Methylation and psychopathy

An interesting molecular explanation for psychopathy is that the oxytocin system is gummed-up by DNA methylation.

Oxytocin is said to be all sorts of things  — the love hormone, the cuddle hormone, the trust hormone — giving the impression that if what the Bacherachian world needs now is love sweet love, then a dousing with oxytocin ought to to it.

Well, sort of. We think it’s more the Salt N Pepa-esque view, viz., “If I. Wanna take a guy. Home with me tonight. It’s none of your business. If she.  Wanna be a freak and. Sell it on the weekend. It’s none of your business.”

Oxytocin seems to be involved with social behavior, sure, but in all sorts of ways — maternal or mate attachment, in-group protectiveness, determining social salience  — we suspect every social behavior has to do with oxytocin if you try hard enough.

At the molecular level, we like the strategy oxytocin (and it’s cousin, vasopressin) take. Each are only 9 amino acids long, which is really small. You can’t fool with them too much before they just don’t bind to their receptors. Normally, with a protein, they’re big enough that you can change out charged amino acids for neutral ones, keep αhelices and clip off loops, fool with salt bridges, that kind of thing. (Your loyal bloggist learned to fool with 3-D crystal structure images while listening to Dark Side of the Moon, which, in our opinion is the best, and maybe only, way to do 3-D protein modeling.) But vasopressin is about as far as oxytocin can change, one amino acid, maybe some side groups or mimetics (we don’t know).

Not so for the oxytocin (and vasopressin) receptors. These receptors can have all kinds of  polymorphisms, control regions, epigenetic proclivities, anatomical locations, copy number, binding abilities and all sorts of things that essentially regulate the amount/timing/location of oxytocin (or vasopressin) activity. So the strategy is to stick with the 9 amino acid ligand, and give the receptor all sorts of leeway.(Good review of the situation here. )

Epigenetic control is just one more molecular way to change the behavior of the oxytocin system. The reports below correlate epigenetics with behavior, which we think is really interesting. (The reports are kind of old, but we’ve been too busy to pay attention to this blog for a while. Sorry.)

These reports demonstrate that the more oxtocin receptor DNA methylation, the more psychopathic behavior (callous, unemotional) is observed. Plus, it looks like the methylation is inherited, or at least picked up in utero.

The reports:

Epigenetic regulation of the oxytocin receptor gene: implications for behavioral neuroscience.
Robert Kumsta, Elisabeth Hummel, Frances S. Chen and Markus Heinrichs,Front. Neurosci., 23 May 2013 | doi: 10.3389/fnins.2013.00083

Methylation of the oxytocin receptor gene and oxytocin blood levels in the development of psychopathy
Mark R. Dadds,Caroline Moul,Avril Cauchi,Carol Dobson-Stone,David J. Hawes,John Brennan and Richard E. Ebstein (2014).
Development and Psychopathology, Volume 26, Issue01, February 2014 pp 33-40

“Environmental risk, Oxytocin Receptor Gene (OXTR) methylation and youth callous-unemotional traits: a 13-year longitudinal study,”
Cecil CA, Lysenko LJ, Jaffee SR, Pingault JB, Smith RG, Relton CL, Woodward G, McArdle W, Mill J, Barker ED, Mol Psychiatry. 2014 Oct;19(10):1071-7. doi: 10.1038/mp.2014.95. Epub 2014 Sep 9.

The technicalities:

First, we will be clear as to the term “meth.” We are not here discussing crystal meth, methanol, methylene, meth this, meth that, meth schmeth. We are referring to methylation, that is, the process of adding a one carbon/3 hydrogen methyl group, the group you learned about in O-chem right before you fell asleep.

When methyl groups are stuck onto DNA, that generally prevents the DNA from doing it’s job of making something else, like RNA —> protein.

DNA Methylation diagram

Skeletal structures for the methylation of methylcytosine to form 5-methylcytosine, using S-adenosyl methionine as the source of the methyl group and giving S-adenosyl-L-homocysteine as the byproduct. Author: D. Macks. Own work. Licensed under Public Domain via ?Wikimedia Commons.

So, methylating DNA is sort of a proxy for saying, “Dial down the protein.”

Where the DNA is the oxytocin receptor — that is, the cell-surface catcher’s mitt for the oxytocin itself — non productive receptor DNA is one more thing to add to the list of “why oxytocin activity may be at a low level.”  As we rambled about above, other reasons might include, the receptor being all bent out of shape, not enough receptors, receptors not in a good neighborhood, and we’re sure all sorts of other reasons. See,Johannes Koehbach, Thomas Stockner, Christian Bergmayr, Markus Muttenthaler and Christian W. Gruber, “Insights into the molecular evolution of oxytocin receptor ligand binding,”  Biochemical Society Transactions (2013) 41, (197–204)  doi:10.1042/BST20120256

Cecil et al. followed the progress of the same children for 13 years. They found that children with callous-unemotional traits (we read as bullies), and relatively low internalizing problems (we read as cutting or other self-harm),  had higher degrees of OXTR methylation at birth. They also tended to have mothers who were psychopaths, had addiction issues, or were criminals. Children who had internalizing problems tended toward lower OXTR methylation, but were exposed to worse household interpersonal situations, like domestic violence.

For youth with low internalizing problems (46%), we found that (i) OXTR methylation at birth associated with higher CU (age 13) as well as decreased experience of victimization during childhood (evocative epigenetic-environment correlation; birth–age 7), (ii) higher prenatal parental risks (maternal psychopathology, criminal behaviors, substance use) associated with higher OXTR methylation at birth and (iii) OXTR methylation levels were more stable across time (birth–age 9). In contrast, for youth with high internalizing problems, CU were associated with prenatal risks of an interpersonal nature (that is, intimate partner violence, family conflict) but not OXTR methylation. Findings support the existence of distinct developmental pathways to CU.

Dads et al. looked at several methylation sites (cpg’s) in the oxytocin receptor DNA, and similarly found

. . .High CU[callous unemotional] traits were associated with greater methylation of the OXTR [oxytocin receptor] gene for two cytosine nucleotide and guanine nucleotide phosphate linked sites and lower circulating OXT in older males. Higher methylation correlated with lower OXT levels. We conclude that greater methylation of OXTR characterizes adolescent males with high levels of CU and CPs [conduct problems], and this methylation is associated with lower circulating OXT and functional impairment in interpersonal empathy. The results add genetic evidence that high CU traits specify a distinct subgroup within CP children, and they suggest models of psychopathy may be informed by further identification of these epigenetic processes and their functional significance.

There are lots of reports of genetics/behavior, but reports of epigenetics and behavior add a whole new 4th dimension. Are epigenetic changes stable? Heritable? Changeable? Can methyl groups change a person’s personality?

Don’t know. But, we imagine that the high-methyl groups might be singing:

What’s the matter with your life?
Why you gotta mess with mine?
Don’t keep sweatin’ what I do
Cause I’m gonna be just fine – check it out

“None Of Your Business” Writer(s): Herby E. Azor. Copyright: Sons Of K-oss Music Inc., WB Music Corp.