“No I do not have ADHD, I am just busy!”, but still very interesting for genetic studies!

Do you sometimes find it difficult to pay attention? Can you be very disorganized at times, or very rigid and inflexible? Although difficulties with attention, organization and rigidity are symptoms of psychiatric disorders, these traits are not unique to people with a diagnosis. And that is very useful for studying the genetics of psychiatric disorders.

Being easily distracted, liking things to go in a certain way, having a certain order in the way you do things, these might all be things you recognize yourself (or someone you know) in, while you (or they) are not diagnosed with any psychiatric disorder. We actually know that many of these symptoms are indeed found in a range in the general population, with some people showing them a lot, some a little and some not at all. If these symptoms are also present in people without a diagnosis then why should we only study people with a diagnosis to learn more about the biology of symptom-based disorders?

Many psychiatric disorders, like attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are disorders that ‘run in the family’. Using family-based and genetic studies it was found that they are actually highly heritable. However the underlying genetic risk factors turned out to be difficult to find. Enormous samples sizes (comparing more than 20 000 people with the disorder to even more individuals without the disorder) were needed to robustly find just a few genetic risk factors, although we know that many more genetic factors contribute. Even though these disorders are highly prevalent, collecting genetic data on psychiatric patients for research is still challenging. Using population-based samples – that include all varieties of people from the general population – can be a good alternative to reach large sample sizes for powerful genetic studies.

Taking together the fact that psychiatric-like symptoms are also, to a certain degree, present in the general population, and the fact that genetic studies can benefit from large(r) sample sizes to find genetic associations, it can be very interesting to study psychiatric-like traits in population-based samples. This is indeed what happened in the field of psychiatric genetics. The first proof-of-concept studies were able to show an astonishing overlap in genetic factors of more than 90% between ADHD and ADHD symptoms in the general population. Our own research group was able to show that certain autistic traits, like rigidity, indeed share a genetic overlap with ASD and that genes that were previously linked to ASD show an association to autistic traits in the population. These results show that genetic factors involved in disorder-like traits are overlapping with genetic factors involved in the clinical diagnosis, and therefore can indeed be used to study the biology of psychiatric disorders.

So next time you feel distracted/rigid/disorganized, don’t get discouraged, but consider signing up for a genetic study. Science might need you!

Janita Bralten is a postdoctoral researcher at the department of Human Genetics in the Radboud university medical center, Nijmegen, the Netherlands. Her research focusses on the genetics of psychiatric disorders.

Further reading:

Bralten J, van Hulzen KJ, Martens MB, Galesloot TE, Arias Vasquez A, Kiemeney LA, Buitelaar JK, Muntjewerff JW, Franke B, Poelmans G. Autism spectrum disorders and autistic traits share genetics and biology. Mol Psychiatry. 2018 May;23(5):1205-1212.

Middeldorp CM, Hammerschlag AR, Ouwens KG, Groen-Blokhuis MM, Pourcain BS, Greven CU, Pappa I, Tiesler CMT, Ang W, Nolte IM, Vilor-Tejedor N, Bacelis J, Ebejer JL, Zhao H, Davies GE, Ehli EA, Evans DM, Fedko IO, Guxens M, Hottenga JJ, Hudziak JJ, Jugessur A, Kemp JP, Krapohl E, Martin NG, Murcia M, Myhre R, Ormel J, Ring SM, Standl M, Stergiakouli E, Stoltenberg C, Thiering E, Timpson NJ, Trzaskowski M, van der Most PJ, Wang C; EArly Genetics and Lifecourse Epidemiology (EAGLE) Consortium; Psychiatric Genomics Consortium ADHD Working Group, Nyholt DR, Medland SE, Neale B, Jacobsson B, Sunyer J, Hartman CA, Whitehouse AJO, Pennell CE, Heinrich J, Plomin R, Smith GD, Tiemeier H, Posthuma D, Boomsma DI. A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts. J Am Acad Child Adolesc Psychiatry. 2016 Oct;55(10):896-905.

