A massive team of international scientists has shed light on how 254 genetic variants can affect the development of particular subcortical structures, potentially influencing some deep-brain operations, they suggested.
Beneath the human brain’s bulging cerebral cortex, smaller structures toil in relative obscurity. Subcortical areas, also known as the ‘deep brain’, play key roles in functions like attention, emotion, motor control and learning.
They’re also involved in many neurological disorders, reports Science Alert. Research has linked variations in the volume of subcortical structures with a range of conditions, including schizophrenia, Parkinson’s disease and ADHD.
The latest findings can help clarify the genetic origins of brain disorders, explains co-author and neuroscientist Paul Thompson from the University of Southern California (USC).
“A lot of brain diseases are known to be partially genetic, but from a scientific point of view, we want to find the specific changes in the genetic code that cause these,” he said.
The investigation represents a huge scientific effort, featuring an international team of 189 researchers who analysed genetic data on 74 898 individual participants across 19 countries, as well as MRI brain scans measuring the volume of subcortical regions such as the amygdala, brainstem, hippocampus, putamen, and thalamus.
This was enabled partly by the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium, an international project based at USC’s Keck School of Medicine that incorporates work from more than 1 000 research labs in 45 countries.
“By conducting this research all over the world, we’re beginning to home in on what has been called ‘the genetic essence of humanity’,” sad Thompson, principal investigator for ENIGMA.
The team used a research technique known as a genome-wide association study (GWAS), which analyses variations in DNA sequences across the genomes of large numbers of people to spot markers of various traits or diseases.
The study uncovered 254 genetic variants associated with volume in various subcortical regions, the authors report, accounting for as much as 10% of observed differences in volume among study participants.
It was “the largest GWAS meta-analysis of intracranial and subcortical brain volumes to date”, the researchers write, yielding insights about the genetic underpinnings of brain-volume variations and corresponding disorders.
The study notably found genetic correlations for eight subcortical brain volumes with Parkinson’s disease, and three with ADHD.
Information like that is vital for developing better treatments, said Miguel Rentería, an associate professor of computational neurogenomics at the Queensland Institute of Medical Research.
“There is strong evidence that ADHD and Parkinson’s have a biological basis, and this research is a necessary step to understanding and eventually treating these conditions more effectively,” added Rentería, the principal investigator for the study.
“Our findings suggest that genetic influences underpinning individual differences in brain structure may be fundamental to understanding the underlying causes of brain-related disorders.”
Previous studies have already established links between certain disorders and subcortical structures, the researchers note, such as Parkinson’s disease and the basal ganglia.
But these findings peel back another big layer, letting us see how genetic variants influence the development of critical brain structures – which in turn could give rise to associated conditions.
The latter remains speculative, the researchers point out. But while more research is still needed to prove whether and how exactly genetic variation might be responsible for brain disorders, this latest study does provide compelling clues.
“This paper, for the first time, pinpoints exactly where these genes act in the brain,” Thompson said.
The study was published in Nature Genetics.
Study details
Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries
Luis García-Marín, Adrian Campos, Santiago Diaz-Torres et al.
Published in Nature Genetics on 21 October 2024
Abstract
Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74 898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signalling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson’s disease and attention-deficit/hyperactivity disorder. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases.
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