Is brain volume a predictive factor?

• A genome-wide association study identified a number of regions of the genome that control the size of subcortical brain structures.
• An international consortium of researchers has found that they can predict the volume of these structures using polygenic scales developed from large cohorts with multiple ancestors.
• They also found a link between genes that influence brain volume and Parkinson’s disease and ADHD.

A genome-wide association study identified a number of novel genetic variants associated with the volume of nine subcortical brain structures.

Scientists have shown that they can predict measurements of parts of the brain using polygenic scores developed using those variants that performed well in cohorts from different ancestors.

Lead author Miguel Renteria, Ph.D directs the Computational Neurogenomics Laboratory within the Mental Health and Neuroscience program at the QIMR Berghofer Institute for Medical Research in Herston, Australia.

He said Medical news today that he and his colleagues “have been studying the genetics of brain structure since ENIGMA Consortium was founded in 2009.”

“My team works at the intersection of human genetics and neuroscience, focusing on how genetic variation shapes individual differences in behavior, cognition and mental health,” he explained.

“Previous studies, including twin studies and studies by the ENIGMA collaborators, have shown that brain morphology is moderately heritable and associated with brain-related diseases. Our goal was to map genetic variants that influence brain structure and investigate whether the same genes also influence the risk of brain-related disorders,” notes Rentería.

Subcortical brain volume has been associated with many developmental, psychiatric, and neurological disorders.

To investigate the influence of genetics on subcortical brain volume, researchers looked at the genomes of 74,898 participants of European descent and also analyzed the volume of:

• brain stemthe “control center” of the brain, responsible for vital functions, including breathing and sleep
• caudate nucleusplaying a key role in the movement
• shellrelated to language learning and use
• hippocampusinvolved in the processes of learning and remembering
• pale ballwhich regulates proprioception, i.e. the ability to sense the body’s position in space
• hillthat processes sensory stimuli
• nucleus accumbenswho controls wakefulness
• almondinvolved in regulating emotions, especially stress and anxiety
• and ventral diencephalon.

All of these measurements were made from MRI scans.

They found 254 independent loci – or regions of the genome – significantly associated with brain volume and found that they accounted for about 35% of the variance observed between participants, suggesting that the remainder of the observed difference was due to environmental factors.

Using the genetic variants discovered at these loci, they developed a polygenic score that they could use to predict the volume of different parts of subcortical brain structures.

They tested this polygenic result using a British biobank cohort and found that it predicted the volume of subcortical brain structures with or without adjustment for total intracranial volume, including in people of different origins.

They also found that the polygenic scores they calculated could predict the volume of subcortical brain structures in people under 18 years of age.

They then looked at the interrelationships between the influence of genes on the volume of various subcortical brain structures and neurological and psychiatric conditions.

Parkinson’s disease has been linked to genes responsible for intracranial and subcortical brain volume. ADHD, insomniaAND neuroticism were negatively correlated with genes controlling intracranial volume.

Opposite results were found for birth weight, birth head circumference, and height, which were positively correlated with intracranial volume, confirming that height is associated with greater intracranial volume.

“We observed a positive genetic correlation between Parkinson’s disease and eight regional brain volumes and a negative correlation between ADHD and three brain volumes. It is important to note that these correlations were independent and our study participants were drawn from both the general population and clinical cohorts, with no specific enrichment for ADHD or Parkinson’s disease.

“My theory is that the underlying mechanisms involve genes that are key to brain development, growth and aging processes,” he suggested.

“We plan further research to precisely determine the biological pathways involved. Understanding these mechanisms may shed light on how brain structure influences susceptibility to both neurodegenerative and psychiatric diseases, potentially guiding future therapeutic strategies,” Rentería added.

Polygenic scores are calculated from cohort data used to predict the phenotype associated with a specific genotype.

A criticism has been that they may not be predictable when used in cohorts with different ancestries compared to the original cohort used to develop the outcome. In this study, the developed polygenic scale was found to be effective for people with different ancestries.

Dr. Brittany Ferrisaid an occupational therapist with the National Council on Aging who was not involved in the study MNT that polygenic results “may be appropriate if based on a sound ethical and scientific basis.”

These types of measurements “use genetic information to study changes in brain structure, potentially helping us learn more about neurological and psychiatric disorders,” she explained.

“However, the thoroughness and relevance of this solution should be carefully examined to ensure that the benefits are worth the risks and ethical concerns,” Ferri cautioned.

“One of the main limitations is the incomplete capture of genetic factors using polygenic indicators. They may miss rare genetic variants or interactions between different genes. These results do not take into account environmental factors important for brain development,” she added.

Clifford Segil, DOa neurologist at Providence Saint John’s Health Center in Santa Monica, California, also not involved in the current study, said MNT that the results were novel and needed to be repeated using MRI in a larger number of people.

“Genetic testing notes increased risk but does not guarantee poor outcomes. The limitation for the clinical neurologist is whether or not the patient has a “genetic risk factor profile”, what do I do with that information. “I don’t have any treatment that can increase the size of the subcortical structure of the brain,” Segil noted.

He further emphasized that: “Parkinson’s disease is clearly a disease of subcortical brain structures, which is well established, and the results of this study justify a renewed search for subcortical brain structure that could cause attention problems, which is not well established. “