This has been supported by two separately conducted meta-analyses in 2016,1,2 where the researchers combined results from previous independent studies using a statistical technique to provide more precise estimates.
In most studies to date, obesity was defined solely by body mass index (BMI) ≥30 kg/m2, based on the World Health Organization classification. In our recent study (published on Psychological Medicine),3 we attempted to revisit the association between ADHD and obesity in 2.5 million individuals identified from the Swedish national registers. Both ADHD and obesity were assessed via clinical diagnosis. We speculate that clinically diagnosed obesity may better reflect the pathological aspect of body fat deposition. Not surprisingly, we observed that people with ADHD were more likely than those without to receive a clinical diagnosis of ADHD during their adolescence and young adulthood.
Genetic alterations common to both ADHD and obesity have been proposed as one of the plausible mechanisms underlying the association. To test this hypothesis, we conducted analysis in the relatives of the 2.5 million individuals. We compared the relatives of those affected by ADHD with the relatives of those unaffected. Here come the findings: first, relatives of individuals with ADHD were at higher risk for obesity diagnosis; second, the association was stronger in full siblings than in half siblings or full cousins; third, the association did not differ much between maternal half siblings and paternal half siblings. The first and the second findings just confirm that ADHD and obesity may run together in families, while the third one actually suggests that such familial co-aggregation is primarily due to the genetic sharing between family members. Here is the reason behind: the degree of genetic sharing between maternal half siblings is similar to that between paternal half siblings, whereas the maternal half siblings in our study were likely to share more of environmental factors than the paternal half siblings. This is because that children tend to live with their mothers following parental separation during the study period in Sweden. Nonetheless, the difference in environmental sharing did not seem to make the association stronger in maternal half siblings than in paternal half siblings.
More evidence for the genetic influence on the association is from our subsequent quantitative genetic analysis. The method is commonly applied to data from identical and fraternal twins to estimate the relative genetic and environmental contributions to the covariance between two traits. We applied the method to data from full and half siblings instead and found that the covariance between ADHD and obesity could be predominantly attributed to genetic factors. Environmental factors seem to play only a limited role in the covariance.
Since ADHD predicts obesity in adolescence and young adulthood, it might be a good idea to monitor children with ADHD for weight gain. Interventions, such as organized physical activity, tailored to those on a suboptimal trajectory might help prevent obesity later in life. Hopefully, clinically actionable genetic variants can be discovered and benefit people suffering from both conditions.
Dr. Qi Chen is a research coordinator in the department of Medical Epidemiology and Biostatistics at Karolinska Institutet. Her research is supported by the CoCA project.
1 Cortese S, Moreira-Maia CR, St Fleur D, Morcillo-Penalver C, Rohde LA, Faraone SV. Association Between ADHD and Obesity: A Systematic Review and Meta-Analysis. Am J Psychiatry 2016; 173: 34-43.
2 Nigg JT, Johnstone JM, Musser ED, Long HG, Willoughby M, Shannon J. Attention-deficit/hyperactivity disorder (ADHD) and being overweight/obesity: New data and meta-analysis. Clinical psychology review 2016; 43: 67-79.
3 Chen Q, Hartman CA, Kuja-Halkola R, Faraone SV, Almqvist C, Larsson H. Attention-deficit/hyperactivity disorder and clinically diagnosed obesity in adolescence and young adulthood: a register-based study in Sweden. Psychol Med 2018 Sep 17: 1-9.
A few weeks ago, researches from all over Europe (and some even from the USA) gathered in Dublin to discuss the progress of the CoCA project. This project, investigating the prevalence and causal factors of ADHD comorbidities, is now almost half way. Time for an update on what’s happening.
ADHD is a risk factor for developing other (psychiatric) disorders
One of CoCA’s aims is to estimate the prevalence of comorbid disorders that occur together with ADHD. By using very large data registries from Norway, Sweden, Denmark and Estonia we can estimate the risk of developing a psychiatric comorbidity when a person has ADHD. For instance, last month a paper was published based on data from Norway, stating that the prevalence of anxiety, depression, bipolar and personality disorders, schizophrenia and substance use disorders is 4 to 9 times higher in adults with ADHD compared to adults without ADHD . Interesting differences between men and women were also observed in this study. Such that depression is much more prevalent in women with ADHD, compared to women without, while in men substance use disorders are more common together with ADHD.
ADHD does not only co-occur with other psychiatric disorders, but also with obesity. Earlier last year, we published a study based on the Swedish national registry, where it was observed that ADHD and being overweight or having obesity share familial risk factors . In other words, when you have a sibling who is overweight or has obesity, you are more likely to have ADHD compared to similar people who do not have overweight siblings.
