ADHD and cannabis use

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.

Further reading

María Soler Artigas et al. Attention-deficit/hyperactivity disorder and lifetime cannabis use: genetic overlap and causality, Molecular Psychiatry (2019) – https://www.nature.com/articles/s41380-018-0339-3

About the author

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.

Are you genetically determined to act aggressively?

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 [1]. 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 [2]. 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 [2]. 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 [3]. 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 [4]. 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 [1].

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 [5]. 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.

References

[1] Gómez, J. M., Verdú, M., González-Megías, A., Méndez, M. (2016). The phylogenetic roots of human lethal violence. Nature 538(7624), 233–237.

[2] 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 Neurosci 26(7), 1418–1427.

[3] 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.

[4] 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.

[5] Asherson, P., Cormand, B. (2016). The genetics of aggression: Where are we now? Am J Med Genet B Neuropsychiatr Genet 171(5), 559–561.

About the author:

Mariliis Vaht, PhD

Research Fellow of Neuropsychopharmacology at Institute of Psychology, University of Tartu, Estonia. Area of research: genetic and environmental factors in longitudinal health study designs.

A complex genomic jigsaw puzzle

The human genome is not a monolithic entity but has been constantly changing throughout the  evolution of the species. The main reason behind is that when new copies of the genome of each individual are generated during reproduction, replication errors (mutations) introduced by the cellular replication machinery which can occur spuriously and be inherited from the next generation onwards.

From a genomic point of view, the magnitude of the error can range from a simple nucleotide change (called single nucleotide variant or SNV) to duplicating/deleting large fragments of the genome (called copy number variants or CNVs), as well as switching the orientation in the genome or rearranging a genomic fragment in a new genomic positions. The most common type of mutation in the human genome is SNV. However, humans also show extensive CNVs compared to other species.

From a functional point of view, all these types of changes can have important phenotypic consequences in the offspring and, ultimately, in the fate of the species when affecting functional genomic elements such as genes.

From an evolutionary point of view, new mutations that modify the phenotype of an individual are the substrate of natural selection. In the most simplistic model of selection, a mutation that confers a higher fitness to the carrier compared to non-carrier individuals will tend to non-stochastically rise in frequency in the population and, ultimately, reach fixation. Conversely, a mutation  that confers a smaller fitness to the carriers compared to non-carriers will be detrimental and erased from the population. Obviously, much more complex evolutionary patterns exist in nature (i.e. multiple genes contributing to a phenotype, ancient ongoing balancing selection, or selection on standing selection among others). However, detecting the fingerprint of these evolutionary events in the genome is more complex than in a simple selective sweep.

For SNVs, several examples of genomic regions have been reported in the literature (i.e. adulthood lactose tolerance and skin pigmentation among others). Nevertheless, little is known about the selective pressures acting on genomic rearrangements and CNVs and their role in the etiology of current complex phenotypes, including diseases.

In the first instance, the last statement certainly seems a counter-intuitive nonsense. How can something that has been selected for increasing the reproductive fitness and henceforth considered as beneficial for the carriers be associated to a disease? However, when digging a bit in the theory of Natural Selection, this scenario of positively selecting a variant that it is causal of current diseases is more than plausible. We must take into account that natural adaptation is result of genes and environment acting at individual level and mostly before and during reproductive ages. As a consequence, a functional change that increases the reproductive fitness of the carrier but has detrimental effects for the individual after reproductive age would still be under positive selective pressures and increase in frequency in the population. However, this is not a sine qua non condition for a genetic variant under positive selection in the past and showing detrimental effects in the present. Natural Selection does not work following an established master plan, but acting on the available genetic diversity and environmental conditions at the time. This time dimension has dramatic effect in the interpretation of positive selection:

  • A genetic variant that was ascertained in the past for a given environment could be detrimental nowadays due to an environmental change. For example, the thrifty gene hypothesis proposes that genetic variants associated to metabolic efficiency and energy storage increased in frequency across the populations in the past as a response to recurrent famines. However, these variants could be harmful at present  in the rich food energy environment of occidental diet and associated with phenotypes such as obesity or diabetes.

 

  • By introgression with other related species such as Neanderthals or Denisovans, our ancestors could have incorporated genetic variants specific from these species. Since these species were well adapted to their environments at the time when anatomically modern humans arrived from Africa, humans could have enhanced their adaptation to the new environments by means of this archaic admixture. Nevertheless, although this scenario has been observed for some loci, the archaic hybridization has also a main negative impact in the genome of humans. Most of the introgression has been lost due to purifying selection and it has been shown that some introgressed genetic variants play a role in complex diseases.

 

  • A supported evolutionary genomic change by natural selection in the past could promote nowadays new disease-associated genomic changes that would unlikely to naturally happen otherwise. This scenario is particularly important in the case of rearrangements and CNVs. For example, a rearrangement allowing increasing or decreasing the dosage of a gene or genes could have been selectively advantageous in the past. However, further favourable modifying the gene dosage modification by the pattern of the rearrangement could have negative side effects lately.

 

The latest point is the scenario that Nuttle et al reported in http://www.nature.com/nature/journal/v536/n7615/full/nature19075.html

Nuttle and colleagues have recently studied the evolutionary history of the 16p11.2 region in humans and the homologous region in other primate species. In previous studies, it was shown that recurrent copy number variation (CNV) at chromosome 16p11.2 accounts for approximately 1% of cases of autism.

Their analyses show that this region has undergone a large number of complex chromosomal rearrangements and duplications during primate evolution and particularly at the human lineage. In particular, the authors have shown that these rearrangements at the primate lineage have provided the genomic scenario for further human-specific rearrangements and fragment duplications. Interestingly, these human-specific duplications have provided the substratum for the rise of  a CNV region with a block size of 102-kbp cassette, containing a set of genes — BOLA2, SLX1 and SULT1A3 —. involved in autism. The authors have shown that the number of copies of BOLA2 modifies the degree of expression of the gene and protein levels, thus providing evidence of functional involvement for the CNV.

If these results are interesting per se for understanding the evolutionary history of this genomic region, more astonishing information could be concluded  while analyzing the genetic variation present at this locus. Based on the number of copies of BOLA2 in current populations (four or more in 99.8% of humans), the presence of even a higher number of copies in an ancient human sample from ~45,000 years ago, the absence of polyploidy in Neanderthals and Denisovans, the lack of evidence of archaic introgression in this region and the presence of a high frequency of rare variants, Nuttle and colleagues conclude that the presence of such large number of copies in humans is not by a stochastic process, but by the action of positive selection.

What are the implications of these findings for autism risk? According to the authors, human evolution would have directionally promoted the increase in the number of copies of the gene at expenses of creating genomic regions (breakpoints) flanking the CNV of high-identity. A collateral side effect of such high-identity breakpoints would be an increased probability of conducting recurrent unequal crossover during the creation of the gametes and the ultimate creation of microdeletions at the 16p11.2 region that have been associated to autism.