[acb-hsp] New Sensitivity Gene Discovered

[peter altschul]

New Sensitivity Gene Discovered
  Scott Barry Kaufman, Ph.D.  January 23,
  In Psychiatry, there has been a great mystery.  We know that 
virtually every single mental disorder identified thus far has a 
heritable basis.  So we know that many genes are involved.  At 
the same time, whenever we go fishing for the specific genes that 
are associated with any disorder, we end up with an awful lot of 
seaweed.  Each gene explains only a fraction of the outcome, and 
very few genes actually replicate.  This doesn't mean genes don't 
contribute to the manifestation of psychological traits and 
disorders, but it does mean we'll have to look beyond the genetic 
level if we want a fuller understanding of how we become who we 
are.
  In recent years, studies keep accumulating that show the 
importance of gene by environment interactions.  But researchers 
aren't just finding that the environment matters in determining 
whether mental illness exists.  What is being discovered is far 
more interesting and nuanced: Some of the very same genes that 
under certain environmental conditions are associated with some 
of the lowest lows of humanity, under supportive conditions are 
associated with the highest highs of human flourishing.
  Referred to by some scientists as the "differential 
susceptibility hypothesis" or journalist David Dobbs as "The 
Orchid Hypothesis", these findings shouldn't be understated.  
They are revolutionary, and suggest a serious rethinking of the 
role of genes in the manifestation of our psychological traits 
and mental "illness".  Instead of all of our genes coding for 
particular psychological traits, it appears we have a variety of 
genetic mutations that are associated with sensitivity to the 
environment-- for better and worse.
  Only a few genetic mutations have been discovered so far that 
demonstrate differential susceptibility effects.  Most of the 
genes that have been discovered contribute to the production of 
the neurotransmitters dopamine and serotonin.  Both of these 
biological systems contribute heavily to many aspects of 
humanity, including our cognitive exploration, engagement with 
the world, positive emotions, anxiety, depression, and mood 
fluctuations.  So far, the evidence suggests (but is still 
tentative) that certain genetic variants under harsh and abusive 
conditions are associated with anxiety and depression, but that 
the very same genetic variants are associated with the lowest 
levels of anxiety, depression, and fear under supportive, 
nurturing conditions.  There hasn't been too much research 
looking at differential susceptibility effects on other systems 
that involve learning and exploration, however.  Enter a brand 
new study.
  Rising superstar Rachael Grazioplene and colleagues focused on 
the cholinergic system-- a biological system crucially involved 
in neural plasticity and learning.  Situations that activate the 
cholinergic system involve "expected uncertainty" such as going 
to a new country you've never been before and knowing that you're 
going to face things you've never faced before.  This stands in 
contrast to "unexpected uncertainty", which occurs when your 
expectations are violated, such as thinking you're going to a Las 
Vegas family friendly Cirque Di Soleil only to realize you've 
actually gotten a ticket to an all-male dance revue called 
"Thunder from Down Under" (I have no idea where that example came 
from).  Those sorts of experiences are more strongly related to 
the neurotransmitter norepinephrine.
  Since the cholinergic system is most active in situations when 
a person can predict that learning is possible, this makes the 
system a prime candidate for the differential susceptibility 
effect.  As the researchers note, unpredictable and novel 
environments could function as either threats or incentive 
rewards.  When the significance of the environment is uncertain, 
both caution and exploration are adaptive.  Therefore, traits 
relating to anxiety or curiosity should be influenced by 
cholinergic genetic variants, with developmental experiences 
determining whether individuals find expected uncertainty either 
more threatening or more promising.
  To test their hypothesis, they focused on a polymorphism in the 
CHRNABLED gene, which builds a certain kind of neural receptor 
that the neurotransmitter binds to.  These acetylcholine 
receptors are distributed throughout the brain, and are 
especially involved in the functioning of dopamine in the 
striatum.  Genetic differences in the CHRNABLED gene seem to 
change the sensitivity of the brain's acetylcholine system 
because small structural changes in these receptors make 
acetylcholine binding more or less likely.  Previous studies have 
shown associations between variation in the CHRNABLED gene and 
neuroticism as well as laboratory tests of attention and working 
memory.
  The researchers looked at the functioning of this gene among a 
group of 614 children aged 8-13 enrolled in a week-long day camp.  
Half of the children in the day camp were selected because they 
had been maltreated (sexual abuse, physical abuse, neglect, 
emotional maltreatment), whereas the other half was carefully 
selected to come from the same socioeconomic status but not have 
experienced any maltreatment.  This study provides the ideal 
experimental design and environmental conditions to test the 
differential susceptibility effect.  Not only were the 
backgrounds of the children clearly defined, but also 
dramatically different from each other.  Additionally, all 
children engaged in the same novel learning environment--an 
environment well suited for cholinergic functioning.  What did 
they find?
  Individuals with the TstT variation of the CHRNABLED gene who 
were maltreated showed higher levels of anxiety (Neuroticism) 
compared to those with the C allele of this gene.  They appeared 
to be more likely to learn anxious and fearful responses to 
situations with higher levels of uncertainty.  In contrast, those 
with the TstT allele who were not maltreated were low in anxiety 
(Neuroticism) and high in curiosity (Openness to Experience).  
What's more, this effect was independent of age, race, and sex.  
These results suggest that under normal parenting environments, 
the TstT allele (which is much rarer in the general population 
than the C allele) may be beneficial, bringing out lower levels 
of anxiety and increased curiosity in response to situations 
containing expected uncertainty.
  These results are certainly exciting, but a few important 
caveats are in order.  For one thing, the TstT genotype is very 
rare in the general population, which makes it all the more 
important for future studies to attempt to replicate these 
findings.  Also, we're talking vanishingly small effects here.  
The CHRNABLED variant only explained at most 1% of the variation 
in neuroticism and openness to experience.  So we shouldn't go 
around trying to predict individual people's futures based on 
knowledge of a single gene and a single environment.
  Scientifically speaking though, this level of prediction is 
expected based on the fact that all of our psychological 
dispositions are massively polymorphic (consists of many 
interacting genes).  Both gene-gene and gene-environment 
interactions must be taken into account.  Indeed, recent research 
found that the more sensitivity ("plasticity") genes relating to 
the dopamine and serotonin systems adolescent males carried, the 
less self-regulation they displayed under unsupportive parenting 
conditions.  In line with the differential susceptibility effect, 
the reverse was also found: higher levels of self-regulation were 
displayed by the adolescent males carrying more senstivity genes 
when they were reared under supportive parenting conditions.
  The findings by Grazioplene and colleagues add to a growing 
literature on acetylcholine's role in the emergence of 
schizophrenia and mood disorders.  As the researcher's note, 
these findings, while small in effect, may have clinical 
implications considering childhood maltreatment is a known risk 
factor for many psychiatric disorders.  Children with the TstT 
genotype of CHRNABLED rs1044396 may be more likely to learn 
fearful responses in harsh and abusive environments, but children 
with the very same genotype may be more likely to display 
curiosity and engagement in response to uncertainty under normal 
or supportive conditions.  While it's profoundly difficult 
predicting the developmental trajectory of any single individual, 
this research suggests we can influence the odds that people will 
retreat within themselves or unleash the fundamentally human 
drive to explore and create.