The prevalence of overweight and obesity has increased worldwide and is affecting millions of adults and children 1. The development of obesity is complex with factors like genetics, individual metabolism, dietary and physical activity choices, food and water availability, education and culture, playing a role 2. Several genome wide association studies have revealed an association between obesity and the gene encoding the transcription factor AP-2 beta (TFAP2B) 3,4. TFAP2B plays an important role during early stages of pregnancy in the development of different parts of the nervous system5. It has been demonstrated that overexpression of TFAP2B in fat cells causes a decrease in the production and release of adiponectin, a protein hormone which is involved in glucose metabolism6, and a diminished response to insulin7. But how does TFAP2B contribute to the development of obesity?

We have now shown in our ECPBHS study a very clear association between one TFAP2B variation (intron 2 VNTR) and measures of obesity and insulin resistance. Our findings have just recently published in the International Journal of Obesity8.

We found that men, who inherited the same variant of that gene from both parents (called 5/5 homozygotes), had significantly higher body weight, body mass index, proportion of body fat and insulin resistance, throughout adolescence to young adulthood. Strikingly, women that were 5/5 homozygotes had the same effects, but these appeared later, in young adulthood.

We hypothesized that the people who are TFAP2B 5/5 homozygotes have a higher risk of obesity because they consume more food. But we found the opposite: by age 25 male 5/5 homozygotes had smaller daily calorie intake and consumption of fats and carbohydrates. In females, these differences in caloric and macronutrient intake, were not observed. We therefor think that the risk is not related to increased food intake, but to differences in metabolism.

In conclusion, the gene TFAP2B increases the risk of obesity, abdominal obesity and insulin resistance in this sample, and is probably related to differences in metabolism. We should consider implementing lifestyle interventions already in childhood for individuals who are 5/5 homozygotes, to reduce the effect of TFAP2B on body weight. The physiological role of TFAP2B in body weight regulation and insulin resistance still needs further research.

REFERENCES:

  1. GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH, et al. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N Engl J Med. 2017; 377: 13-27. doi:10.1056/NEJMoa1614362
  2. Lee BY, Bartsch SM, Mui Y, Haidari LA, Spiker ML, Gittelsohn J. A systems approach to obesity. Nutr Rev. 2017; 75: 94-106. doi:10.1093/nutrit/nuw049
  3. Locke AE, Kahali B, Berndt SI, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015; 518: 197-206. doi:10.1038/nature14177
  4. Felix JF, Bradfield JP, Monnereau C, et al. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index. Hum Mol Genet. 2016; 25: 389-403. doi:10.1093/hmg/ddv472
  5. Moser M, Rüschoff J, Buettner R. Comparative analysis of AP-2α and AP-2β gene expression during murine embryogenesis. Developmental Dynamics. 1997; 208: 115-124. doi:10.1002/(SICI)1097-0177(199701)208:1<115::AID-AJA11>3.0.CO;2-5
  6. Ikeda K, Maegawa H, Ugi S, et al. Transcription factor activating enhancer-binding protein-2beta. A negative regulator of adiponectin gene expression. J Biol Chem. 2006; 281: 31245-31253. doi:10.1074/jbc.M605132200
  7. Tao Y, Maegawa H, Ugi S, et al. The transcription factor AP-2beta causes cell enlargement and insulin resistance in 3T3-L1 adipocytes. Endocrinology. 2006; 147: 1685-1696. doi:10.1210/en.2005-1304
  8. Joost U, Villa I, Comasco E, Oreland L, Veidebaum T, Harro J. Association between Transcription Factor AP-2B genotype, obesity, insulin resistance and dietary intake in a longitudinal birth cohort study. Int J Obes [in press]. doi:10.1038/s41366-019-0396-y
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Twin studies have been used for decades to estimate the relative importance of genes and environments for traits, behaviors and disorders. A very large meta-analysis of all twin studies conducted during the past 50 years (almost 3000 publications) revealed that across all studied traits the average reported heritability was 49%, meaning that about 50% of the variation in traits is due to genetic factors (1).