If you are interested in joining a scientific study see for example:

https://www.ru.nl/donders/vm-site/proefpersonen/engelse-versies-centers/participants/donders-centre-cognition-en/

or

https://www.impactadhdgenomics.com/patienten/nl/deelnemen (Dutch only)

Cocaine dependence is in part genetic, and it shares genetic risk factors with other psychiatric conditions and personality traits.

Cocaine is one of the most used illicit drugs worldwide and its abuse produces serious health problems. In Europe, around 5.2% of adults (from 15 to 64 years old) have tried cocaine, but only 20% will develop addiction. Why? Genetics is part of the answer. Cocaine dependence is a complex psychiatric disorder that results from the interaction of both environmental and genetic risk factors. Twin and adoption studies indicate that genetic alterations contribute substantially to cocaine dependence susceptibility, which has an estimated genetic load (heritability) as high as 65-79%. Although many studies with focus on candidate genes have been performed, only a few risk variants for cocaine dependence have been identified and replicated so far.

https://www.
flickr.com/photos/30478819@N08/24042216187

In this study we performed a meta-analysis of genome-wide association studies (GWAS) of cocaine dependence using more than 6,000 European ancestry individuals. This approach allowed us to inspect a huge number of genetic variants distributed all along the genome that are common in the general population. We identified a gene (HIST1H2BD) associated with cocaine dependence that is located in a region on chromosome 6 enriched in genes that encode histones, proteins that combine with DNA, protecting it and contributing to the activation (or inhibition) of genes. Some of these genes have previously been associated with schizophrenia.

Several studies have shown that substance use disorders (SUD), and especially cocaine dependence, co-occur in patients with other psychiatric disorders and personality traits. Such comorbidity is associated with increased severity for all disorders, although it is unclear whether this relationship is causal or the result of shared genetic and/or environmental risk factors. We calculated the shared genetics (genetic correlation) between cocaine dependence and six comorbid conditions. For the first time we found significant genetic correlation with attention deficit/hyperactivity disorder (ADHD), schizophrenia, major depression and risk- taking behavior. We also used another approach (polygenic risk score analysis, PRS) to prove that all tested comorbid conditions are associated with cocaine dependence status, suggesting that cocaine dependence is more likely in individuals that carry genetic risk factors for the tested conditions than in those that do not.

To our knowledge, this is the largest reported GWAS meta-analysis in European-ancestry individuals with cocaine dependence. We identified suggestive risk factors for the disorder in several genomic regions and found evidence for shared genetic risk factors between cocaine dependence and several co-occurring psychiatric traits. However, the size of the sample is still limited and further studies are needed to confirm our results.

Read more at: https://www.sciencedirect.com/science/article/pii/S0278584619301101?via%3Dihub

Judit Cabana-Domínguez and Bru Cormand

Judit Cabana Domínguez is a Postdoctoral researcher at the Genetics, Microbiology and Statistics Department at the University of Barcelona.

Bru Cormand is Full Professor of Genetics at the Genetics, Microbiology and Statistics Department at the University of Barcelona.

Epigenetic signature for attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is considered a complex disorder caused by underlying genetic and environmental risk factors. To make it even more complex, environmental factors can influence the expression of genes. This is called epigenetics.

Given the large proportion of the heritability of ADHD still to be explained, there is a growing interest in the epigenetic mechanisms that modulate gene expression. microRNAs (miRNA) are small parts in the human genome that do not code for genes, but instead regulate the expression of other genes by promoting the degradation or suppressing the translation of those target genes. miRNA therefore provide a means to integrate effects of genetic and environmental risk factors.

The human genome encodes more than 2500 different miRNAs, the majority of which are expressed in the brain. miRNAs are known to be involved in the development of the central nervous system and in many neurological processes including synaptic plasticity and synaptogenesis. Given the limited accessibility of the human brain for studying epigenetic modifications, miRNA profiling in peripheral blood cells is often used as a non-invasive proxy to study transcriptional and epigenetic biosignatures, and to identify potential clinical biomarkers for psychiatric disorders.

