Low SES and the brain

I'm interested in psychoneuroimmunology and just recently I made a website for running sets of genes against the neuroanatomically impressive Allen Human Brain atlas (also works on the Allen fetal brain data).

This lets me find out which brain regions show specific expression for a given set of genes when compared to the rest of the genome and brain.

I dropped in the genes from "Low early-life social class leaves a biological residue manifested by decreased glucocorticoid and increased proinflammatory signaling" by Greg Miller and colleagues. I combined the over and under expressed lists to see where they are turned on across 416 brain regions (nonparametric, AUC/ROC analysis, 1-6 donors per region). The p-values have been FDR corrected for number of regions.

The area I'd guess at is the hypothalamus and 7 of it's 29 regions are significant with all 7 up regulated. Going deeper it's the paraventricular nucleus and supraoptic nucleus in the anterior region. In the tuberal region the arcuate and lateral subregions have higher expression.  The paraventricular nucleus (ranked #1 of 416) and supraoptic nucleus are good to see because they link to oxytocin and vaspressin. Both of those have been linked to maternal related behaviour - and so has early life SES.

Here's the top 12 of the 416 regions:

Rank	Name	Donors	Q-value  (FDR corrected p-value)
1	Supraoptic Nucleus, Left	5	0.000004
2	Supraoptic Nucleus, Right	2	0.000004
3	central grey of the pons, Right	1	0.00001
4	Substantia Nigra, pars reticulata, Left	6	0.0001
5	central grey of the pons, Left	2	0.0003
6	arcuate nucleus of medulla, Right	2	0.001
7	Globose Nucleus, Right	2	0.001
8	Paraventricular Nucleus of the Hypothalamus, Left	5	0.001
9	Emboliform Nucleus, Right	2	0.001
10	globus pallidus, internal segment, Right	2	0.001
11	pontine raphe nucleus, Left	3	0.001
12	Paraventricular Nucleus of the Hypothalamus, Right	1	0.002

It seems the cerebellar cortex turns down these genes while the cerebellar nuclei (globus, emboliform nucleus) turns them on. I'm not sure how to interpret that, but it might be cell type driven.

Periaqueductal gray/central grey of the pons is also strong. That's nice to see because it contains vasopressin and oxytocin receptors and it's in the CAN/central autonomic network. A few of these overlap with the CAN network but I haven't put a p-value on that.

Again, I just wanted to put this neat little result out there online as it's a distraction that has some value I reckon. If anyone is interested I can use different gene lists, narrow to major brain divisions and try it on fetal data (12-16 post conception weeks).

Update: It seems vasopressin and oxytocin are linked to the immune response (from rat studies). Vasopressin and oxytocin neurons activate when LPS is given, and it seems strong in the supraoptic nucleus.

Update: Dr. Miller noted that I'm using gene expression results from blood so it's pretty indirect (I should've mentioned this). My response is that it's rough, but I'm trying to get a perspective into the brain. There's psychiatric studies where they use blood gene expression for looking at Parkinson's and schizophrenia cases. Also, over 90% of genes are turned on the brain.

Update: I found out the hypothalamus is unique in it's connection with the blood. It lacks a normal blood brain barrier it seems. I will have to look at unrelated studies of blood and see if any list of blood expressed genes will express specifically in the hypothalamus.

SAT1 (spermidine/spermine N1-acetyltransferase 1), suicide and skin color

The other day a frieind of mine - Nancy Yu posted a link on google+ to a recent article "A Blood Test for Suicide?"

After reading the news version, it seems like a pretty solid finding came out in a few studies - SAT1. In terms of molecular function the article states "which is involved in cellular damage and stress". I'm guessing the referenced articles have more to say about Sat1 but I decided to crunch some data instead of reading.

By data, I mean prenatal RNA-seq gene expression data from the Brainspan consortium. I used only the pre-natal samples which include 233 samples from 18 donor brains. For crunching, I have a co-expression method setup to look for co-expressing GO groups and all I have to do is give it a gene and run it. It's guilt by association.

So out of curiosity I do this every now and then. This potential suicide biomarker seemed like a good target.

I can explain more if someone requests. I just wanted to put this out there as it's a small finding. If someone is interested I will give all the details and run on the adult samples or other Allen data.

I ran SAT1 and new GO group appeared on top: "developmental pigmentation" (39 genes), it's defined as "The developmental process that results in the deposition of coloring matter in an organism, tissue or cell.". From my quick look, this appears to be a novel finding.