The data from these registries can not only be used to estimate prevalence, but also to predict the risk someone has to develop other disorders. Our partners in the USA are using advanced machine learning tools to predict within the ADHD population who will develop comorbid disorders. Using the Swedish registry data they have found that having an ADHD diagnosis combined with a high number of injuries before the age of 12 predicts a comorbid substance use disorder at a later age. High risk taking behavior could mediate this association, and may therefore be a trait to investigate further and monitor in young people with ADHD. These data are now being further investigated and have not yet been published.
Publications on other registries and data will come out soon, so keep your eye on this blog for more information on the co-occurrence of (psychiatric) disorders in persons with ADHD.
ADHD and (psychiatric) comorbidities share genetic variants
When you know that ADHD often co-occurs with other disorders, the next question is to understand how and why. Our geneticists are trying to map the genetic overlap between the different disorders and identify shared genetic risks. Much of the work is still ongoing, but you can expect some exciting findings to be published very soon. What I can already share is the recent publication on how polygenic risk scores of ADHD overlap with other disorders and traits . Polygenic risk scores (PRS) were calculated based on 12 genetic loci that are associated with ADHD based on earlier studies. In other words, the more risk variants you have on these loci, the higher your risk is for ADHD. Using the UK Biobank data, the researchers found that ADHD PRS were associated with higher body mass index, neuroticism, anxiety, depression, alcohol and nicotine use, risk taking and lower general cognitive ability (verbal-numerical reasoning). This suggests that the genes that contribute to ADHD are also involved in other traits and disorders that are often observed in people with ADHD. More knowledge on these genetic factors is expected from the studies that are now being conducted.
Searching for new treatment possibilities for ADHD and comorbid disorders
At the moment, there are no good treatments for obesity and substance use disorders, and there is little progress in the development of medication for ADHD in combination with depression. Within the CoCA project we are therefore investigating new treatment possibilities. In Frankfurt, Barcelona and London the first people with ADHD have received bright light therapy and physical exercise training to reduce symptoms of depression (the PROUD study). In Nijmegen this study will soon start as well. Meanwhile in Rostock (Germany), the circadian rhythm of participants with ADHD and other disorders is being measured. And in Frankfurt researchers are investigating the effects of dopamine agonists and antagonists on the reward system in the brain.
CoCA researchers in Norway have been searching the literature for new druggable targets for ADHD and comorbid disorders. A publication on many promising druggable genes can be expected soon. The first group of targets will be tested in an animal models.
Collaborations with patient organisations
Two representatives of ADHD patient organisations also joined our meeting: Andrea Bilbow from ADHD Europe, who is a partner in the CoCA project, and Ken Kilbride from ADHD Ireland. It was good to have these experts with us, and discuss with them how we can best translate our research findings to the people who should benefit from these findings. In Ireland for instance, there is very little knowledge about adult ADHD amongst health care professionals. It is therefore essential that our knowledge is also transferred to them, so that they can provide better care.
With the help of Andrea and Ken, we came up with a lot of new ideas for ADHD Awareness Month. During the entire month of October we aim to generate more awareness about. We will specifically target schools, such as universities and German Berufschule to inform both pupils and teachers about how to recognise ADHD and comorbidities, in adolescence and adulthood.
With the project being almost half way, we feel that we’re progressing very well (and our external advisor Jim Swanson – who attend the meeting as well – agrees!). In the coming year, we expect many exciting publications to appear and we will organise several symposia on international scientific conferences to share with you what we’ve found. By collaborating with patient organisations across Europe we will also share our knowledge with patients, family members, health care professionals and teachers. You can follow all of our progress on this blog!
This blog was written by Jeanette Mostert. Jeanette is dissemination manager of the CoCA project.
1: Solberg, Halmøy, Engeland, Igland, HAavik & Kungsøyr (2018) Gender differences in psychiatric comorbidity: a population‐based study of 40 000 adults with attention deficit hyperactivity disorder. Acat Psychiatria Scandinavia, 137 (3): 176 – 186. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838558/
2: Chen, Kuja-Halkola, Sjölander, Serlachius, Cortese, Farone, Almgvist & Larsson (2017) Shared familial risk factors between attention-deficit/hyperactivity disorder and overweight/obesity – a population-based familial coaggregation study in Sweden. Journal of child psychology and psychiatry, 58 (6): 711-718. https://www.ncbi.nlm.nih.gov/pubmed/28121008
The nature vs nurture debate has been a topic of interest in science for many, many years. It is still unknown to what extent hereditary (nature) and environmental (nurture) factors affect human traits. These two sets of factors have traditionally been considered largely independent of one another. Recently however, more and more studies are focusing on the intermixed effect of nature and nurture.
