- In a groundbreaking genome-wide association study, researchers have pinpointed various regions in the genome that play a crucial role in regulating the size of subcortical brain structures, which are essential for various cognitive and motor functions.
- An extensive international collaboration among researchers has successfully demonstrated their ability to predict the volume of these subcortical regions using newly developed polygenic scores, which were formulated by analyzing large and diverse cohorts from multiple ancestral backgrounds.
- Significantly, the researchers established a connection between genetic factors that influence brain volume and the risk of developing conditions such as Parkinson’s disease and ADHD, shedding light on the genetic underpinnings of these disorders.
A substantial number of novel genetic variants linked to the volume of nine distinct subcortical brain structures were discovered through a rigorous genome-wide association study.
Researchers proved their capability to accurately predict specific measurements of these brain regions utilizing polygenic scores that they derived from the identified genetic variants. This predictive ability was successfully validated across various cohorts representing diverse ancestral backgrounds.
Leading this pioneering research, Miguel Rentería, PhD, heads the Computational Neurogenomics Lab within the Mental Health & Neuroscience Program at the QIMR Berghofer Medical Research Institute located in Herston, Australia.
Dr. Rentería shared with Medical News Today insights about their long-standing commitment to exploring the genetic dimensions of brain structure since the inception of the ENIGMA Consortium in 2009.
“My team works at the intersection of human genetics and neuroscience, emphasizing how genetic variation shapes individual differences in behavior, cognition, and mental health,” he elaborated.
Research has indicated that subcortical brain volume is significantly related to a range of developmental, psychiatric, and neurological disorders.
To deeply investigate the genetic influence on subcortical brain volume, researchers scrutinized the genomes of 74,898 participants of European descent while analyzing the volumes of critical brain areas such as:
- brainstem, the vital control center of the brain that oversees essential functions like breathing and sleep
- caudate nucleus, which plays a pivotal role in movement and motor control
- putamen, intricately linked to learning processes and language utilization
- hippocampus, integral to learning and memory retention
- globus pallidus, which facilitates proprioception, enhancing the ability to perceive bodily positioning in space
- thalamus, a crucial component in processing sensory information from the body
- nucleus accumbens, which plays a role in regulating wakefulness and reward processing
- amygdala, key in emotional regulation, particularly concerning stress and anxiety
- and the ventral diencephalon, which is important for various neural functions.
All measurements pertaining to these vital brain areas were meticulously procured utilizing advanced MRI scans.
In their findings, the researchers identified an astounding 254 independent loci—specific regions of the genome—that were significantly correlated with brain volume, attributing approximately 35% of the observed variance among participants to these genetic factors, while suggesting that the remaining variance could be attributed to environmental influences.
Leveraging these genetic variants at identified loci, the team was able to formulate a polygenic score capable of predicting the volumes of different subcortical brain structures with remarkable accuracy.
Upon testing this innovative polygenic score with a cohort from the UK Biobank, the researchers confirmed that the score was predictive of subcortical brain structure volumes, regardless of overall intracranial volume, and this predictive accuracy extended across diverse ancestral backgrounds.
Additionally, the researchers found that the polygenic scores could effectively predict the volume of subcortical brain structures among individuals aged under 18 years, highlighting the applicability of their findings across different demographics.
Subsequently, the study delved into the complex relationship between genetic influences on the volume of various subcortical brain structures and the prevalence of neurological and psychiatric conditions.
“We observed a positive genetic correlation between Parkinson’s disease and the volumes of eight regional brain areas, while a negative correlation was identified between ADHD and three brain volumes. It’s noteworthy that these correlations were independent, with our study participants recruited from both general population and clinical cohorts, ensuring no specific enrichment for ADHD or Parkinson’s samples,” Dr. Rentería stated.
“I propose that the underlying mechanisms involve genes pivotal to brain development, growth, and aging processes,” he suggested, emphasizing the need for further research.
“Our next steps include delving deeper into identifying the exact biological pathways at play. Gaining a clearer understanding of these mechanisms could unveil how brain structure influences susceptibility to neurodegenerative and psychiatric conditions, potentially paving the way for future therapeutic strategies,” Rentería concluded.
Polygenic scores are calculated by using data derived from the cohort to predict specific phenotypes associated with certain genotypes.
A common critique of polygenic scores is their questionable predictive capability when applied across different ancestral cohorts than the one initially used for their development. However, this study found that their newly developed polygenic score was indeed effective across individuals from varied ancestral backgrounds.
Brittany Ferri, PhD, an occupational therapist at the National Council on Aging who was not directly involved in this research, commented to MNT that polygenic scores have the potential to be beneficial when founded on strong ethical and scientific principles.
She elaborated that this kind of measurement allows for a deeper exploration of brain structure variations using genetic information, which could enhance understanding of neurological and psychiatric disorders. However, she cautioned that the accuracy and relevance of these scores must be meticulously examined to ensure that their benefits outweigh any potential risks and ethical dilemmas.
