Genes influence structure of cerebral cortex

For a long time researchers have been trying to answer the question: What is the role of genetics in the development of the brain? An interesting paper has recently appeared in Science that brings us closer to finally answering the question.

The cerebral cortex in the human brain is that outer layer of grey matter that is folded into groves (sulci) and ridges (gyri). It is involved in higher level cognition from sensory processing, through to decision making and action. Now, using ‘computational brain mapping approaches’ we can see and label ‘the consistent folding patterns across individual cortices’, as in the the picture above.

As the fetal brain develops, the predominant neuronal cell type in the cortex, excitatory neurons, ‘are generated from neural progenitor cells in the developing germinal zone. The radial unit hypothesis posits that the expansion of cortical surface area (SA) is driven by the proliferation of these neural progenitor cells, whereas thickness (TH) is determined by the number of their neurogenic divisions. Variation in global and regional measures of cortical SA and TH have been reliably associated with neuropsychiatric disorders and psychological traits such as cognitive function, Parkinson’s disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.’

‘Twin and family-based brain imaging studies indicate that SA and TH measurements are highly heritable and are influenced by largely different genetic factors. Despite extensive studies of genes affecting cortical structure in model organisms, our current understanding of the genetic variation affecting human cortical size and patterning is limited to rare, highly penetrant variants. These variants often disrupt cortical development, leading to altered postnatal structure. However, little is known about how common genetic variants influence human cortical SA and TH. ‘

‘To identify genetic loci associated with variation in the human cortex,’ a ‘genome-wide association meta-analyses of cortical SA and TH measures’ was conducted. 51,665 people, mainly European (approx 94%), ‘from 60 cohorts from around the world’ were studied.

A genome-wide association study (GWAS) is an observational study of a genome-wide set of genetic variants in different individuals to see if any variant is associated with a trait. GWAS’s typically focus on associations between single-nucleotide polymorphisms (SNPs) and traits like major human diseases.

First, ‘cortical measurements were extracted from structural brain magnetic resonance imaging (MRI) scans in 34 regions defined by the commonly used Desikan-Killiany atlas, which establishes coarse partitions of the cortex.’ Analysis of ‘two global measures, total SA and average TH, as well as SA and TH for the 34 regions were averaged across both hemispheres.’ This yielded ’70 distinct phenotypes.’

Next, within each of the 60 cohorts, ‘an additive model’ was used ‘to conduct a genome-wide association study (GWAS) for each of the 70 phenotypes. ‘

‘Across the 70 cortical phenotypes,’ a total of ‘306 loci that were genome-wide significant in the principal meta-analysis’ were found. Of these, 118 have not been previously associated with either intracranial volume (ICV) or cortical SA, TH, or volume.’  ‘Gene-based effects’ were examined, ‘allowing for a 50-kb window around genes’, and ‘significant associations for 253 genes across the 70 cortical phenotypes were found’.

To identify whether common variation associated with cortical structure relates to either gene regulation within a given tissue type, developmental time period, or cell type, partitioned heritability analyses using sets of gene regulatory annotations from adult and fetal brain tissues were performed.

Other studies examined ‘shared genetic effects between cortical structure and other traits.’ Significant ‘positive genetic correlations between total SA and general cognitive function, educational attainment, and Parkinson’s disease,’ indicated that allelic influences resulting in larger total SA are, in part, shared with those influencing greater cognitive capabilities as well as increased risk for Parkinson’s disease.

‘For total SA, significant negative genetic correlations were detected with insomnia, attention deficit hyperactivity disorder (ADHD), depressive symptoms, major depressive disorder, and neuroticism, again indicating that allelic influences resulting in smaller total SA are partly shared with those influencing an increased risk for these disorders and traits.’

The findings from these studies suggest that total SA is influenced by common genetic variants that may alter gene regulatory activity in neural progenitor cells during fetal development, supporting the radial unit hypothesis. By contrast, the strongest evidence of enrichment for average TH was found in active regulatory elements in the adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning.

Slowly we inch closer. The genes within the DNA within the nucleus of the cell body control the functions that keep the neuron alive and functioning, so it seems logical that genes play a part in the structural and functional development of the brain. Complex computational studies such as these are producing powerful insights into brain structure and function in health and disease. Marrying these techniques with those producing the connectome are producing valuable libraries for further research.

And then there’s the effect of environment and upbringing into this complicated mix.

There is more about the structure and function of the cortex in my book How the Brain Thinks.