We recently investigated the role of microRNAs in ADHD at a molecular level, by conducting the first genome-wide integrative study of microRNA and gene expression profiles in blood of individuals with ADHD and healthy controls. We identified three miRNAs (miR-26b-5p, miR-185-5p and miR-191-5p) that have different expression levels in people with ADHD, compared to those without ADHD. When we investigated downstream miRNA-mediated mechanisms underlying the disorder this provided evidence that aberrant expression profile of these three miRNA may underlie changes in the expression of genes related with myo-inositol signaling. This mediates the biological response of a large number of hormones and neurotransmitters on target cells. We also found that these miRNAs specifically targeted genes involved in neurological disease and psychological disorders.

These findings show that epigenetic modifications through microRNAs play a role in ADHD, and provide novel insights into how these miRNA-mediated mechanisms contribute to the disorder. In the future, these miRNAs may be used as peripheral biomarkers that can be easily detected from blood, as is shown in the figure.

What´s next?

The mechanism through which miRNAs modify gene expression is complex and dynamic. Therefore, future studies are required to provide deeper insights into the epigenetic mechanisms underlying ADHD, and to identify specific molecular networks that may be crucial in the development of the disorder.

Further reading

Cristina Sánchez-Mora et al. Epigenetic signature for attention-deficit/hyperactivity disorder: identification of miR-26b-5p, miR-185-5p, and miR-191-5p as potential biomarkers in peripheral blood mononuclear cells, Neuropsychopharmacology, volume 44, pages 890–897 (2019).

https://www.nature.com/articles/s41386-018-0297-0

About the author

Cristina Sánchez-Mora is postdoctoral researcher at the Psychiatry, Mental Health and Addictions group at Vall d’Hebron Institut de Recerca (VHIR). Her research is part of the CoCA consortium that investigates comorbid conditions of ADHD

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.

Researchers have found the first risk genes for ADHD

Our genes are very important for the development of mental disorders – including ADHD, where genetic factors capture up to 75% of the risk. Until now, the search for these genes had yet to deliver clear results.   In the 1990s, many of us were searching for genes that increased the risk for ADHD because we know from twin studies that ADHD had a robust genetic component.   Because I realized that solving this problem required many DNA samples from people with and without ADHD, I created the ADHD Molecular Genetics Network, funded by the US NIMH.  We later joined forces with the Psychiatric Genomics Consortium (PTC) and the Danish iPSYCH group, which had access to many samples.

The result is a study of over 20,000 people with ADHD and 35,000 who do not suffer from it – finding twelve locations (loci) where people with a particular genetic variant have an increased risk of ADHD compared to those who do not have the variant.  The results of the study have just been published in the scientific journal Nature Genetics, https://www.nature.com/articles/s41588-018-0269-7.

These genetic discoveries provide new insights into the biology behind developing ADHD. For example, some of the genes have significance for how brain cells communicate with each other, while others are important for cognitive functions such as language and learning.

We study used genomewide association study (GWAS) methodology because it allowed us to discover genetic loci anywhere on the genome.  The method assays DNA variants throughout the genome and determines which variants are more common among ADHD vs. control participants.  It also allowed for the discovery of loci having very small effects.  That feature was essential because prior work suggested that, except for very rare cases, ADHD risk loci would individually have small effects.

The main findings are:

  1. A) we found 12 loci on the genome that we can be certain harbor DNA risk variants for ADHD. None of these loci were traditional ‘candidate genes’ for ADHD, i.e., genes involved in regulating neurotransmission systems that are affected by ADHD medications. Instead, these genes seem to be involved in the development of brain circuits.
  2. B) we found a significant polygenic etiology in our data, which means that there must be many loci (perhaps thousands) having variants that increase risk for ADHD. We will need to collect a much larger sample to find out which specific loci are involved;

We also compared the new results with those from a genetic study of continuous measures of ADHD symptoms in the general population. We found that the same genetic variants that give rise to an ADHD diagnosis also affect inattention and impulsivity in the general population.  This supports prior clinical research suggesting that, like hypertension and hypercholesteremia, ADHD is a continuous trait in the population.  These genetic data now show that the genetic susceptibility to ADHD is also a quantitative trait comprised of many, perhaps thousands, of DNA variants

