Are you genetically determined to act aggressively?

Posted on by Mariliis Vaht

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

Posted on by Prof. Stephen Faraone

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

Posted on by dittedemontis

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

Posted on by asingh31

A complex genomic jigsaw puzzle

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

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

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

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

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

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

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

 

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

 

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

 

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

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

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

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

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