Called M1 and M3, these so-called gene networks appear to influence cognitive function – which includes memory, attention, processing speed and reasoning.
Crucially, the scientists have discovered that these two networks – which each contain hundreds of genes – are likely to be under the control of master regulator switches. The researchers are now keen to identify these switches and explore whether it might be feasible to manipulate them. The research is at a very early stage, but the scientists would ultimately like to investigate whether it is possible to use this knowledge of gene networks to boost cognitive function.
Researchers hypothesized that gene regulatory networks starting from the human hippocampus could be informative for genes and pathways relevant to diverse cognitive abilities and neurodevelopmental disease. Hippocampus gene-regulatory networks were inferred a priori, without reference to cognitive phenotypes using fresh-frozen hippocampus samples that had been surgically removed from 122 patients undergoing temporal lobectomy for epilepsy. Conservation of modules was then tested using distinct expression datasets from non-diseased post-mortem hippocampus samples (n=63) and healthy mouse hippocampus samples (n=100). From this, we identified 4 cross-species conserved hippocampal gene co- expression modules whose co-expression relationships are unrelated to epilepsy (M1, M3, M11 and M19). We then used independent gene expression datasets to show that these modules were conserved widely across the human cortex and expressed under tight developmental regulation during brain development. The modules were then integrated with GWAS data relating to four cognitive abilities (general fluid cognitive ability, processing speed, crystalized cognitive ability and verbal delayed recall) in two independent community cohorts (GS:SFHS and LBC1936), and de novo mutation data from parent-offspring trios across five neurodevelopmental disorders (ASD, SCZ, ID, EE, DDD) to reveal convergent gene co-expression modules for healthy human cognitive abilities and neurodevelopmental disease. Full details relating to datasets, experimental methods and references are provided in the manuscript. TLE=temporal lobe epilepsy; ASD=autism spectrum disorder;
Dr Michael Johnson, lead author of the study from the Department of Medicine at Imperial College London, said: “We know that genetics plays a role in intelligence but until now haven’t known which genes are relevant. This research highlights some of genes involved in human intelligence, and how they interact with each other.
“What’s exciting about this is that the genes we have found are likely to share a common regulation, which means that potentially we can manipulate a whole set of genes whose activity is linked to human intelligence. Our research suggests that it might be possible to work with these genes to modify intelligence, but that is only a theoretical possibility at the moment – we have just taken a first step along that road.”
In the study, published in the journal Nature Neuroscience, the international team of researchers looked at samples of human brain from patients who had undergone neurosurgery for epilepsy. The investigators analysed thousands of genes expressed in the human brain, and then combined these results with genetic information from healthy people who had undergone IQ tests and from people with neurological disorders such as autism spectrum disorder and intellectual disability.
They conducted various computational analyses and comparisons in order to identify the gene networks influencing healthy human cognitive abilities. Remarkably, they found that some of the same genes that influence human intelligence in healthy people were also the same genes that cause impaired cognitive ability and epilepsy when mutated.
Dr Johnson added: “Traits such intelligence are governed by large groups of genes working together – like a football team made up of players in different positions. We used computer analysis to identify the genes in the human brain that work together to influence our cognitive ability to make new memories or sensible decisions when faced with lots of complex information. We found that some of these genes overlap with those that cause severe childhood onset epilepsy or intellectual disability.
“This study shows how we can use large genomic datasets to uncover new pathways for human brain function in both health and disease. Eventually, we hope that this sort of analysis will provide new insights into better treatments for neurodevelopmental diseases such as epilepsy, and ameliorate or treat the cognitive impairments sometimes associated with these devastating diseases.”
Genetic determinants of cognition are poorly characterized, and their relationship to genes that confer risk for neurodevelopmental disease is unclear. Here we performed a systems-level analysis of genome-wide gene expression data to infer gene-regulatory networks conserved across species and brain regions. Two of these networks, M1 and M3, showed replicable enrichment for common genetic variants underlying healthy human cognitive abilities, including memory. Using exome sequence data from 6,871 trios, we found that M3 genes were also enriched for mutations ascertained from patients with neurodevelopmental disease generally, and intellectual disability and epileptic encephalopathy in particular. M3 consists of 150 genes whose expression is tightly developmentally regulated, but which are collectively poorly annotated for known functional pathways. These results illustrate how systems-level analyses can reveal previously unappreciated relationships between neurodevelopmental disease–associated genes in the developed human brain, and provide empirical support for a convergent gene-regulatory network influencing cognition and neurodevelopmental disease.
SOURCEs – Imperial College of London, Nature Neuroscience
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