1. Methods and theory of classical twin design

By comparing the differences and similarities between twins, researchers use them as a natural experiment to study whether a trait, phenotype or disease is due to nature (genetic predisposition) or nurture (environmental factors).

In order to get a better understanding of twin studies, one must first understand the two types of twins:

  • Monozygotic (MZ) or identical twins were conceived in a single egg, which split and forms two embryos. Therefore, MZ twins share all their genes (100%), and are definitely the same sex.
  • Dizygotic (DZ) or fraternal twins were developing from a separate egg and each egg is fertilized by its own sperm cell, and therefore sharing on average 50% of their genes. DZ twins could be of the same sex or different sex.

Based on the different degree of genetic and the similar extent of prenatal and later environmental factors sharing between MZ and DZ twins, MZ twin pairs may show a higher similarity on a given trait, as compared with DZ twins, if genes significantly influence that trait. On the other hand, if MZ and DZ twin pairs share a trait to an equal extent, it is likely that the environment influences the trait more than genetic factors.

The similarity for a given trait is estimates via intra-class correlations (ICC), and similarity across different traits by the cross-twin cross-trait correlations (CTCT). Comparison of correlations across MZ and DZ pairs allows for the variance (V) of a given trait to be decomposed into three factors:

  • Genetic factors, including additive genetic factors (A), and dominant genetic factors (D)
  • Shared environmental factors (C), that is events that happen to both twins, affecting them in the same way. For example, the socio-economic status of the family, the general personality and general parenting styles and beliefs of the parents.
  • Non-shared or unique environmental factors (E), that is events happen to one twin but not the other one, or the events affect either twin in a different way. For example, school and classroom environment, also including measurement error.

Under then assumptions of no interaction and no covariance between A, C, D, and E, the total variance of a phenotype (P) can be expressed as:

𝑉𝑎𝑟,𝑃.=𝐴+𝐷+𝐶+𝐸

Narrow sense heritability is defined as the proportion of variance in a trait due to additive genetic effects (A):

,-2.=,𝑉𝑎𝑟(𝐴)-𝑉𝑎𝑟(𝑃).

Broad sense heritability as the proportion of variance due to additive and dominance genetic effects (A+D):

,-2.=,𝑉𝑎𝑟(𝐴+𝐷)-𝑉𝑎𝑟(𝑃).

The classical twin model can be extended to explore bivariate and multivariate traits association, and test for differences between males and females by using sex-limitation models. More information on how to conduct classical and advanced twin model fitting analyses, please refer to (2) and (3).

2. Important advantages of twin studies

  • Estimate the relative importance of genetic factors (i.e., heritability) of one or more traits
  • Help identify shared genetic factors that influence different traits, behaviors and disorders.
  • Explore the causal status of environmental risk factors by controlling for genetic and shared environmental confounding.
  • Offers unique opportunities to study the gene-environmental interplay, including both gene-environmental correlations and gene-environmental interactions.

In summary, the twin study design is considered an important behavioral genetic approach that has been used in many fields, including biology, psychology and sociology. Using a substantial amount of the published twin research (and other genetic informative studies, e.g. sibling comparison, adoption studies), Plomin et al. summarized the top 10 replicated and important findings (4). These findings included:

  • All psychological traits show significant and substantial genetic influence;
  • No traits are 100% heritable, highlighting the importance of environmental factors, and
  • The heritability is caused by many genes of small effect.

Most of these findings or discoveries that could only have been found using genetically sensitive research designs.

In the Eat2BeNice project, we are currently using data from Swedish Twin Register (https://ki.se/en/research/the-swedish-twin-registry) to estimate the heritability of unhealthy eating habits and ADHD symptoms in adults, and also to investigate the relative importance of genetic, shared environmental and non-shared environmental factors for the overlap between adult ADHD symptoms and different dietary habits diets. We will also test specific hypothesis regarding gene-environmental interactions.

Authors:
Lin Li, MSc, PhD student in the School of Medical Science, Örebro University, Sweden.