For this method, I'm still not sure how to put a p-value on things but in both methods the SAT1 to developmental pigmentation co-expression signal is significant after correction for the 4,032 GO groups tested. What is most astounding, is that SAT1 has a higher co-expression score with the developmental pigmentation genes than any other gene tested - including the 39 genes that are already annotated as developmental pigmentation. That's as specific as it gets.

Also, "lamellipodium membrane" comes out for cellular component.

Next, I decided to look up relationship between suicide and pigmentation as I have some faith in this result. I was happy to find "Suicide rate and skin color" by Voracek M. It has a short abstract:

"In two previously described samples of 53 and 43 nations, higher suicide rates of men, women, and the elderly population consistently corresponded to lighter skin color. This ecological (aggregate-level) association was independent of national differences in affluence, as measured by per capita Gross Domestic Product."

I stopped at that point as I don't have time to dive into the literature and I couldn't find that as a PDF. Instead I decided to just post this and email it out to Dr. Gustavo Turecki, Dr. Martin Voracek and Dr. Alexander Niculescu III. Hopefully they can take it further.

The four top co-expressing genes are:
RAB27A(0.48), EDNRB(0.47), MYO5A(-0.47), HPS6(-0.46)

The top ten list is:

1. developmental pigmentation
2. regulation of cation channel activity
3. fatty acid transmembrane transport
4. regulation of transmembrane transport
5. bone remodeling
6. pigment cell differentiation
7. calcium-mediated signaling
8. bone resorption
9. regulation of viral genome replication
10. amine transport

Update: Dr. Niculescu responded via email and mentioned that "Melanoma Signalling" shows up in the ingenuity pathway analyses they did. That's in Table S4 in their paper - Discovery and validation of blood biomarkers for suicidality. That's using a bunch of genes for input - not just SAT1, so that's nice to hear about as I'm not sure if I would have found it by reading through the paper.

Also, here's a good quote from the Le-Niculescu et al. paper "SAT1-overexpressing mice had alterations in their polyamine pool, hair loss, infertility and weight loss." (with links to two references).

Update 2: I managed to get the Voracek full text paper. It's very short and provides country level correlations for mostly european nations. Again, I'm not sure what to make of it.  Here's a quote: "This pattern suggests that the correspondence of higher suicide rates with lighter skin color and vice versa across nations is unlikely to be due to national differences in affluence" (Voracek, 2006). It would be nice to see plots of the Voracek data. It cites another paper that links eye color to method of suicide: "Tattoos, eye color and method for suicide." I can't find the PDF for that so I should stop the distraction as I doubt there is more individual level data.

Update 3: I recently heard that light therapy works for PTSD and there's one pilot study in depression. I emailed the first and last authors of the pilot study. I got a quick response from Dr. Hamblin who noted that sunlight is beneficial but the light therapy penetrates much deeper. Still, this a lot of speculation but I wonder if SAT1 is absorbing sunlight that's needed to keep the brain normal.

Update 4: I just read a writeup (needs reg) on this talk at the APA 2014 conference: Abstract NR2-186. "The Correlation of Excessive Indoor Tanning With Depression and Suicidal Behavior Among Adolescents: Results From the 2011 Youth Risk Behavior Survey" by Kelly E. Taylor, also Dr. Gathright is mentioned. Looks like there is a huge association for depression but also several suicide related measures (odds ratio for treatment for suicide attempt is 13.1!, N=15,425).

Update 5: This not strongly related but I wanted to point out a study that linked disruption of circadian rhythm with depression. In this study there was data from 20 suicide cases. It's a bit indirect, but light is strongly related to circadian rhythm.

Update 6: On Dr. Turecki's suggestion, I took a look at the postnatal BrainSpan data and 'developmental pigmentation' doesn't show up. I'm surprised to see the change, one thing I noticed is that SAT1 is negatively correlated with the majority of genes in the postnatal data. The top ten from the postnatal data (345 samples) are:

1. cerebellar cortex formation
2. regulation of receptor-mediated endocytosis
3. cerebellar Purkinje cell layer morphogenesis
4. membrane depolarization
5. cerebellar Purkinje cell layer development
6. cellular copper ion homeostasis
7. membrane depolarization involved in regulation of action potential
8. membrane depolarization involved in regulation of cardiac muscle cell action potential
9. cellular response to prostaglandin stimulus
10. positive regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process

One note is that the ethnicity distribution between prenatal and postnatal samples is very different, so I should take a closer look at that when I have time.


Update 7: Neat paper looking at UV exposure - seems it's addictive. "Skin β-Endorphin Mediates Addiction to UV Light"