The cortex and ADHD: the second project of the ENIGMA-ADHD collaboration.

After the first project on subcortical brain volumes in ADHD, published in Lancet Psychiatry in 2017 , ENIGMA-ADHD now analysed cortical data of 2246 people with a diagnosis of ADHD and 1713 people without, aged between four and 63 years old.  The data came from 37 research groups from around the world. FreeSurfer (imaging software) parcellations of thickness and surface area of 34 cortical regions were compared between cases and controls in 3 separate age groups; children, adolescents and adults.

ENIGMAADHD2JPG

Subtle differences only in the group of children were found. The childhood effects were most prominent and widespread for the surface area of the cortex. More focal changes were found for thickness of the cortex. All differences were subtle and detected only at a group level, and thus these brain images cannot be used to diagnose ADHD or guide its treatment.

These subtle differences in the brain’s cortex were not limited to people with the clinical diagnosis of ADHD: they were also present – in a less marked form – in youth with some ADHD symptoms. This second finding results from a collaboration between the ENIGMA-ADHD Working Group and the Generation-R study from Rotterdam, which has brain images on 2700 children aged 9-11 years from the general population. The researchers found more symptoms of inattention to be associated with a decrease in cortical surface area. In a third study, using the NeuroImage data from Nijmegen and Amsterdam, familial effects on those regions that showed case-control differences were investigated.  Siblings of those with ADHD showed changes to their cortical surface area that resembled their affected sibling. This suggests that familial factors such as genetics or shared environment may play a role in brain cortical characteristics.

We identified cortical differences that are consistently associated with ADHD combining data from many different research groups internationally. We find that the differences extend beyond narrowly-defined clinical diagnoses and are seen, in a less marked manner, in those with some ADHD symptoms and in unaffected siblings of people with ADHD. This finding supports the idea that the symptoms underlying ADHD may be a continuous trait in the population, which has already been reported by other behavioural and genetic studies.’ In the future, the ADHD Working Group, which is led by Martine Hoogman and Barbara Franke from the Radboudumc in Nijmegen, hopes to look at additional key features in the brain- such as the structural connections between brain areas – and to increase the representation of adults affected by ADHD, in whom limited research has been performed to date.

Link to the article: Hoogman et al., Brain Imaging of the Cortex in ADHD: A Coordinated Analysis of Large-Scale Clinical and Population-Based Samples

To learn more about other projects that are carried out using ENIGMA-ADHD data, please also read the paper by Yanli Zhang-James and colleagues on bioRxiv. Here, the ENIGMA-ADHD data of the first and the second project were used to do prediction modelling.  

The ADHD Working Group is one of over 50 working groups of the ENIGMA Consortium, in which international researchers pull together to understand the brain alterations associated with different disorders and the role of genetic and environmental factors in those alterations. For more information about ENIGMA-ADHD please visit our website http://enigma.usc.edu/ongoing/enigma-adhd-working-group/ or contact Martine Hoogman martine.hoogman (at) radboudumc.nlenigma_300dpi

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.

Who is the average patient with ADHD?

Is there an ‘average ADHD brain’? Our research group (from the Radboudumc in Nijmegen) shows that the average patient with ADHD does not exist biologically. These findings were recently published in the journal. Psychological Medicine.

Most biological psychiatry research heavily relies on so-called case-control comparisons. In this approach a group of patients with for instance ADHD is compared against a group of healthy individuals on a number of biological variables. If significant group effects are observed those are related to for instance the diagnosis ADHD. This often results in statements such as individuals with ADHD show differences in certain brain structures. While our results are in line with those earlier detected group effects, we clearly show that a simple comparison of these effects disguises individual differences between patients with the same mental disorder.

Modelling individual brains

In order to show this, we developed a technique called ‘normative modelling’ which allows us to map the brain of each individual patient against typical development. In this way we can see that individual differences in brain structure across individuals with ADHD are far greater than previously anticipated. In future, we hope that this approach provides important insights and sound evidence for an individualized approach to mental healthcare for ADHD and other mental disorders.

Individual differences in ADHD

When we studied the brain scans of individual patients, the differences between those were substantial. Only a few identical abnormalities in the brain occurred in more than two percent of patients. Marquand: “The brains of individuals with ADHD deviate so much from the average that the average has little to say about what might be occurring in the brain of an individual.”

Personalized diagnosis of ADHD

The research shows that almost every patient with ADHD has her or his own biological profile. The current method of making a diagnosis of psychiatric disorders based on symptoms is therefore not sufficient, the authors say: “Variation between patients is reflected in the brain, but despite this enormous variation all these people get the same diagnosis. Thus, we cannot achieve a better understanding of the biology behind ADHD by studying the average patient. We need to understand for each individual what the causes of a disorder may be. Insights based on research at group level say little about the individual patient.”

Re-conceptualize mental disorders

The researchers want to make a fingerprint of individual brains on the basis of differences in relation to the healthy range. Wolfers: “Psychiatrists and psychologists know very well that each patient is an individual with her or his own tale, history and biology. Nevertheless, we use diagnostic models that largely ignore these differences. Here, we raise this issue by showing that the average patient has limited informative value and by including biological, symptomatic and demographic information into our models. In future we hope that this kinds of models will help us to re-conceptualize mental disorders such as ADHD.”

Further reading

Wolfers, T., Beckmann, C.F., Hoogman, M., Buitelaar, J.K., Franke, B., Marquand, A.F. (2019). Individual differences v. the average patient: mapping the heterogeneity in ADHD using normative models. Psychological Medicine, https://doi.org/10.1017/S0033291719000084 .