Henrik Larsson, PhD, professor in the School of Medical Science, Örebro University and Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Sweden.

REFERENCES

  1. Polderman TJ, Benyamin B, de Leeuw CA, Sullivan PF, van Bochoven A, Visscher PM, et al. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nature genetics. 2015;47(7):702-9.
  2. Neale, M. C. and Meas, H. M. Methodology for genetic studies of twins and families. and the paper Rijsdijk FV & Sham PC. (2002),
  3. Analytic Approaches to Twin Data using Structural Equation Models. Briefings in Bioinformatics, 3 (2), 119 -133.
  4. Plomin, Robert, et al. “Top 10 replicated findings from behavioral genetics.” Perspectives on psychological science11.1 (2016): 3-23.

 

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Behavior results from the complex interplay between genes and environment. Our genes predispose us to how we act and feel, by influencing how our brain develops and functions. This way, certain genetic variants in our genome increase the risk of developing mental health problems (while others may decrease this risk). Whether someone actually develops a mental health disorder or not, depends on many other factors in our environment, such as stressors and experiences. Nonetheless, studying these genetic risk factors for mental health conditions is an important aspect of understanding these disorders.

As an example of such research, we have now identified several genetic risk factors that contribute to cocaine dependence. For this we combined genetic data from a lot of studies, including more than 6000 individuals. What’s even more interesting is that we found that the genetic variants that are related to cocaine dependence are correlated with the genetic risk factors for other conditions such as ADHD, schizophrenia and major depression. What this means is that certain small variations in DNA increase the risk for not just cocaine dependence, but actually several psychiatric conditions. Probably, there is a common biological mechanism that underlies all these conditions. Thanks to our genetic research, we are now only a small step closer towards unraveling these mechanisms.

We also wrote a blog post explaining our research findings. You can read it here: https://mind-the-gap.live/2019/07/04/cocaine-dependence-is-in-part-genetic-and-it-shares-genetic-risk-factors-with-other-psychiatric-conditions-and-personality-traits/

The original publication can be found here: https://www.sciencedirect.com/science/article/pii/S0278584619301101?via%3Dihub

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In our Eat2BeNice project, we want to know how lifestyle-factors, and nutrition contribute to impulsive, compulsive, and externalizing behaviours. The best way to investigate this is to follow lifestyle and health changes in individuals for a longer period of time. This is called a prospective cohort study, as it allows us to investigate whether lifestyle and nutrition events at one point in time are associated with health effects at a later point.

Luckily we can make use of the LifeGene project for this. LifeGene is a unique project that aims to advance the knowledge about how genes, environments, and lifestyle-factors affect our health. Starting from September 2009, individuals aged 18 to 45 years, were randomly sampled from the Swedish general population. Participants were invited to include their families (partner and children). All study participants will be prompted annually to respond to an update web-based questionnaire on changes in household composition, symptoms, injuries and pregnancy.

The LifeGene project (1) consists of two parts: First, a comprehensive web-based questionnaire to collect information about the physical, mental and social well-being of the study participants. Nine themes are provided for adults: Lifestyle (including detailed dietary intake and nutrition information), Self-care, Woman’s health, Living habits, Healthy history, Asthma and allergy, Injuries, Mental health and Sociodemographic. The partners and children receive questions about two to four of these themes. For children below the age of 15 the parents are requested to answer the questions for them.

The second part is a health test: at the test centres, the study participants are examined for weight, height, waist, hip and chest circumference, heart rate and blood pressure, along with hearing. Blood and urine samples are also taken at the test centres for analysis and bio-banking.

Up until 2019, LifeGene contains information from a total of 52,107 participants. Blood, serum and urine from more than 29,500 participants are stored in Karolinska Institute (KI) biobank. From these we can analyze genetic data and biomarkers for diabetes, heart disease, kidney disease and other somatic diseases. Based on LifeGene, we aim to identify nutritional and lifestyle components that have the most harmful or protective effects on impulsive, compulsive, and externalizing behaviors across the lifespan, and further examine whether nutritional factors are important mediators to link impulsivity, compulsivity and metabolic diseases(e.g. obesity, diabetes). We will update you on our results in the near future.

