People’s brain structure linked to their genetic risk of major depression, stud finds

Depression is among the most widespread psychiatric disorders, experienced by an estimated 3.8% of the global population. It is characterized by persistent low mood and a loss of interest in most activities, as well as possible disruptions in eating and sleeping habits.

The most severe and persistent form of depression, known as major depression (MD), can be highly debilitating, often disrupting the lives of affected individuals and preventing them from working or engaging in other daily activities. Past studies suggest that depression is often caused by a combination of genetic and environmental factors.

The genetic risk of developing depression or other mental health disorders is estimated using so-called polygenic risk scores (PRS). These are estimates of an individual’s predisposition to a specific condition based on the cumulative effect of various genetic variants.

Researchers at University of Edinburgh, the University of Melbourne, Vrije University Amsterdam and other institutes recently carried out a large-scale study aimed at exploring the relationship between PRS values for MD and people’s brain structure. Their paper, published in Molecular Psychiatry, reports specific patterns in the volume and surface area of specific brain structures that are linked to a higher genetic risk for depression.

“The neurobiological associations of genetic risk for MD remain under-explored in large samples, with no comprehensive mega-analysis conducted to date,” wrote Xueyi Shen, Yara J. Toenders and their colleagues.

“Our study analyzed data from 11 separate studies, encompassing 50,975 participants from the ENIGMA Major Depressive Disorder Working Group. We developed highly consistent genetic and neuroimaging protocols and applied these throughout all participating studies, together with rigorous genetic methods to remove overlap between the polygenic risk scores (PRS) training and testing samples.”

As part of their study, Shen, Toenders and their colleagues analyzed a large amount of genetic and neuroimaging data collected as part of 11 international studies. Based on this data, they calculated PRS values that estimated the genetic risk that the study participants would be diagnosed with MD at some point in their lives. Finally, they examined the brain scans collected from the participants and tried to determine whether higher PRS values were linked to specific patterns in the volume of various brain regions.

“Elevated PRS for MD correlated with lower intracranial volume and lower global measure of cortical surface area,” wrote the authors. “The most significant cortical association was observed in the surface area of the frontal lobe, particularly in the left medial orbito-frontal gyrus. In subcortical regions, lower volumes of the thalamus, hippocampus, and pallidum correlated with higher PRS of MD.”

Overall, the researchers found that the volume and surface area of intracranial and cortical regions were smaller in people with higher PRS values for depression than in those with lower values. The brain areas that appeared to be smaller in those who were genetically more likely to develop depression included the left medial orbitofrontal gyrus, the hippocampus, the thalamus and the pallidum.

Individuals under 25 years old also presented differences in the volume and surface area of the same brain structures that were linked to the estimated PRS. While these differences were less pronounced than those observed in adults above 25, the patterns detected were the same.

“Subsequent Mendelian randomization analysis revealed potentially causal effects of smaller left hippocampal volume on higher liability for MD,” wrote the authors. “Our findings represent an example of how extensive international collaborations can significantly advance our neurogenetic understanding of MD and give insights to avenues for early interventions in those at high risk for developing MD.”

This recent study sheds new light on the specific patterns in brain structure linked to a higher genetic risk of facing MD. In the future, these insights could contribute to the development of new personalized therapeutic interventions for MD.

© 2025 Science X Network

Depression is among the most widespread psychiatric disorders, experienced by an estimated 3.8% of the global population. It is characterized by persistent low mood and a loss of interest in most activities, as well as possible disruptions in eating and sleeping habits.

The most severe and persistent form of depression, known as major depression (MD), can be highly debilitating, often disrupting the lives of affected individuals and preventing them from working or engaging in other daily activities. Past studies suggest that depression is often caused by a combination of genetic and environmental factors.

The genetic risk of developing depression or other mental health disorders is estimated using so-called polygenic risk scores (PRS). These are estimates of an individual’s predisposition to a specific condition based on the cumulative effect of various genetic variants.

Researchers at University of Edinburgh, the University of Melbourne, Vrije University Amsterdam and other institutes recently carried out a large-scale study aimed at exploring the relationship between PRS values for MD and people’s brain structure. Their paper, published in Molecular Psychiatry, reports specific patterns in the volume and surface area of specific brain structures that are linked to a higher genetic risk for depression.

“The neurobiological associations of genetic risk for MD remain under-explored in large samples, with no comprehensive mega-analysis conducted to date,” wrote Xueyi Shen, Yara J. Toenders and their colleagues.

“Our study analyzed data from 11 separate studies, encompassing 50,975 participants from the ENIGMA Major Depressive Disorder Working Group. We developed highly consistent genetic and neuroimaging protocols and applied these throughout all participating studies, together with rigorous genetic methods to remove overlap between the polygenic risk scores (PRS) training and testing samples.”

As part of their study, Shen, Toenders and their colleagues analyzed a large amount of genetic and neuroimaging data collected as part of 11 international studies. Based on this data, they calculated PRS values that estimated the genetic risk that the study participants would be diagnosed with MD at some point in their lives. Finally, they examined the brain scans collected from the participants and tried to determine whether higher PRS values were linked to specific patterns in the volume of various brain regions.

“Elevated PRS for MD correlated with lower intracranial volume and lower global measure of cortical surface area,” wrote the authors. “The most significant cortical association was observed in the surface area of the frontal lobe, particularly in the left medial orbito-frontal gyrus. In subcortical regions, lower volumes of the thalamus, hippocampus, and pallidum correlated with higher PRS of MD.”

Overall, the researchers found that the volume and surface area of intracranial and cortical regions were smaller in people with higher PRS values for depression than in those with lower values. The brain areas that appeared to be smaller in those who were genetically more likely to develop depression included the left medial orbitofrontal gyrus, the hippocampus, the thalamus and the pallidum.

Individuals under 25 years old also presented differences in the volume and surface area of the same brain structures that were linked to the estimated PRS. While these differences were less pronounced than those observed in adults above 25, the patterns detected were the same.

“Subsequent Mendelian randomization analysis revealed potentially causal effects of smaller left hippocampal volume on higher liability for MD,” wrote the authors. “Our findings represent an example of how extensive international collaborations can significantly advance our neurogenetic understanding of MD and give insights to avenues for early interventions in those at high risk for developing MD.”

This recent study sheds new light on the specific patterns in brain structure linked to a higher genetic risk of facing MD. In the future, these insights could contribute to the development of new personalized therapeutic interventions for MD.

© 2025 Science X Network