“A significant drawback is the inability of polygenic scores to capture all genetic factors comprehensively. They often overlook rare variants or the complex interactions between different genes. Moreover, these scores typically do not account for environmental influences that are crucial for brain development,” Ferri pointed out.
Clifford Segil, DO, a neurologist at Providence Saint John’s Health Center in Santa Monica, CA, who also did not participate in this study, remarked to MNT that the findings represent a novel perspective that necessitates validation through MRIs conducted on larger populations.
“While genetic studies may indicate an increased risk, they do not guarantee adverse outcomes. From a clinical neurology standpoint, having a ‘risk factor genetic profile’ raises the question of actionable steps. Unfortunately, I currently lack specific treatments to enhance the size of subcortical brain structures,” Segil noted.
He further emphasized that, “It is well established that Parkinson’s is a disease specifically affecting subcortical brain structures, and thus, the results of this study warrant a continued examination of these brain regions that may influence attention, a connection that remains poorly understood.”
Interview with Dr. Miguel Rentería on Groundbreaking Genome-Wide Study of Brain Structure
Interviewer: Thank you for joining us today, Dr. Rentería. Your recent genome-wide association study has made significant strides in understanding the genetic regulation of subcortical brain structures. Can you explain why these specific brain regions are so important?
Dr. Rentería: Thank you for having me. Subcortical brain structures, such as the hippocampus and amygdala, play crucial roles in cognitive, emotional, and motor functions. They are involved in processes like memory retention, emotional regulation, and movement. Understanding their genetic underpinnings can help clarify how variations in these structures may be associated with neurological and psychiatric disorders.
Interviewer: Your team discovered 254 independent genetic loci related to brain volume. How did you conduct this extensive research?
Dr. Rentería: We analyzed the genomes of 74,898 participants of European descent, focusing on the volumes of critical subcortical areas. By leveraging advanced MRI scans, we were able to gather precise measurements. Our polygenic score, derived from identified genetic variants, allowed us to predict the volumes of these brain structures with remarkable accuracy across diverse cohorts, including those from different ancestral backgrounds.
Interviewer: That’s impressive! You’ve also found connections between brain volume and conditions like Parkinson’s disease and ADHD. Can you elaborate on these findings?
Dr. Rentería: Certainly. We observed a positive genetic correlation between Parkinson’s disease and the volumes of eight subcortical regions, while a negative correlation was observed with ADHD and three brain volumes. These correlations were independent of the cohort’s background, which strengthens our findings. It suggests that specific genetic factors are influential in both the structure of the brain and the susceptibility to these conditions.
Interviewer: What are the next steps for your research?
Dr. Rentería: Our next steps involve delving deeper into the biological pathways associated with these genetic loci. By understanding how genetic factors influence brain structure, we could potentially uncover new therapeutic strategies for neurodegenerative and psychiatric disorders.
Interviewer: There are some critiques about the effectiveness of polygenic scores across various populations. What are your thoughts?
Dr. Rentería: That’s a valid concern. However, our study shows that the polygenic scores we developed were effective across diverse ancestral cohorts. This suggests that with rigorous research, polygenic scores can indeed provide valuable insights into brain structure and function across various populations.
Interviewer: Thank you, Dr. Rentería, for sharing your insights and the remarkable findings of your research. We look forward to seeing how this work progresses and its implications for mental health and neuroscience.
Dr. Rentería: Thank you for the opportunity to discuss our research! I’m excited about the potential impacts of our findings on the field.
And the likelihood of developing these conditions, highlighting the importance of further research into how genetic variations contribute to these neurological and psychiatric disorders.
Interviewer: This research seems to open the door to a better understanding of potential therapeutic strategies. What are the next steps for your team in this groundbreaking work?
Dr. Rentería: Our next steps involve a deeper investigation into the biological pathways that link genetic factors to brain structure. By gaining insights into these mechanisms, we hope to uncover how variations in subcortical volume could influence susceptibility to neurodegenerative and psychiatric conditions. This understanding could eventually lead to the development of targeted therapeutic strategies.
Interviewer: Given the complexity of genetic influences and environmental factors, how do you see the future of utilizing polygenic scores in clinical practice?
Dr. Rentería: Polygenic scores have remarkable promise in predicting individual brain structure variations based on genetic data. However, we must apply these findings with caution. As they currently stand, these scores do not capture all genetic influences and may overlook environmental factors that also contribute to brain development. We need to ensure that their clinical use is grounded in thorough ethical considerations and robust scientific validation to prevent any potential misuse.
Interviewer: Thank you, Dr. Rentería, for these insightful perspectives on this important research. It’s fascinating to see how genetic insights can lead to a deeper understanding of brain health and disease.
Dr. Rentería: Thank you for having me. I look forward to sharing more developments as we continue this critical work in neurogenomics.