For more information, please go to the LifeGene homepage www.lifegene.se. LifeGene is an open-access resource for many national and international researchers and a platform for a myriad of biomedical research projects. Several research projects are underway at LifeGene https://lifegene.se/for-scientists/ongoing-research/.

This was co-authored by Henrik Larsson, professor in the School of Medical Science, Örebro University and Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Sweden.

AUTHORS:
Lin Li, MSc, PhD student in the School of Medical Science, Örebro University, Sweden.

Henrik Larsson, PhD, professor in the School of Medical Science, Örebro University and Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Sweden.

REFERENCES:

  1. Almqvist C, Adami HO, Franks PW, Groop L, Ingelsson E, Kere J, et al. LifeGene–a large prospective population-based study of global relevance. Eur J Epidemiol. 2011;26(1):67-77.
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Represented by a conscious propensity to harm others against their will, aggressiveness is a complex behavior depending on which environmental conditions we have been living in, and the kind of features we have inherited from our ancestors. Humans tend to be an aggressive species.

Among mammals, members of the same species cause only 0.3 percent of deaths of their conspecifics (a member of the same species) [1]. Astonishingly, in Homo sapiens, the rate is nearly 7 times higher, around 2% (1 in 50)!

More than 1.3 million people worldwide die each year because of violence in all of its forms (self-directed, interpersonal and collective), accounting for 2.5% of global mortality. There are two critical conditions that endorse aggressive behavior: being fiercely territorial and living in social groups.

From the evolutionary perspective, aggression is usually described as adaptive. Struggle for resources like habitat, mates and food have had a key role in forming aggressive behavior in humans. Genetic variants that promote aggression have been more likely to be passed on to the next generation because they have increased the chances of survival. Indeed, among tribes of extremely violent hunter-gatherers, 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.

Although there are several biological aspects related to aggression, their predictive value continues to be rather low. It is possible to inherit a predisposition to acting violently, but scientists also emphasize that modeling violence in the home environment is the most certain way of propagating aggressive behavior. Children learn to act violently through the simple observation of aggressive models. The way parents manage the inevitable conflicts that arise between themselves and their children is central to the learning of aggression. When parents are unable to stop the child from escalating the intensity of conflict, and when they at least intermittently reinforce the child’s coercive behavior, the child learns that escalation is a viable method of resolving conflict. When this conflict strategy is applied to interactions with siblings or peers, and if it is also reinforced in these contexts, this conflict escalation is likely to include acts of aggression [3].

In addition to being hereditary and learned through social modeling, there is one other crucial component to aggressive behavior: self-control. In humans, the urge to react aggressively stems from the ancient parts located deep in the brain.

The structure capable of controlling those impulses is evolutionally much newer and located just behind the forehead – the frontal lobes. Unfortunately, this “top-down” conscious control of violent impulses is slower to act in contrast with the circuits of eruptive violence deep in the brain. People convicted of murder had been found to have reduced activity in the prefrontal cortex and increased activity in deeper regions [4]. Although there are plenty of examples of people with prefrontal cortex damage who do not commit violent acts, these findings clearly demonstrate that the damage to the prefrontal cortex impairs decision making and increases impulsive behavior.

Early physical aggression needs to be dealt with care. Long-term studies of physical aggression clearly indicate that most children, adolescents and even adults eventually learn to use alternatives to physical violence [5].

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 [6]. By identifying 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.

This post is adapted from an earlier blog on MiND the Gap/

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] Hodges, E.V.E., Card, N.A., Isaacs, J. (2003). Learning of Aggression in the Home and the Peer Group. In: Heitmeyer, W., Hagan, J. (eds) International Handbook of Violence Research. Springer, Dordrecht.

[4] Raine, A., Buchsbaum, M., LaCasse, L. (1997). Brain abnormalities in murders indicated by positron emission tomography, Biol Psychiatry 42(6), 495–508.

[5] 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.