This blog was written by Thomas Wolfers and Andre Marquand from the Radboudumc and Donders Institute for Brain, Cognition and Behaviour in Nijmegen, The Netherlands. On 15 March 2019 Thomas Wolfers will defend his doctoral thesis entitled ‘Towards precision medicine in psychiatry’ at the Radboud university in Nijmegen. You can find his thesis at http://www.thomaswolfers.com

German study first to show direct medical costs of ADHD and its comorbid conditions across the lifespan

Having ADHD is expensive. A study of German insurance data has shown that the medical costs of a person with ADHD are 1500 euro higher per year, compared to a person without ADHD. But that’s not all; individuals with ADHD are far more likely to suffer from additional conditions such as mood and anxiety problems, substance abuse or obesity. Treatment of these conditions can cost up to an additional 2800 euro per year. As ADHD – especially in adults – is still poorly recognised and diagnosed, these numbers may not reflect the complete picture of ADHD medical costs. Improving diagnosis and adult mental healthcare may prevent mental health problems later in life and actually reduce costs, argue Berit Libutzki and her co-authors.

ADHD (Attention Deficit / Hyperactivity Disorder) is a developmental condition. Symptoms arise before the age of 12 and are characterised by age-inappropriate and impairing behaviour in terms of problems with attention, impulsivity and hyperactivity. World-wide prevalence of children with ADHD is estimated around 5%, while in adults this is around 2.5%. This means that in about half of the children problems do not subside with age. For these people, ADHD is a lifelong condition that often impairs health, career and social life.

To estimate the economical costs of ADHD, Berit Libutzki and her colleagues from HGC Healthcare Consultants GmbH analysed the (anonymised) health insurance data of almost four million Germans. They compared the medical costs of people with an ADHD diagnosis to those of a well-matched group without ADHD.

medical costs per person_figure

The results showed that the medical costs of a person with ADHD are on average 1508 euro higher than those of a person without ADHD. These costs are mainly due to treatments in hospitals and by psychiatrists. ADHD medication itself (such as Methylphenidate) are in third place, contributing to only 11% of the additional costs. Other interesting findings from the study are that medical costs are a bit higher in women compared to men, and that costs are much higher in individuals over 30 years old compared to younger age groups. After the age of 18, the costs of for example ADHD medication drop, while psychiatrist costs and costs for other (non-ADHD) medications increase notably. Also sick payment is high in adult ADHD patients, leading to a significant increase in costs. One of the explanations for these cost increases could be a gap in care after leaving the regular care of a paediatrician at age 18, and the development of disorders that arise in addition to ADHD.

medical costs increase_figure

ADHD plus additional (mental) health problems

It has been shown before that having ADHD puts you at a much higher risk of developing additional (comorbid) disorders. Mood disorders – such as depression – and anxiety are most frequent; in the German data two-thirds of ADHD individuals over 30 had such an additional diagnosis (compared to only a fifth of adults without ADHD). Substance abuse and obesity are more common in people with ADHD as well. These comorbidities should not be underestimated as they add strongly to the burden of disease. The study shows that substance abuse and morbid obesity are even the most costly, especially in adulthood. In total, the surplus costs associated with these conditions are 1420-2715 euro higher for ADHD individuals, compared to individuals who suffer from mood or anxiety disorder, substance abuse, or obesity alone.

comorbid disorders_figure

Scientists think that certain genetic factors that play a role in ADHD also make a person more vulnerable for these comorbid health conditions. Libutzki and her team are part of the European research consortium Comorbid Conditions of ADHD (CoCA) that investigates the shared biological mechanisms of ADHD and these additional disorders. “Through this research we hope to find leads to prevent these disorders from developing, and improve mental health care.”, says the leader of the CoCA consortium Prof. Dr. Andreas Reif of the University Hospital Frankfurt.

“It is intriguing to speculate that these comorbidities, which were shown to be the important cost drivers in adulthood, could be prevented if mental healthcare were provided more constantly over the lifespan” write the authors. “The prevention of the development of comorbidities with age should be the focus of mental health care. Early treatment starting in childhood and continued treatment of adolescents into adulthood seem therefore advisable.”

Improving diagnosis and adult mental health care

There is one caveat in the study by Libutzki, that is also acknowledged by the authors: many people, especially adults, are not diagnosed with ADHD, even though they experience the symptoms. “Our knowledge gap is especially large in adulthood”, says Dr. Catharina Hartman from the University Medical Centre Groningen, The Netherlands. “The prevalence of adult ADHD in the health insurance data was very low (0.2 %). Given that the population prevalence for adult ADHD is 2,5 %, this indicates that many adults with ADHD are currently not diagnosed or treated. They may nonetheless make high direct costs since their ADHD may not be recognised, or they make indirect costs through unemployment or criminality.” This would indicate that the costs reported by the study are underestimated. On the other hand, adults often find out about their ADHD only after consulting a psychiatrist for other mental health problems. This would indicate that estimated costs and prevalence of comorbid disorders with ADHD in adulthood are overestimated, compared to when you were to include also all undiagnosed people with ADHD, and diagnosed persons who do not make costs (i.e. milder cases of ADHD).

The study thus provides a partial view on the costs of ADHD during the lifespan. That said, it is among the first to show in detail the lifespan medical costs of ADHD and comorbid disorders in Germany. These findings are likely to be representative of other western-European countries. Policy makers in these countries are strongly advised to investigate ways to improve the transition from child to adult mental healthcare and increase awareness about adult ADHD. This will not only improve the quality of life of many adults but may also save money.

Further reading

Libutzki, Ludwig, May, Jacobsen, Reif and Hartman (2019). Direct medical costs of ADHD and its comorbid conditions on basis of claims data analysis.  European Psychiatry, 58: 38-44. https://www.europsy-journal.com/article/S0924-9338(19)30019-7/abstract

The findings from this study are also summarised in an infographic: https://my.visme.co/projects/1jok0qg8-medical-costs-adhd

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