Is brain volume a predictive factor?

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

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

Researchers showed they could predict measurements of parts of the brain using polygenic scores they developed using these variants, which worked in cohorts of different ancestry.

Lead author Miguel Renteria, PhD directs the Computational Neurogenomics Lab in the Mental Health & Neuroscience Program at the QIMR Berghofer Medical Research Institute in Herston, Australia.

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

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

“Previous research, including from twin studies and ENIGMA collaborators, has shown that brain morphology is moderately heritable and linked to brain-related disorders. Our goal was to map the genetic variants that influence brain structure and investigate whether the same genes also influence the risk of brain-related disorders,” said Rentería.

Subcortical brain volume has been associated with a number of developmental, psychiatric, and neurological disorders.

To investigate the role of genetics on subcortical brain volume, researchers looked at the genomes of 74,898 participants of European descent, in addition to analyzing the volumes of:

• brain stemthe ‘control center’ of the brain, responsible for vital functions including breathing and sleep
• caudate nucleuswhich plays a key role in movement
• putamenlinked to learning and language use
• hippocampusinvolved in learning and memory processes
• globus palliduswhich regulates proprioception, or the ability to sense where the body is in space
• thalamusthat processes sensory input
• core accumbensthat regulates vigilance
• amygdalainvolved in emotional regulation, especially stress and anxiety
• and the ventral diencephalon.

All these measurements come from MRI scans.

They identified 254 independent loci – or regions of the genome – that were significantly associated with brain volume, and found that these accounted for approximately 35% of the variance 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, which they could use to predict the volume of different parts of the subcortical brain structures.

They tested this polygenic score using a British biobank cohort, and found that it was predictive of the volume of subcortical brain structures, with and without adjustment for overall intracranial volume, including in people of different ancestry.

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

They then looked at the interaction between the influence of genes on the volume of different subcortical brain structures and neurological and psychiatric disorders.

Parkinson’s disease was correlated with genes related to intracranial and subcortical brain volumes. ADHD insomniaAnd neuroticism were negatively correlated with genes controlling intracranial volume.

Conversely, the opposite was found for birth weight, birth head circumference and length, 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 that our study participants were drawn from both the general population and clinical cohorts, without being specifically enriched for ADHD or Parkinson’s.”

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

“We plan to conduct further research to identify the exact biological pathways involved. Understanding these mechanisms could illuminate how brain structure influences susceptibility to both neurodegenerative and psychiatric disorders, potentially guiding future therapeutic strategies,” Rentería said.

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

They have been criticized that they may not be predictive when used in cohorts of different ancestry than the original cohort used to develop the score. In this study, the developed polygenic score proved to be effective in people of different origins.

Brittany Ferri, PhDsaid an occupational therapist from the National Council on Aging, who was not involved in this study MNT that polygenic scores “can be appropriate if they are based on sound ethical and scientific foundations.”

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

“How accurate and relevant it is, however, must be carefully considered to ensure the benefits are worth the risks and ethical concerns,” Ferri warned.

“One important limitation is the incomplete representation of genetic factors by polygenic scores. They could miss rare genetic variants or the interactions between different genes. These scores do not take into account environmental factors that are important for brain development,” she added.

Clifford Segil, DOtold a neurologist at Providence Saint John’s Health Center in Santa Monica, CA, also not involved in the current study MNT that the results were new and needed to be repeated using MRIs in more people.

“Genetic studies indicate an increased risk, but no guaranteed bad outcomes. The limitation as a clinical neurologist is that if a patient has a ‘risk factor genetic profile’, what should I do with this information. I don’t have any treatment to increase the size of a subcortical brain structure,” Segil noted.

He further emphasized that: “Parkinson’s disease is clearly a disease of subcortical brain structures, which has been known for a long time, and the results of this study justify repeated searches for a subcortical brain structure that could cause problems with attention , which is not yet well known. ”