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

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We, human beings in Western society, make over 200 food choices each day (1). That’s a lot! Fortunately (or, according to others, unfortunately), we don’t actually have to think about each and every one of them, or at least not consciously. If our food choices are not so much a conscious decision, then how do we make them? A lot has been written about external factors influencing our food choices, for instance, alluring displays in supermarkets or the availability of unhealthy foods in our day-by-day environment. In this blog, I will address the potential role of genetics on food choices: to what extent do our genes determine what we eat?

Eating behaviours are complex, i.e. they are very diverse and influenced by many different factors. When we investigate complex behaviours, we are unlikely to find simple explanations. In other words: we do not expect to find one gene that makes me prefer pizza margarita over pizza fungi, nor will we find a single gene responsible for my triple-chocolate ice cream consumption. There are, however, some instances in which specific genes have relatively simple and straightforward effects on our food choices. This is the case when genetic variants code for food sensitivities.

A famous example is the LCT gene (or, more precisely, the C>T change at 13910 bases upstream of the LCT gene in the 13th intron of the MCM6 gene). The LCT gene codes for lactase persistence, or lactose tolerance after childhood. Worldwide, the majority of people (and most other mammals, for that matter) no longer tolerate dairy products after childhood. For them, consuming milk products causes nausea, bloating and cramping within 2-3 hours. As a result, they will soon learn not to consume dairy products. Those who have the lactase persistence gene, however, don’t have any problems digesting dairy products and, thus, are more likely to consume them (2). Geographical region is important here: while in Northern European countries such as the UK and Finland, 90-100% of people tolerate dairy products, in South-East Asia and Australia this number is close to 0% (3).

A similar situation seems to occur for genes coding for certain taste receptors on the tongue. The TAS2R38 gene, for instance, makes some people extremely sensitive to bitter taste. This, of course, will cause them to avoid bitter foods such as cruciferous vegetables (4). A recent study has even identified a small number of genes that together cause people to either love or hate marmite (5)! Another gene variant (CYP1A1), coding for caffeine clearance from the body, causes carriers to drink less or more coffee and tea (6).

Thus, when food sensitivities are involved, food choices can be driven by specific genes. Most food choices, however, have very little to do with food sensitivities and are much more complex. Pizza Margarita or Pizza Funghi? Triple-chocolate ice cream today or maybe tomorrow? While for such complex food choices there is no single gene responsible, our genetic make-up still does have influence. Typically, for complex behaviours, many different genes can be identified. While each gene individually contributes only a little bit, together they can actually have quite an effect on your food choices. For instance, a recent study identified seven genetic variants each having a small effect on carbohydrate intake. Taken together, genes explained 8% of the variation in carbohydrate intake between individuals (7).

In conclusion: while some genetic variants have rather drastic effects on our food choices, by giving us a physical adverse reaction to certain foods, there are only few of them. Most of our food choices are much more complex. These are influenced by multiple genes at the same time, and even together these genes have only limited influence.

REFERENCES
1. Wansink, B., & Sobal, J. (2007). Mindless eating: The 200 daily food decisions we overlook. Environment and Behavior, 39(1), 106-123. doi: 10.1177/0013916506295573

2. Szilagyi, A. (2015). Adaptation to Lactose in Lactase Non Persistent People: Effects on Intolerance and the Relationship between Dairy Food Consumption and Evolution of Diseases. Nutrients, 7(8):6751-79. doi: 10.3390/nu7085309

3. Itan, Y., Jones, B.L., Ingram, C.J.E., Swallow, D.M. & Thomas, M.G. (2010). A worldwide correlation of lactase persistence phenotype and genotypes. BMC Evol Biol, 10:36. doi: 10.1186/1471-2148-10-36

4. Feeney, E., O’Brien, S., Scannell, A., Markey, A. & Gibney, E.R. (2011). Genetic variation in taste perception: does it have a role in healthy eating? Proc Nutr Soc, 70(1):135-43. doi: 10.1017/S0029665110003976.

