Epigenetic signatures of recurrent suicide attempts with cross-ethnic and cross-tissue validation highlight the NEK4-ITIH1 locus

Every year, suicide claims more than 700,000 lives, making it one of the leading causes of death for young people worldwide. Yet, the tools doctors use to predict who is at risk remain deeply imperfect. They rely on conversations and questionnaires, which can be subjective and often fail to foresee a crisis before it happens. In high-burden settings like South Korea, where the rate is among the highest in the world, the need for a more objective way to understand this risk is urgent. Scientists have looked to the body's biological record for answers, specifically to a mechanism called DNA methylation. This process acts like a chemical switch on our genes, turning them on or off without changing the genetic code itself. These switches can be flipped by life experiences, such as severe stress, and they can stay flipped for years, creating a lasting biological memory of what a person has endured. If researchers could find a specific pattern of these switches that appears in people who attempt suicide, it might offer a way to identify risk with greater accuracy than words alone.

A team of researchers set out to find this pattern, but they faced a significant hurdle. Previous studies looking at blood samples from people who had attempted suicide mostly found signals related to the immune system and inflammation. These signals were often vague, likely reflecting general stress from illness or lifestyle rather than the specific biology of suicidal thoughts. The researchers suspected that these studies missed the real story because they treated all suicide attempts as the same event. In reality, the number of times a person has tried to end their life is one of the strongest predictors of future risk. The team hypothesized that by weighing the data according to how many times a person had attempted suicide, they could filter out the noise of general stress and find the specific biological changes that accumulate with repeated crises.

To test this, the scientists analyzed blood samples from 69 individuals in South Korea who had attempted suicide, comparing them to 207 people without a history of mental illness. They did not just look for differences between the two groups; they assigned a weight to each sample based on the number of prior attempts the person had made. They then used a computer method to repeatedly shuffle the data, keeping only the genetic markers that appeared consistently across different combinations of people. This rigorous filtering process, which combined the focus on repeated attempts with statistical stability, narrowed thousands of potential signals down to 365 specific locations on the DNA. Unlike previous findings, these 365 markers were not linked to inflammation. Instead, they pointed strongly toward the brain's nervous system, highlighting genes involved in how brain cells connect, how they communicate, and how the body's internal clock regulates mood.

The researchers then asked if these markers changed in proportion to the number of attempts. They found that 28 of the 365 locations showed a clear trend: the more times a person had attempted suicide, the more their DNA switches at these spots had shifted away from the normal pattern. These specific spots were located near genes known to control the circadian rhythm, the physical remodeling of brain connections, and the production of essential brain chemicals. This suggested that the biological burden of repeated suicidal behavior leaves a measurable, cumulative mark on the body's genetic regulation.

To ensure these findings were not just a fluke of the Korean population or specific to blood, the team tested their markers in two completely different groups. First, they looked at brain tissue from a dataset of people who had died by suicide in the United Kingdom. Even though brain tissue is very different from blood, the same markers helped distinguish those who had died by suicide from controls. Next, they tested the markers on blood samples from 47 suicide attempters in Lithuania. Despite the different ethnicity and the fact that the Lithuanian group had different specific markers within the same region, the overall pattern held up. The model successfully identified risk in all three groups, proving that these biological signals are robust and not limited to one type of tissue or one population.

The most striking discovery was a specific region on chromosome 3, located between two genes called NEK4 and ITIH1. In both the Korean blood samples and the UK brain tissue, a single spot in this region emerged as the most powerful indicator of suicide risk. While the exact spot that lit up in the Lithuanian blood was slightly different, it was still within the same neighborhood of the genome. This area is already known to be a hotspot for genetic risk factors in bipolar disorder and schizophrenia, conditions often linked to suicide. The gene NEK4, in particular, is known to influence the density of dendritic spines—the tiny connections between brain cells—and to regulate the emotional fluctuations tied to the body's daily clock. The fact that this same region showed altered chemical switches in both blood and brain suggests that the body carries a signature of suicidal risk that can be detected through a simple blood draw.

The study also revealed a nuance in how these changes occur. While some markers grew stronger with every additional attempt, the most powerful marker in the NEK4-ITIH1 region appeared to be elevated in anyone with a history of attempts, regardless of how many times they had tried. This suggests that this specific change might be an early threshold event, a biological shift that happens when a person first enters a state of suicidal crisis, rather than a change that only accumulates over time.

The researchers acknowledge that their study has limits. The number of people they studied was relatively small, and because they looked at samples taken at a single point in time, they cannot say for certain whether these chemical changes caused the suicidal behavior or resulted from it. They also noted that the specific location of the strongest signal varied slightly between populations, indicating that more diverse studies are needed before this could be used in a clinical setting. However, the consistency of the results across blood, brain, and different ethnic groups offers a rare and promising glimpse into the biology of suicide. By focusing on the history of repeated attempts, the team found a way to see past the noise of general stress and identify a neurobiological signature that lives in the blood, offering a potential path toward more objective tools for understanding and preventing suicide.