pointer to: The Neurocritic’s coverage on the association of low-efficiency alleles of MAOA and credit card debt.  Will there be a genotype box to check on future credit card applications? More posts on MAOA here.

pointer to: download Power Point presentation hosted on the HUGO website entitled, “From the human genome to human behaviour: how far have we travelled?” (both English and Russian text) – by Ian Craig and Nick Yankovsky, Education Council Human Genome Organisation.

Covers recent findings on MAOA and 5HTT several and others also covered here.

Congrats to Hsien on the new position!

Amidst a steady flow of upbeat research news in the behavioral-genetics literature, there are many inconvenient, uncomfortable, party-pooping sentiments that are more often left unspoken.  I mean, its a big jump – from gene to behavior – and just too easy to spoil the mood by reminding your colleagues that, “well, everything is connected to everything” or “that gene association holds only for that particular task“.  Such may have been the case often times in the past decade when the so-called imaging-genetics literature emerged to parse out a role for genetic variation in the structure and functional activation of the brain using various neuroimaging methods.  Sure, the 5HTT-LPR was associated with amygdala activation during a face matching task, but what about other tasks (and imaging modalities) and other brain regions that express this gene.  How could anyone (let alone NIMH) make sense out of all of those – not to mention the hundreds of other candidate genes poised for imaging-genetic research?

With this in mind, it is a pleasure to meet the spoiler-of-spoilers! Here is a research article that examines a few candidate genetic polymorphisms and compares their findings across multiple imaging modalities.  In his article, “Neural Connectivity as an Intermediate Phenotype: Brain Networks Under Genetic Control” [doi: 10.1002/hbm.20639] Andreas Meyer-Lindenberg examines the DARPP32, 5HTT and MAOA genes and asks whether their associations with aspects of brain structure/function are in any way consistent across different neuroimaging modalities.  Amazingly, the answer seems to be, yes.

For example, he finds that the DARPP32 associations are consistently associated with the striatum and prefrontal-striatal connectivity – even as the data were collected using voxel-based morphometry, fMRI in separate tasks, and an analysis of functional connectivity.  Similarly, both the 5HTT and MAOA gene promoter repeats also showed consistent findings within a medial prefrontal and amygdala circuit across these various modalities.

This type of finding – if it holds up to the spoilers & party poopers – could radically simplify the understanding of how genes influence cognitive function and behavior.  As suggested by Meyer-Lindenberg, “features of connectivity often better account for behavioral effects of genetic variation than regional parameters of activation or structure.”  He suggests that dynamic causal modeling of resting state brain function may be a powerful approach to understand the role of a gene in a rather global, brain-wide sort of way.  I hope so and will be following this cross-cutting “connectivity” approach in much more detail!

Rare mutations that knock-out the function of monoamine oxidase a gene have long been known to give rise to developmental changes that increase the propensity of males to engage in aggressive behavior.  The effects of so-called natural variants – that may slightly reduce or increase the amount of activity of the MAOA protein – can be harder to understand since they are less-definitive and perhaps more easily masked or influenced by the environment and developmental mileu.  Nevertheless, the role of natural, common variation in the maoa gene and its relation to aggressive behavior in boys remains of interest – witness a news report today, “‘Warrior Gene’ Linked To Gang Membership, Weapon Use: FSU Study”.

Rather than debate the validity and merits of such sensational headlines, it may be more productive to understand how & why naturally occurring genetic variation might influence the development of the brain in a way that makes it more difficult for adolescents and adults to control their aggressive impulses.  Clearly, healthy males have a predisposition to act out moreso than females, which – while at odds with our modern societal norms – comes along with our evolutionary legacy and phylogenetic relationship to other primates and mammals where male aggression is the rule.  In this sense, the really exciting story, is not whether there is something amiss with schoolboys who carry certain genetic variants of maoa, but how such variants work over the course of normal brain development and why, in terms of our own evolutionary history, we carry such variants.

That male-male aggression can be a means to differentiate male fitness and – via sexual selection in females – reduce mutational load, has been widely shown across the sexually-reproducing biome.  Thus, while variants such as the high expression 4-repeat VNTR in maoa have likely been helpful, rather than hurtful, in the establishment and survival of our noble species, it may be a difficult task to prove such a proposition.  As Stephen Jay Gould once wrote, “Thus, we are presented with unproved and unprovable speculations about the adaptive and genetic basis of specific human behaviors: why some (or all) people are aggressive, xenophobic, religious, acquisitive, or homosexual” (Our Natural Place, p. 243).  Nevertheless, we may learn a bit about ourselves as we relate genetic variation to both cognitive science and to rigorous phylogenetic analysis.

