Genomic research provides clues into PTSD

A psychiatrist at Emory University and her colleagues used gene expression analysis to study the biological mechanisms underlying PTSD and comorbid depression

ChallengePost-traumatic stress disorder (PTSD) and depression affect millions around the world, yet little is known about the biological mechanisms underlying these disorders.
SolutionAliza Wingo, MD, of Emory University and colleagues used JMP® Genomics to look at data from the Grady Trauma Project, examining genome-wide differential gene expression profiles in the blood.
ResultsWingo and her colleagues found that the enzyme DICER1 may be involved in biological pathways underlying PTSD.

About seven or eight of every 100 people in the United States will suffer from post-traumatic stress disorder (PTSD) at some point in their lives. It’s a staggering statistic for a condition that can have such a profound impact not only on the sufferers themselves but also on their families and communities.

PTSD affects veterans and civilians alike

PTSD is a debilitating anxiety disorder that can precipitate after an individual is exposed to a traumatic event – warfare, sexual assault, a serious traffic collision, urban gun violence, etc. The United States Department of Veterans Affairs estimates that between 11 percent and 20 percent of veterans having served in Iraq and Afghanistan since the beginning of Operation Iraqi Freedom in 2003 now suffer from PTSD. And the incidence of PTSD among survivors of urban trauma is even higher; one 2012 study indicated that more than 40 percent of trauma patients at Chicago’s Cook County Hospital showed signs of PTSD, as did more than half the victims of gun violence involved in the study.

PTSD is even more common among those already suffering from existing mental health issues. “PTSD is a serious concern in the veteran population and among inner-city residents who experience significant stress or who have been exposed in greater frequency to traumatic life experiences,” says psychiatrist Aliza Wingo, MD, of the Emory University School of Medicine. Wingo is among those investigating PTSD’s biological mechanisms with data from the Grady Trauma Project, a timely initiative of Grady Memorial Hospital in Atlanta.

Clinical data is a rich source of genetic and gene expression information

The Grady Trauma Project is revolutionizing the way we think about PTSD. Ten years’ worth of data from the hospital’s Emergency Department serves as the basis for new research inquiries into both the psychological and biological factors underlying the PTSD phenotype. Researchers like Wingo hope that with a new understanding of predictive factors, they will be able to develop more effective early interventions and improve long-term outcomes for sufferers of this tragic disorder.

The Grady Trauma Project provided Wingo and her collaborators with data from a cohort of 6,863 at-risk inner city participants, among which the observed PTSD rate was 28.4 percent. It’s a highly complex data set that has been used by researchers in a number of different fields through the years. Wingo’s work draws on both genetic and gene expression information to understand those biological mechanisms that underlie psychological resilience. In recent years, Wingo has sought to identify the genetic signatures of PTSD based on a genome-wide differential gene expression survey of PTSD with comorbid depression.

Her target? DICER1, an enzyme that generates mature microRNAs in the blood and brain. “DICER1 is especially interesting because it’s implicated in other mechanisms in the body like DNA repair and microRNA generation,” Wingo says. Though PTSD affects the brain, it’s difficult to obtain sufficient brain data. As a result, she has had to find an alternative approach. “The most significant challenge I’ve encountered,” she says, “is studying gene expression in the blood – as opposed to in the brain.”

JMP® Genomics integrates seamlessly with R for dynamic, quality-controlled analyses

To tackle the challenges inherent in this novel approach to gene expression data, Wingo, a user of the open source software environment R, opted for a two-pronged approach: R in concert with JMP Genomics. JMP Genomics saved her time with its many robust, prebuilt routines for visualizing and analyzing expression microarray data, while R was her go-to analytics engine for analyzing large data sets like RNA sequencing or microRNA sequencing data. By integrating the two, says Wingo, you get the best of both worlds.

“The quality control of microarray gene expression data is one of the aspects of my research in which JMP Genomics helps make processes more manageable,” Wingo says. The advantage of JMP Genomics is that the software has a pool of validated advanced methods for quality control without the coding requirement.

The “QC pipeline,” as she calls it, in JMP Genomics helps to identify data quality issues and pinpoint outliers that should be removed prior to analysis. The basic expression workflow also permits investigators to look at samples after applying statistical normalization. And quality control results can be visualized in interactive graphics.

Wingo also relies on JMP Genomics to conduct differential gene expression analysis with the software’s microarray capabilities. In addition to detailed statistics on each gene, JMP Genomics provides dynamic visualizations that quickly pointed Wingo to genes with interesting expression patterns.

An important step in furthering our understanding of PTSD’s biological mechanisms

Ultimately, Wingo and her colleagues observed that DICER1 expression in the blood of patients with PTSD was significantly lower than levels observed in control groups. Wingo and colleagues were then able to link lower blood DICER1 expression to increased activity in the amygdala in the face of fearful stimuli – one of the primary correlates for PTSD. Importantly, her findings make the case that the enzyme DICER1 is involved in the molecular mechanisms of PTSD with comorbid depression.

“It’s an initial step to try and understand all the biological mechanisms of PTSD. And we need more follow-up studies,” she says. But these findings are promising: “The mechanism that we found in the blood – that is, the DICER1 and microRNA expression pathway – is very similar to what other researchers have found in the brain of stressed mice.”

JMP Genomics is great for analyzing microarray gene expression data.
Aliza Wingo, MD

Emory University