The recent deCODE paper published in the journal Science is one such study. Kong et al. studied genetic nurturing effects on educational attainment (highest degree of an education one has completed). They showed how parental and sibling genetic information can shape the environment that consequently affects the child. The study was performed in an Icelandic population using parent-offspring data which enabled the researchers to look at the both transmitted and non-transmitted maternal and paternal alleles. The genetic material that has not been passed from the parents to the child had an average effect size of 34.2% the effect of transmitted alleles.
When performing genome-wide association studies (GWAS) one is looking at the association between the transmitted alleles in a child and the trait. The results of the GWAS have been interpreted as the direct effects. However, the existence of the nurturing effects as shown by this study is highlighting how an indirect effect (genetic nurturing) is amplfying GWAS results.
More attention should be given to investigating the effect of the non-transmitted alleles. Knowing that many neuropsychiatric disorders run in families, and that parental behaviour is having an important environmental effect on children, it may be worth looking into the effects of genetic nurturing on neurodevelopmental disorders.
In children, it is common to observe traits of ADHD such as being easily distracted, blurting out answers in the classroom, being always ‘on the go’, or fidgeting. However, there are also children on the other extreme, those who have excellent attention, sit quietly in class, and are well-organized with their homework. Are they a mirror-image of ADHD or are they expressing overly controlled and inflexible behaviours?
Scientists believe that attention-deficit hyperactivity disorder (ADHD) does not exist in an all-or-nothing fashion – where you either have the disorder or not – but on a continuum. Just as we differ in height (from short to tall) or weight (under- to overweight), we differ in attentiveness, impulsiveness and activity levels. This is why many of us recognize ADHD traits in ourselves, even though ADHD as a diagnosis only affects around 6% of youth. High extreme ADHD traits at one end of the continuum are well-studied (those with a diagnosis) but what about those at the other end of the spectrum – those with “low extreme ADHD traits”?
Mirror image of high ADHD traits? Low extreme ADHD traits might simply be a mirror image of what we see for high ADHD traits. So instead of the inattention and impulse control problems that we commonly observe, those at the low extreme may be perfectly self-controlled individuals, with excellent attention and impulse control skills. For example, we might expect these to be children who are well-adjusted because they are able to pay attention to the teacher, are very organized in their homework, and able to regulate negative emotions such as anger, allowing them to build a positive family and friendship circle.
Too much of a good thing? On the other hand, excellent attention skills and impulse control may become maladaptive when one has ‘too much of a good thing’, reflecting hyperfocus at the cost of being unable to switch attention when needed, or being overly controlling of one’s behaviour. Hence, we might expect children at the low extreme to also have problems at school or home, due to being less spontaneous or flexible, overly rigid or inhibited, or inactive.
Twins with low ADHD traits To investigate whether these extremely low ADHD traits reflect a mirror image of ADHD, or instead too much of a good thing, my colleagues and I examined data from over 2000 16-year old British twins drawn from the so-called Twins Early Development Study. The twins rated individual differences in their own ADHD traits from low to high on a rating scale.
We found that children with the lowest ADHD traits had the lowest levels of depression and conduct problems. They were also the happiest and most satisfied with their lives, did the best at school, showed the most prosocial behavior, and had the least chaotic home environments. Hence, low extreme ADHD traits appear to be highly positive, adaptive traits, consistent with a mirror image of high extreme ADHD traits.
Nature and nurture What’s interesting about twin studies is that we can address how heritable certain traits are. We know that ADHD is one of the most highly heritable childhood psychiatric disorders. That is, high ADHD traits are mainly attributable to genes (nature). How does this fare for children with extremely low ADHD traits? We were surprised to find that low ADHD traits were not significantly heritable. Instead, low ADHD traits were strongly influenced by the environment (nurture). For example, the shared environment between family members influences siblings in the family to have similar low ADHD traits.
Importantly, just because high ADHD traits are heritable does not mean that environmental interventions are not effective for ADHD. Both medication and behavioural interventions such as parent management training are evidence-based treatment options for ADHD. In this light, our results are very interesting. If we can identify positive or protective environments influencing low ADHD traits, this could possibly provide clues for interventions for those with high ADHD traits or to prevent individuals from developing ADHD.