One great example of a recent paper that covers the link from genes to cognition is, “MAO A VNTR polymorphism and variation in human morphology: a VBM study” by Cerasa et al., [PMID: 18596609].  Here the team investigates the structure of the human male brain using a method known as voxel-based-morphometry (VBM) that allowed them to ask where in the brain one might observe grey-matter changes that are correlated to genotype?  After an analysis of 33 high-maoa-expressing males vs. 26 low-expressing males, the team found that only in the orbitofrontal cortex were such associations significant.  This, as noted by the team, is of interest, since the orbitofrontal cortex is an area of the brain that is known to regulate impulsivity.  In this study, the high-expressing males had lower levels of grey matter in the orbitofrontal cortex, a result that is in-line with a previous finding – however it remains somewhat out of trend with earlier findings showing that smaller orbitofrontal cortex volumes (without respect to genotype) are associated with higher impulsivity and findings that show that boys with the high-expression form of MAOA were less likely to engage in aggressive behavior.

Clearly, this little bit of the genome containing the MAOA-VNTR has a complex – but interesting story to tell.  The gene does not seem to show any evidence for recent positive selection, so perhaps the role of maoa and its effects on aggression were worked out long before our lineage came along.  Indeed, now we must learn to bear our genetic legacy proudly and humanely.  Good luck!

As I and many other 23andMe participants begin to confront our genetic innards, we will likely ask whether any of the information is predictive.  Can we expect to read-off our genomic information and say, “I have risk for this, this, and this, and so I’ll change my life to compensate ?“  Certainly, in the area of mental health, there are genetic variants that confer bits of risk toward anxiety, depression, cognitive decline etc., but does the raw genomic information – alone – form a basis for diagnosis and proscriptive change?  In most cases, NO.  Rather, the genome is not unlike a plant seed, that will produce full leafy greens in rich soil, but merely a few buds in poor soil.

A great example of this can be seen in the recent paper, “What is an “Adverse” Environment? Interactions of Rearing Experiences and MAOA Genotype in Rhesus Monkeys” by Karere er al. [doi: 10.1016/j.biopsych.2008.11.004].  In this paper, they compared the emotional development of rhesus monkey infants (n=473) who carry different versions of an MAOA promoter polymorphism – so-called ‘low’ vs. ‘high’ transcriptional level alleles – and also who were reared in different social contexts.  Some of the existing literature on MAOA-environment interactions suggests that abuse or neglect during childhood predisposes individuals who carry the ‘low’ allele (this allele leads to less MAOA protein and less catabolism of 5HT and DA).  In this study, the environment was varied according to numbers of social companions and physical size of the neighborhood – (i) a field enclosure with up to 150 mixed adults & children, (ii) corncrib enclosure with 1 adult male, 2-5 females and various child playmates, (iii) mother-only small enclosure, and (iv) no-mother nursury rearing.

Which environment led to the emotional reactivity (anxiety, aggression etc.) that has been previously associated with the MAOA ‘low’ allele?  Interestingly, it was not the wild & wooly ‘field enclosure’ where infants can interact in a rich, species-typical manner.  Rather, it was the MAOA ‘low’ genotypic infants raised in the smaller groups who showed more signs of emotional reactivity, with cage-mother-only-rearing being the most extreme group.  The authors note that this finding may alter our expectations about what type of environment is optimal vs. adverse and suggest that in the smaller enclosures, the relative isolation underlies the development of anxiety.

From a more general perspective, this study raises questions about how we – humans – should interpret our genomic information.  What environmental conditions enhance or protect us from the potential genetic risk we carry?  How did my early rearing interact with my MAOA allele?  Something to discuss on Mother’s Day.

Image by cibomahto via Flickr

A recent paper from Andreas Heinz and colleagues (doi: 10.1038/nn2222) provides more neuroimaging evidence in humans for a a circuit that regulates our responsivity to stimuli that evoke emotional responses.  The basic circuitry involves the amygdala (a place in the brain where emotional memories are registered), the prefrontal cortex (a part of the brain that is involved in making decisions and assessing threats) and the cingulate cortex (a place in the brain where expectations are compared to sensory inputs & outgoing responses).  These 3 brain regions are interconnected in a loop through various synaptic contacts and the responsivity of these synapses can be modulated by neuomodulators such as dopamine, serotonin and noradrenaline.  It turns out, that several neuroimaging studies have begun to demonstrate that this (relatively) simple circuitry underlies human personality and temperament. In the Heinz study, the level of dopamine that was released into the amygdala was correlated with levels of functional activation to emotional stimuli as well as a dimension of temperament known as negative affect.

I recall once having taken the Meyers-Briggs assessment in graduate school and had a blast comparing my results with my wife – who was almost my polar opposite. Now, the latest neuroimaging and imaging-genetic research has begun to explain the complexities of human personality in basic neural circuitry where genes such as 5HTT and MAOA ‘turn up’ or turn down’ the gain on various synaptic contacts in this circuit – leading to the immense, yet systematic variation in personality and temperament that makes our social lives so interesting.  As I navigate my way through marriage and parenthood, I’m often glad I took the personality test with my wife many years ago.  It always helps to see things from the other person’s perspective.  Now, as she obtains her 23andMe profile, perhaps we will begin to compare our genomes together – the ultimate form of marriage counseling !!  Click here for more personality tests.