5. Roos, T.R., Kulemin, N.A., Ahmetov, I.I., Lasarow, A. & Grimaldi, K. (2017). Genome-Wide Association Studies Identify 15 Genetic Markers Associated with Marmite Taste Preference. BioRxiv (preprint). doi: 10.1101/185629

6. Josse, A.R., Da Costa, L.A., Campos, H. & El-Sohemy, A. (2012). Associations between polymorphisms in the AHR and CYP1A1-CYP1A2 gene regions and habitual caffeine consumption. Am J Clin Nutr, 96(3):665-71. doi: 10.3945/ajcn.112.038794.

7. Meddens, S.F.W., de Vlaming, R., Bowers, P., Burik, C.A.P., Karlsson Linnér, R., Lee, C., et al. (2018). Genomic analysis of diet composition finds novel loci and associations with health and lifestyle. BioRxiv (preprint). doi: 10.1101/383406

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We have discussed the association between ADHD and obesity in our first blog (https://newbrainnutrition.com/adhd-and-obesity-does-one-cause-the-other/), briefly summarized, evidence from various study designs suggested that shared etiological factors might contribute to the above association. Recently, a large genome-wide association study (GWAS) on risk genes for ADHD reported a significant genetic correlation between ADHD and a higher risk of overweight and obesity, increased BMI, and higher waist-to-hip ratio, which further supported that there could be genetic overlap between obesity and ADHD (1).

Considering the previously described occurrence of unhealthy dietary intake in children and adolescents with ADHD in our second blog (https://newbrainnutrition.com/unhealthy-diets-and-food-addictions-in-adhd/), along with the fact that bad eating behaviours are crucial factors for the development of obesity, We can speculate that the shared genetic effects between ADHD and unhealthy dietary intake may also explain the potential bidirectional diet-ADHD associations. Is there any available evidence to support the above hypothesis?

To date, dopaminergic dysfunctions underpinning reward deficiency processing (or neural reward anticipation), was reported as a potential shared biological mechanism, through which the genetic variants could increase both the risk for ADHD and unhealthy dietary intake or obesity. Via the Gut-Brain axis, a two-way and high-speed connection, the gut can talk to the brain directly. According to the study (2), a higher proportion of bacteria that produce a substance that can be converted into dopamine was found in the intestines of people with ADHD than those without ADHD. Using functional magnetic resonance imaging (fMRI), they further found that the participants with more of these bacteria in their intestines displayed less activity in the reward sections of the brain, which constitutes one of the hallmarks of ADHD. We are therefore proposing the idea that there could be a biological pathway- ‘dietary habits-gut (microorganism)-reward system (dopamine)-ADHD’, through which the shared genetic effects between ADHD and unhealthy dietary intake may play a role.

In order to determine whether the genetic overlap between ADHD and dietary habits actually exists, we will in our next Eat2beNice project use twin methodology and unique data from the Swedish Twin Register. We will keep you updated!

This was co-authored by Henrik Larsson, professor in the School of Medical Science, Örebro University and Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Sweden.

Authors:
Lin Li, MSc, PhD student in the School of Medical Science, Örebro University, Sweden.

Henrik Larsson, PhD, professor in the School of Medical Science, Örebro University and Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Sweden.

REFERENCES:
1. Demontis D, Walters RK, Martin J, Mattheisen M, Als TD, Agerbo E, et al. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nature genetics. 2019;51(1):63.

2. Aarts E, Ederveen TH, Naaijen J, Zwiers MP, Boekhorst J, Timmerman HM, et al. Gut microbiome in ADHD and its relation to neural reward anticipation. PLoS One. 2017;12(9):e0183509.

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Our body is colonized by trillions of microorganisms that are important for vital processes. Gut microbiota are the microorganisms living in the intestinal gut and play an essential role in digestion, vitamin synthesis and metabolism, among others. The mouth and the large intestine contain the vast majority of gut microbiota whether the stomach only contains few thousands of microorganisms, especially due to the acidity of its fluids. Microbiota composition is constantly changing, affecting the well-being and health of the individual.

