Exciting findings on ADHD comorbidities shared on 3rd meeting of CoCA researchers in Dublin

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. 

CoCA Dublin
All attendees of CoCA’s 3rd general assembly meeting in Dublin

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

What’s next?

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.

Further reading

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

3: Du Rietz, Coleman, Glanville, Wan Choi, O’Reilly & Kuntsi (2018) Association of Polygenic Risk for AttentionDeficit/Hyperactivity Disorder With Co-occurring Traits and Disorders. Biological Psychiary CNNI, in press. https://www.sciencedirect.com/science/article/pii/S2451902217302318?via%3Dihub

 

 

The interplay of nature and nurture

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.

More information about the study discussed here can be found at the following link: http://science.sciencemag.org/content/359/6374/424

The other side of ADHD

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?

corinaillustration-1024x426

© image by Roselyn Chauvin

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.

More information
The article about low ADHD traits

The article is winner of the 2016 Kramer-Pollnow Young Investigator Award

More on the Twins Early Development Study

This blog is written by Corina Greven.  Edited by Lieneke.

This blog was originally published on www.blog.donders.ru.nl. This is the official blog of the Donders Institute on brains and science.

donders_banner_bilingual

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.

How can we make sense of comorbidity?

Comorbidity, defined as the simultaneous occurrence of more than one disorder in a single patient, is commonplace in psychiatry and somatic medicine. In research, as well as in routine clinical settings.

In March 2016 the new H2020 collaborative project “CoCA” (Comorbidity in adult ADHD) was officially launched, with a 3-day kick-off meeting in Frankfurt, Germany. This ambitious project, which is coordinated by professor Andreas Reif and is co-maintaining this shared blog, will investigate multiple aspects of comorbidity in ADHD.

For instance, CoCA will “identify and validate mechanisms common to the most frequent psychiatric conditions, specifically ADHD, mood and anxiety disorders, and substance use disorders (SUD), as well as a highly prevalent somatic disorder, i.e. obesity”.

As reflected in this bold mission, most scientists trained in the biological sciences agree that studies of overlapping and concurrent phenomena may reveal some underlying common mechanisms, e.g. shared genetic or environmental risk factors.

However, particularly in psychiatry and psychology, the origins of comorbidity have been fiercely debated. Critics have argued that observed comorbidities are “artefacts” of the current diagnostic systems (Maj, Br J Psychiatry, 2005 186: 182–184).

This discussion relates to fundamental questions of how much of our scientific knowledge reflects an independent reality, or is merely a product of our own epistemological traditions. In psychiatry, the DSM and ICD classification systems have been accused of actively producing psychiatric phenomena, including artificial diagnoses and high comorbidity rates, rather than being “true” representations of underlying phenomena.  Thus, the “constructivist” tradition argues that diagnostic systems are projected onto the phenomena of psychiatry, while “realists” acknowledge the presence of an independent reality of psychiatric disorders.

In an attempt to explain these concepts and their implications, psychiatric diagnoses and terminology have been termed “systems of convenience”, rather than phenomena that can be shown to be true or false per se (van Loo and Romeijn, Theor Med Bioeth. 2015, 41-60). It remains to be seen whether such philosophical clarifications will advance the ongoing debate related to the nature of medical diagnoses and their co-occurrence.

CoCA will not resolve these controversies. Neither can we expect that our new data will convince proponents of such opposing perspectives.

It is important to acknowledge the imperfections and limitations of concepts and instruments used in (psychiatric) research.

However, it may provide some comfort that similar fundamental discussions have a long tradition in other scientific disciplines, such as physics and mathematics. Rather  than being portrayed as a weakness or peculiarity of psychiatric research, I consider that an active debate, with questioning and criticism is considered an essential part of a healthy scientific culture.

Hereby, you are invited to join this debate on this blog page!Wooden ruler vector