Genetic link found between suicide risk and brain structure in large-scale study

People with a higher genetic predisposition to attempting suicide tend to show differences in brain structure, according to a new study published in the journal Human Brain Mapping. The researchers found that specific genetic markers associated with suicide attempt risk also overlap with those related to brain volume, particularly in subcortical regions involved in emotion, reward, and cognitive control.

The findings point to a small but statistically meaningful genetic correlation between suicide attempts and total brain volume, and suggest that shared genetic influences may be expressed in distinct ways across development. While previous studies have independently tied suicidal behavior and brain structure to genetic factors, this new research indicates that they may be more intertwined than previously understood.

Suicide attempt is one of the strongest predictors of suicide death and remains a pressing global health concern. Although environmental stressors, psychiatric conditions, and trauma history contribute to risk, there is growing recognition that suicide also has biological underpinnings. Large-scale genetic studies have identified heritable components of suicidal behavior, and structural brain changes have been reported in individuals with a history of suicide attempts.

However, researchers have yet to fully determine whether these biological features share a common genetic basis. If suicide risk and variations in brain morphology stem from overlapping genetic pathways, identifying those regions and gene sets could help reveal new targets for intervention or prediction. The new study aimed to clarify the degree to which the genetic architecture of suicide attempt overlaps with regional brain volume in both adults and adolescents.

“My colleagues and I were specifically interested in determining whether genetic risk for suicide behaviors could be reflected in neurodevelopmental differences early in life. Suicide behavior is very difficult to predict, and understanding risk factors for suicidal behavior early in development prior to the emergence of these behaviors could be one avenue towards prevention,” said study author Jill A. Rabinowitz, an assistant professor at Robert Wood Johnson Medical School at Rutgers University.

The research team used data from two of the largest genome-wide association studies available: one on suicide attempts, including nearly one million individuals, and one on brain imaging, which included structural MRI data from approximately 75,000 participants. The suicide attempt dataset included both people who had made nonfatal attempts and those who had died by suicide. The brain imaging data included measurements of total brain volume and nine subcortical regions, such as the caudate, putamen, amygdala, hippocampus, and thalamus.

To examine shared genetic factors, the researchers first applied a statistical technique known as linkage disequilibrium score regression, which estimates genome-wide genetic correlations between traits. Then, to look for specific areas of the genome influencing both suicide attempts and brain volumes, they used GWAS-pairwise analysis, which examines smaller segments of the genome to detect local genetic overlap. These segments were then mapped to genes using functional annotation tools.

To explore how these genetic relationships might emerge during adolescence, the researchers also examined data from over 5,000 European-ancestry participants in the Adolescent Brain Cognitive Development (ABCD) study. Using polygenic scores for suicide attempt—scores that summarize the cumulative effect of thousands of genetic variants—they tested whether higher genetic risk was associated with differences in brain volume in this younger cohort.

The strongest genome-wide genetic correlation emerged between suicide attempt risk and intracranial volume. The correlation was modest (r = -0.10) but statistically significant, suggesting that genetic factors associated with a higher likelihood of suicide attempt are also linked to smaller overall brain volume. This aligns with earlier neuroimaging research indicating that individuals with a history of suicide attempt tend to have smaller intracranial volume.

Zooming in on specific brain regions, the researchers identified ten genomic segments that appeared to influence both suicide attempt risk and at least one subcortical brain structure. Seven of these were associated with the thalamus, two with the putamen, and one with the caudate nucleus. These areas are involved in various cognitive, emotional, and motor processes, and have been implicated in psychiatric conditions such as depression and schizophrenia.

Several genes were mapped to these overlapping genomic segments. One of the most prominent was DCC, a gene involved in axonal guidance and synaptic development, which was associated with both suicide risk and volume of the caudate and putamen. Other implicated genes, including members of the histone cluster (e.g., HIST1H2BN and HIST1H4L), were located in a highly complex region of the genome known as the major histocompatibility complex, which is involved in immune function and has also been linked to psychiatric disorders.

In conditional analyses, the researchers found that associations between suicide risk and thalamic volume within this region were likely due to separate genetic signals rather than a single shared variant. This suggests that while the same region of the genome may influence both traits, it may do so through distinct genetic mechanisms.

In the adolescent sample from the ABCD study, higher polygenic risk for suicide attempt was significantly associated with smaller volume of the right nucleus accumbens, a brain region involved in reward sensitivity and motivation. This association remained significant even after correcting for multiple comparisons. Notably, the nucleus accumbens did not show overlap in the adult genomic segment analyses, suggesting that different brain regions may reflect genetic vulnerability at different stages of development.

“We found that people with higher genetic risk for suicide attempt tend to have smaller overall brain volume and differences in specific brain regions like the thalamus and caudate nucleus,” Rabinowitz told PsyPost. “In adolescents, a higher genetic risk for suicide attempt was also associated with a smaller volume in the nucleus accumbens, a region involved in reward and motivation. These findings suggest that certain brain structures may help explain how genetic risk for suicide is expressed in the brain early in life, offering insight for future prevention efforts.”

There are some limitations to consider. The genetic analyses were based exclusively on individuals of European ancestry, which means the results may not generalize to other populations. Future studies should aim to replicate these findings in more diverse samples.

Additionally, while the study identifies genetic overlap, it cannot determine whether these shared genetic factors causally influence both suicide risk and brain structure. It’s possible that genes influence one trait, which in turn affects the other. Future research using causal inference methods like Mendelian randomization could help clarify the direction of these relationships.

“It is important to note that findings are not causal; that is, we did not find that genetic risk causes brain structure differences, but rather that an association exists between genetic liability for suicide attempt and neurodevelopment,” Rabinowitz explained. “It will be important to consider third variables in future research, such as environmental exposures, that may be potential pathways through which genetic propensity for suicidal behavior is linked to brain structure differences. I look forward to continuing to conduct research that incorporates genetic and novel biobehavioral and neural phenotypes that may be associated with suicidal behavior across the lifespan.”

The study, “Genetic Links Between Subcortical Brain Morphometry and Suicide Attempt Risk in Children and Adults,” was authored by Zuriel Ceja, Luis M. García-Marín, I-Tzu Hung, Sarah E. Medland, Alexis C. Edwards, Miguel E. Rentería, and Jill A. Rabinowitz.