Each individual has a unique microbiota composition, and it depends on several factors including diet, diseases, medication and also the genetics of the individual (host) (Figure). Some medicines, especially antibiotics, reduce bacterial diversity. Strong and broad spectrum antibiotics can have longer effects on gut microbiota, some of them up to several years. Genetic variation of an individual also affects the microbiota composition, and the abundance of certain microorganisms is partly genetically determined by the host.

The main contributor to gut microbiota diversity is diet, accounting for 57% of variation. Several studies have demonstrated that diet’s composition has a direct impact on gut microbiota. For example, an study performed on mice showed that “Western diet” (high-fat and sugar diet), alters the composition of microbiota in just one day! On the other hand, vegetarian and calorie restricted diet can also have an effect on gut microbiota composition.

Prebiotics and probiotics are diet strategies more used to control and reestablish the gut microbiota and improve the individual’s health. Probiotics are non-pathogenic microorganisms used as food ingredients (e.g. lactobacillus present in yoghurt) and prebiotics are indigestible food material (e.g. fibers in raw garlic, asparagus and onions), which are nutrients to increase the growth of beneficial microorganisms.

In the last years the new term psychobiotics has been introduced to define live bacteria with beneficial effects on mental health. Psychobiotics are of particular interest for improving the symptomatology of psychiatric disorders and recent preclinical trials have show promising results, particularly in stress, anxiety and depression.

Overall, these approaches are appealing because they can be introduced in food and drink and therefore provide a relatively non-invasive method of manipulating the microbiota.

AUTHORS:
Judit Cabana-Domínguez and Noèlia Fernàndez-Castillo

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Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopment disorder characterized by inattention or hyperactivity–impulsivity, or both. It might seem paradoxical, but many studies indicate that individuals with a diagnosis of ADHD suffer from overweight and obesity. Therefore, it is important to understand the underlying mechanism that put individuals with ADHD at risk for obesity.

 Evidence from within-individual study
A systematic review and meta-analysis (1) based on 728,136 individuals from 42 studies, suggested a significant association between ADHD and obesity both in children/adolescents and adults. The pooled prevalence of obesity was increased by about 70% in adults with ADHD and 40% in children with ADHD compared with individuals without ADHD. However, due to the lack of longitudinal and genetically-informative studies, the meta-analysis was unable to explain the exact direction of association and the underlying etiologic mechanisms. There are several potential explanations:

  • ADHD causing obesity: The impulsivity and inattention components of ADHD might lead to disordered eating patterns and poor planning lifestyles, and further caused weight gain.
  • Obesity causing ADHD: Factors associated with obesity, for example dietary intake, might lead to ADHD-like symptoms through the microbiota-gut-brain axis.
  • ADHD and obesity may share etiological factors: ADHD and obesity may share dopaminergic dysfunctions underpinning reward deficiency processing. So the same biological mechanism may lead to both ADHD and obesity. This is difficult to investigate within individuals, but family studies can help to test this hypothesis.

We will further investigate these possibilities in the Eat2beNICE research project by using both perspective cohort study and twin studies.

Evidence from a recent within-family study
Recently, a population-based familial co-aggregation study in Sweden (2) was conducted to explore the role of shared familial risk factors (e.g. genetic variants, family disease history) in the association between ADHD and obesity. They identified 523,237 full siblings born during 1973–2002 for the 472,735 index males in Sweden, and followed them until December 3, 2009. The results suggest that having a sibling with overweight/obesity is a risk factor for ADHD. This makes it likely that biological factors (that are shared between family members) increase the risk for both ADHD and obesity.

Evidence from across-generation study
Given that both ADHD and obesity are highly heritable complex conditions, across-generation studies may also advance the understanding of the link between ADHD and obesity.

A population-based cohort study (3) based on a Swedish nationwide sample of 673,632individuals born during 1992-2004, was performed to explore the association between maternal pre-pregnancy obesity and risk of ADHD in offspring. The sibling-comparison study design was used to test the role of shared familial factors for the potential association. The results suggest that the association between maternal pre-pregnancy obesity and risk of ADHD in offspring might be largely explained by shared familial factors, for example, genetic factors transmitted from mother to child that contribute to both maternal pre-pregnancy obesity and ADHD.