The study also examined the genetic overlap with other disorders and traits in analyses that ask the questions:  Do genetic risk variants for ADHD increase or decrease the likelihood a person will express other traits and disorders.   These analyses found a strong negative genetic correlation between ADHD and education. This tell us that many of the genetic variants which increase the risk for ADHD also make it more likely that persons will perform poorly in educational settings. The study also found a positive correlation between ADHD and obesity, increased BMI and type-2 diabetes, which is to say that variants that increase the risk of ADHD also increase the risk of overweight and type-2 diabetes in the population.

This work has laid the foundation for future work that will clarify how genetic risks combine with environmental risks to cause ADHD.  When the pieces of that puzzle come together, researchers will be able to improve the diagnosis and treatment of ADHD.

Stephen Faraone is distinguished Professor of Psychiatry and of Neuroscience and Physiology at SUNY Upstate Medical University and is working on the H2020-funded project CoCA. 

The first risk genes for ADHD has been identified

A major international collaboration headed by researchers from the Danish iPSYCH project, the Broad Institute of Harvard and MIT, Massachusetts General Hospital, SUNY Upstate Medical University, and the Psychiatric Genomics Consortium has for the first time identified genetic variants which increase the risk of ADHD. The new findings provide a completely new insight into the biology behind ADHD.

 

Risk variants for  ADHD
Our genes are very important for the development of ADHD, where genetic factors capture up to 75% of the risk. Until now, the search for locations in the genome with genetic variation that is involved in ADHD has not delivered clear results. A large genetic study performed by researchers from the Psychiatric Genomics Consortium have compared genetic variation across the entire genome for over 20,000 people with ADHD and 35,000 who do not suffer from it – finding twelve locations where people with a particular genetic variant have an increased risk of ADHD compared to those who do not have the variant.

The special about the new study is the large amount of data. The search for genetic risk variants for ADHD has spanned decades but without obtaining robust results. This time the study really expanded the number of study subjects substantially, increasing the power to obtain conclusive results.

The results of the study have just been published in the scientific journal Nature Genetics.

The new genetic discoveries provide new insights into the biology behind developing ADHD. For example, some of the genes have significance for how brain cells communicate with each other, while others are important for cognitive functions such as language and learning. Overall, the results show that the risk variants typically regulate how much a gene is expressed, and that the genes affected are primarily expressed in the brain.

The same genes affect impulsivity in healthy people
In the study, the researchers have also compared the new results with those from a genetic study of continuous measures of ADHD behaviours in the general population. The researchers discovered that the same genetic variants that give rise to an ADHD diagnosis also affect inattention and impulsivity in the general population. This result tells us, that the risk variants are  widespread in the population. The more risk variants a person has, the greater the tendency to have ADHD-like characteristics will be as well as the risk of developing ADHD.
The study also evaluated the genetic overlap with other diseases and traits, and a strong negative genetic correlation between ADHD and education was identified. This means that on average genetic variants which increase the risk of ADHD also influence performance in the education system negatively for people in the general population who carry these variants without having ADHD.

Conversely, the study found a positive correlation between ADHD and obesity, increased BMI and type-2 diabetes, which is to say that variants that increase the risk of ADHD also increase the risk of overweight and type-2 diabetes in the population.

What´s next?
The new findings mean that the scientists now – after many years of research – finally have robust genetic findings that can inform about the underlying biology and what role genetics plays in the diseases and traits that are often cooccurring with ADHD. In addition, the study is an important foundation for further research into ADHD. Studies can now be targeted, to focus on the genes and biological mechanisms identified in the new study in order to achieve a deeper understanding of how the genetic risk variants affect the development of ADHD with the aim of ultimately providing better help for people with ADHD.


References:

Demontis and Walters et al. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nature Genetics, 2018. https://doi.org/10.1038/s41588-018-0269-7

https://www.nature.com/articles/s41588-018-0269-7