Researching Resiliency

Though it’s one of the most common psychiatric disorders in terms of lifetime prevalence, the root causes of post-traumatic stress disorder (PTSD) are still dimly understood. For a start, we still don’t know why after a traumatic event, some people develop PTSD and others don’t.

Take, for instance, the mental-health epidemic that roiled New Orleans in the wake of Hurricane Katrina. Researchers tracked 532 low-income mothers who lived in the area during Hurricane Katrina. Four years after the disaster, about 33 percent of participants had PTSD symptoms. But the majority did not.

What accounts for these differences? In addition, what factors determine whether a patient recovers from PTSD? Seventeen percent of patients don’t get better, even with the best care. As with all mental illness, there are countless, complex factors at work. But identifying genes associated with PTSD could unlock the mysteries behind who’s at risk and who recovers with current treatments. “Many people have been exposed to extreme trauma due to urban violence, conflict, war, and terrorism,” said Patrick Sullivan, director of the Center of Psychiatric Genomics at the University of North Carolina’s School of Medicine. “We don’t understand why some people recover and some people continue to carry a major burden.”

Thanks to a collaborative partnership with Cohen Veterans Biosciences (CVB), Karestan Koenen, a professor of psychiatric epidemiology at Harvard’s T.H. Chan School of Public Health, is leading an effort at the Broad Institute to uncover PTSD’s genetic links. In the largest study of its kind, the Broad’s Stanley Center for Psychiatric Research is collecting, sequencing and analyzing up to 25,000 PTSD patients. “Within a year’s time, we should make enormous strides in identifying the genetic architecture of PTSD. And I hope in the next couple of years, we’ll make phenomenal progress in our overall understanding of PTSD’s biology,” said Koenen.

Significantly, the study will capture samples from a diverse population. Koenen also leads the Stanley Center’s Global Neuropsychiatric Genomics Initiative, which aims to offset a history of Eurocentric data in psychiatric genetics. She’s leveraging her longtime contacts at the Psychiatric Genomics Consortium (PGC), a global, collaborative confederation of investigators in the field.

So far, Koenen has amassed an ethnically diverse collection of 20,730 samples of PTSD patients and controls. The gift from CVB will help her add even more samples to her existing data sets. By the end of this year, she expects to obtain another 46,000 samples—roughly 14,000 cases and 32,000 controls. “The whole point of this effort was to jumpstart a process that normally takes several years,” said Magali Haas, CEO and president of CVB. “That is what drove us to fund this at this scale with clearly defined milestones.”

The samples will continue to come from a diverse population of patients, including African Americans, Latinos, European Americans, and South Africans. “There are rapidly improving computational methods capable of mapping large samples’ heterogeneities and making sense of that information,” said Arieh Shalev, a professor of psychiatry at the New York University School of Medicine.

The sheer quantity of samples is also critical. Serious psychiatric conditions arise from complex factors, thus the genetics are more subtle and variable. Therefore, in order to gain enough statistical power to capture those effects, any genome-wide association study of psychiatric illnesses requires tens of thousands of samples. This was the lesson gleaned from the breakthrough study in 2014 of schizophrenia that identified more than 100 locations in the genome associated with the disease. Unlike previous studies, the 2014 study included nearly 37,000 samples from patients with schizophrenia.

Previous GWAS studies of PTSD have included fewer than 15,000 patient samples. With her target of 25,000 samples, Koenen believes she will have better luck. “It’ll be evidence that her approach can work and that it will need redoubled efforts and more resources,” said Steve Hyman, Director of Stanley Center and a core institute member at the Broad. As with any genetic discovery, her findings will hopefully lead scientists to the mechanisms that underlie PTSD—and to better treatment in the future.

It’s too early to say which genes might turn up as culprits, but Koenen underscores three new findings. First, there is conclusive evidence that PTSD is, indeed, heritable. Second, its heritability is higher in women than in men. Third, the genetic risk for PTSD overlaps with that of other psychiatric disorders, including ADHD and depression. What’s more, Koenen notes that genes associated with the immune and inflammatory systems have emerged consistently in GWAS studies. “It raises intriguing questions about the intersection of physical and mental health,” she said.

Koenen’s drive to study the genetic underpinnings of PTSD stems directly from her own experiences with it. In 1991, when she was 22, she was assaulted while serving as a Peace Corps volunteer in Niger. Koenen later started reading about the disorder as part of her own recovery—and learned how poorly understood it was, even by trained physicians. “I became fascinated by why some patients develop [PTSD] and others don’t—and by what makes some people resilient and others vulnerable,” she said.

Today, those questions are still informing her work. Her own experience with PTSD helps to remind her that for each data point, “there’s a human who’s experienced something really horrible.” In the years to come, she’s optimistic her research will help pave a path toward a better understanding of why some patients are fortunate enough to recover. “PTSD research at this scale wouldn’t have been possible twenty years ago,” she said. “Just the fact that the Broad is involved in it, shows there’s been a huge shift.”