Together, based on previous evidence from various study designs, there is evidence to suggest that the association between ADHD and obesity mainly is caused by shared etiological factors. However, future studies on different population are still needed to further test these findings.

REFERENCES:
1. Cortese S, Moreira-Maia CR, St Fleur D, Morcillo-Penalver C, Rohde LA, Faraone SV. Association Between ADHD and Obesity: A Systematic Review and Meta-Analysis. The American journal of psychiatry. 2016;173(1):34-43.

2. Chen Q, Kuja-Halkola R, Sjolander A, Serlachius E, Cortese S, Faraone SV, et al. Shared familial risk factors between attention-deficit/hyperactivity disorder and overweight/obesity – a population-based familial coaggregation study in Sweden. J Child Psychol Psychiatry. 2017;58(6):711-8.

3. Chen Q, Sjolander A, Langstrom N, Rodriguez A, Serlachius E, D’Onofrio BM, et al. Maternal pre-pregnancy body mass index and offspring attention deficit hyperactivity disorder: a population-based cohort study using a sibling-comparison design. Int J Epidemiol. 2014;43(1):83-90.

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Why 12 genetic markers for ADHD are exciting news for New Brain Nutrition

We are finally here: for the first time, genome-wide significant markers are identified that increase the risk for Attention Deficit / Hyperactivity Disorder (ADHD). This research was conducted by an international consortium of more than 200 experts on genetics and ADHD, and includes several researchers that are also involved in our Eat2beNICE project (the scientific basis of this New Brain Nutrition website). The findings were recently published in the prestigious journal “Nature Genetics” and will greatly advance the field of ADHD genetics research.

Why is this finding so important?

The genetics of ADHD are very complex. While ADHD is highly heritable, there are likely to be thousands of genes that contribute to the disorder. Each variant individually increases the risk by only a tiny fraction. To discover these variants, you therefore need incredibly large samples. Only then can you determine which variants are linked to ADHD. The now published study by Ditte Demontis and her team combined data from many different databases and studies, together including more than 55,000 individuals of whom over 22,000 had an ADHD diagnosis.

We can now be certain that the twelve genetic markers contribute to the risk of developing ADHD. Their influence is however very small, so these markers by themselves can’t tell if someone will have ADHD. What’s interesting for the researchers is that none of these markers were identified before in much smaller genetic studies of ADHD. So this provides many new research questions to further investigate the biological mechanisms of ADHD. For instance, several of the markers point to genes that are involved in brain development and neuronal communication.

Why are our researchers excited about this?

A second important finding from the study is that the genetic variants were not specific to ADHD, but overlapped with risk of lower education, higher risk of obesity, increased BMI, and type-2 diabetes. If genetic variants increase both your risk for mental health problems such as ADHD, and for nutrition-related problems such as obesity and type-2 diabetes, then there could be a shared biological mechanism that ties this all together.

We think that this mechanism is located in the communication between the gut and the brain. A complex combination of genetic and environmental factors influence this brain-gut communication, which leads to differences in behaviour, metabolism and (mental) health.genetic markers for adhd

The microorganisms in your gut play an important role in the interaction between your genes and outside environmental influences (such as stress, illness or your diet). Now that we know which genes are important in ADHD, we can investigate how their functioning is influenced by environmental factors. For instance, gut microorganisms can produce certain metabolites that interact with these genes.

The publication by Ditte Demontis and her co-workers is therefore not only relevant for the field of ADHD genetics, but brings us one step closer to understanding the biological factors that influence our mental health and wellbeing.

Further Reading

Demontis et al. (2018) Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nature Genetics. https://www.nature.com/articles/s41588-018-0269-7

The first author of the paper, Ditte Demontis, also wrote a blog about the publication. You can read it here: https://mind-the-gap.live/2018/12/10/the-first-risk-genes-for-adhd-has-been-identified/

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